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Beylerli O, Gareev I, Kaprin A, Ahmad A, Chekhonin V, Yang S, Yang G. Hemorrhagic and ischemic risks of anti-VEGF therapies in glioblastoma. Cancer Gene Ther 2025:10.1038/s41417-025-00914-8. [PMID: 40394233 DOI: 10.1038/s41417-025-00914-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/11/2025] [Accepted: 05/02/2025] [Indexed: 05/22/2025]
Abstract
Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies-such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.
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Affiliation(s)
- Ozal Beylerli
- Central Research Laboratory, Bashkir State Medical University, Ufa, Russia
| | - Ilgiz Gareev
- Central Research Laboratory, Bashkir State Medical University, Ufa, Russia
| | - Andrey Kaprin
- National Medical Research Radiological Centre (NMRRC) of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Vladimir Chekhonin
- Pirogov Russian National Research Medical University of the Ministry of Healthcare of Russian Federation, Moscow, Russia
- Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Healthcare of Russian Federation, Moscow, Russia
- Endocrinology Research Center, Moscow, Russia
| | - Shanshan Yang
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
| | - Guang Yang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
- Heilongjiang Province Neuroscience Institute, Harbin, China.
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Concannon KF, Glisson BS, Doebele RC, Huang C, Marotti M, Camidge DR, Heymach JV. A Phase I Open-Label Study of Cediranib Plus Etoposide and Cisplatin as First-Line Therapy for Patients With Extensive-Stage Small-Cell Lung Cancer or Metastatic Neuroendocrine Non-Small-Cell Lung Cancer. Clin Lung Cancer 2024; 25:601-611. [PMID: 39307607 DOI: 10.1016/j.cllc.2024.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/27/2024] [Indexed: 11/05/2024]
Abstract
INTRODUCTION Small cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC). METHODS Patients received up to six 21-day cycles of etoposide (100 mg/m2, days 1-3) and cisplatin (80 mg/m2, day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose. RESULTS Twenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage. CONCLUSIONS Cediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity.
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Affiliation(s)
- Kyle F Concannon
- Department of Hematology/Onscology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Bonnie S Glisson
- Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Robert C Doebele
- Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO
| | - Chao Huang
- Department of Medical Oncology, University of Kansas, Kansas City, KS
| | | | - D Ross Camidge
- Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO
| | - John V Heymach
- Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; AstraZeneca, Macclesfield, United Kingdom.
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Murphy AD, Porter C, White A, Irving A, Adams R, Ray R, Casbard A, Mahmood RD, Karanth S, Zhou C, Pugh J, Wheeler C, Roberts V, Arnetoli G, Salih Z, Hasan J, Mitchell C, Morgan RD, Clamp AR, Jayson GC. Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial. Int J Gynecol Cancer 2024; 34:1034-1040. [PMID: 38724236 DOI: 10.1136/ijgc-2024-005455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/25/2024] [Indexed: 07/03/2024] Open
Abstract
OBJECTIVE Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER EudraCT 2016-004618-93.
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Affiliation(s)
| | | | - Ann White
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Alys Irving
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Richard Adams
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Ruby Ray
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Angela Casbard
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Reem D Mahmood
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Suman Karanth
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Cong Zhou
- National Biomarker Centre, CRUK Manchester Institute, Manchester, UK
| | - Julia Pugh
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Chelsey Wheeler
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Victoria Roberts
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Giorgio Arnetoli
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Zena Salih
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Jurjees Hasan
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Claire Mitchell
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Robert D Morgan
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Andrew R Clamp
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Gordon C Jayson
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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Lau DK, Collin JP, Mariadason JM. Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer. Biomedicines 2024; 12:1117. [PMID: 38791079 PMCID: PMC11118914 DOI: 10.3390/biomedicines12051117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/18/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.
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Affiliation(s)
- David K. Lau
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Department of Oncology, Monash Health, Clayton, VIC 3168, Australia
| | - Jack P. Collin
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
| | - John M. Mariadason
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
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Ng CHL, Damrose EJ. The Clinical Impact of Vascular Endothelial Growth Factor/Receptor (VEGF/R) Inhibitors on Voice. Case Rep Otolaryngol 2023; 2023:1902876. [PMID: 37038462 PMCID: PMC10082679 DOI: 10.1155/2023/1902876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/09/2023] [Accepted: 02/28/2023] [Indexed: 04/04/2023] Open
Abstract
Background. Vascular endothelial growth factor/receptor (VEGF/R) inhibitors are used in chemotherapy protocols to limit tumor angiogenesis. Recent evidence shows they are associated with hoarseness, but their impact on vocal cord function has not been fully identified. Objectives. To describe the preliminary laryngeal findings in patients undergoing chemotherapy with VEGF/R inhibitors, and to describe possible mechanisms of their effect on vocal fold function. Methods. A retrospective case series was conducted in a tertiary medical center between July 2008 and August 2022. Cancer patients developing hoarseness while undergoing chemotherapy with VEGF/R inhibitors underwent videolaryngostroboscopy. Results. The study included four patients. There were three females and one male, treated for breast, lung, and unknown primary cancer, respectively. All 4 patients developed hoarseness 2–7 days after initiating treatment with the VEGF/R inhibitor drugs aflibercept (n = 1) and bevacizumab (n = 3). In all patients, videolaryngostroboscopy revealed vocal fold bowing and pronounced glottic insufficiency. There were no signs of mucositis or paralysis. In three patients, treatment involved speech therapy, with or without vocal fold augmentation. The average follow-up was 10 months (range 8–12 months). In 2 patients, there was a return of normal voice quality with resolution of vocal fold bowing. In one patient, who remained on chemotherapy, there was persistent bowing. Conclusions. VEGF/R inhibitors are associated with vocal fold bowing and glottic insufficiency. This appears to be a reversible side effect. To our knowledge, this is only the second clinical description of the effect of VEGF/R inhibitors on vocal fold function.
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Affiliation(s)
- Christina Hui Lee Ng
- Department of Otolaryngology Head and Neck Surgery, Sengkang General Hospital, Singapore
| | - Edward J. Damrose
- Division of Laryngology, Department of Otolaryngology Head and Neck Surgery, Stanford University Medical Center, Stanford, CA, USA
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Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now? Biomedicines 2022; 10:biomedicines10092113. [PMID: 36140214 PMCID: PMC9495728 DOI: 10.3390/biomedicines10092113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 12/27/2022] Open
Abstract
Ovarian cancer is one of the most lethal gynaecological malignancies worldwide. Despite high success rates following first time treatment, this heterogenous disease is prone to recurrence. Oncogenic activity of receptor tyrosine kinases is believed to drive the progression of ovarian cancer. Here we provide an update on the progress of the therapeutic targeting of receptor tyrosine kinases in ovarian cancer. Broadly, drug classes that inhibit tyrosine kinase/pathways can be classified as small molecule inhibitors, monoclonal antibodies, or immunotherapeutic vaccines. Small molecule inhibitors tested in clinical trials thus far include sorafenib, sunitinib, pazopanib, tivantinib, and erlotinib. Monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, trastuzumab, and seribantumab. While numerous trials have been carried out, the results of monotherapeutic agents have not been satisfactory. For combination with chemotherapy, the monoclonal antibodies appear more effective, though the efficacy is limited by low frequency of target alteration and a lack of useful predictive markers for treatment stratification. There remain critical gaps for the treatment of platinum-resistant ovarian cancers; however, platinum-sensitive tumours may benefit from the combination of tyrosine kinase targeting drugs and PARP inhibitors. Immunotherapeutics such as a peptide B-cell epitope vaccine and plasmid-based DNA vaccine have shown some efficacy both as monotherapeutic agents and in combination therapy, but require further development to validate current findings. In conclusion, the tyrosine kinases remain attractive targets for treating ovarian cancers. Future development will need to consider effective drug combination, frequency of target, and developing predictive biomarker.
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Rahman MK, Al-Zubaidi Y, Bourget K, Chen Y, Tam S, Zhou F, Murray M. Preclinical Evaluation of Ixabepilone in Combination with VEGF Receptor and PARP Inhibitors in Taxane-Sensitive and Taxane-Resistant MDA-MB-231 Breast Cancer Cells. J Pharm Sci 2022; 111:2180-2190. [PMID: 35700798 DOI: 10.1016/j.xphs.2022.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/08/2022] [Accepted: 06/08/2022] [Indexed: 10/18/2022]
Abstract
Long-term use of cytotoxic agents promotes drug-resistance in triple-negative breast cancer (TNBC). The identification of new drug combinations with efficacy against drug-resistant TNBC cells in vitro is valuable in developing new clinical strategies to produce further cancer remissions. We undertook combination analysis of the cytotoxic agent ixabepilone with small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and poly (ADP-ribose) polymerase (PARP) in taxane-sensitive (231C) and taxane-resistant (TXT) MDA-MB-231-derived cells. As single agents, the VEGFR inhibitors cediranib and bosutinib decreased both 231C and TXT cell viability, but four other VEGFR inhibitors and two PARP inhibitors were less effective. Combinations of ixabepilone with either cediranib or bosutinib synergistically decreased 231C cell viability. However, only the ixabepilone/cediranib combination was synergistic in TXT cells, with predicted 15.3-fold and 1.65-fold clinical dose reductions for ixabepilone and cediranib, respectively. Flow cytometry and immunoblotting were used to further evaluate the loss of cell viability. Thus, TXT cell killing by ixabepilone/cediranib was enhanced over ixabepilone alone, and expression of proapoptotic cleaved caspase-3 and the Bak/Bcl-2 protein ratio were increased. These findings suggest that the synergistic activity of the ixabepilone/cediranib combination in taxane-sensitive and taxane-resistant cells may warrant clinical evaluation in TNBC patients.
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Affiliation(s)
- Md Khalilur Rahman
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences; Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia
| | - Yassir Al-Zubaidi
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences
| | - Kirsi Bourget
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences; Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia
| | - Yongjuan Chen
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences
| | - Stanton Tam
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences
| | - Fanfan Zhou
- Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia
| | - Michael Murray
- Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences; Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia.
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Hubbard JM, Yin J, Schenk EL, Qin R, Reid J, Strand C, Fiskum J, Menefee M, Lin G, Doyle LA, Ivy P, Erlichman C, Adjei A, Haluska P, Costello BA. Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies. Invest New Drugs 2022; 40:115-123. [PMID: 34515877 PMCID: PMC8766914 DOI: 10.1007/s10637-021-01175-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.
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Affiliation(s)
- Joleen M. Hubbard
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Jun Yin
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Erin L. Schenk
- Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Rui Qin
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Joel Reid
- Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, United States
| | - Carrie Strand
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Jack Fiskum
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | | | - Grace Lin
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, United States
| | - L. Austin Doyle
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
| | - Percy Ivy
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
| | - Charles Erlichman
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Alex Adjei
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Paul Haluska
- Bristol Myers Squibb, Lawrenceville, NJ 08648, United States
| | - Brian A. Costello
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
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Piotrowska A, Beserra FP, Wierzbicka JM, Nowak JI, Żmijewski MA. Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells. Front Oncol 2022; 11:763895. [PMID: 35004285 PMCID: PMC8740239 DOI: 10.3389/fonc.2021.763895] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/01/2021] [Indexed: 01/12/2023] Open
Abstract
Regardless of the recent groundbreaking introduction of personalized therapy, melanoma continues to be one of the most lethal skin malignancies. Still, a substantial proportion of patients either fail to respond to the therapy or will relapse over time, representing a challenging clinical problem. Recently, we have shown that vitamin D enhances the effectiveness of classical chemotherapeutics in the human malignant melanoma A375 cell line. In search for new combination strategies and adjuvant settings to improve melanoma patient outcomes in the current study, the effects of cediranib (AZD2171), an oral tyrosine kinase inhibitor of VEGFR1-3, PDGFR, and c-KIT, used in combination either with 1,25(OH)2D3 or with low-calcemic analog calcipotriol were tested on four human malignant melanoma cell lines (A375, MNT-1, RPMI-7951, and SK-MEL-28). Melanoma cells were pretreated with vitamin D and subsequently exposed to cediranib. We observed a marked decrease in melanoma cell proliferation (A375 and SK-MEL-28), G2/M cell cycle arrest, and a significant decrease in melanoma cell mobility in experimental conditions used (A375). Surprisingly, concurrently with a very desirable decrease in melanoma cell proliferation and mobility, we noticed the upregulation of VEGFR2 at both protein and mRNA levels. No effect of vitamin D was observed in MNT-1 and RPMI-7951 melanoma cells. It seems that vitamin D derivatives enhance cediranib efficacy by modulation of VEGFR2 expression in melanoma cells expressing VEGFR2. In conclusion, our experiments demonstrated that vitamin D derivatives hold promise as novel adjuvant candidates to conquer melanoma, especially in patients suffering from vitamin D deficiency. However, further extensive research is indispensable to reliably assess their potential benefits for melanoma patients.
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Affiliation(s)
- Anna Piotrowska
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | | | | | - Joanna Irena Nowak
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Altaf S, Saleem F, Sher AA, Ali A. Potential therapeutic strategies to combat HCC. Curr Mol Pharmacol 2022; 15:929-942. [PMID: 34979895 DOI: 10.2174/1874467215666220103111009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 08/16/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a complex, life threatening and most common neoplasm in the world. HCC tumors are genetically and phenotypically heterogeneous and involve various molecular mechanisms and stimulation of several signaling pathways such as Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptors (EGFR), Insulin growth factor, Ras/extracellular signal-stimulated kinase, mammalian goal of rapamycin (mTOR), c-mesenchymal-epithelial transition factor-1 (c-Met), Hedgehog, Wnt and apoptotic signaling. Lately, in patient's multi-kinase cascade blockers such as sorafenib, selumetinib and regorafenib have increased survival rate of progressive HCC. This development presents a step forward towards the therapy of liver cancer infection and attests that molecular systemic rehabilitations can be useful in HCC treatment. The development of these systemic therapeutic agents has further expanded the research area for surplus molecular mediators to auxiliary increase cure rate of patients. This article reviews the complete consideration of focus on cascades, current enduring clinical tests by means of HCC therapeutic mediators, and imminent prospects in the cure of HCC.
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Affiliation(s)
- Sidra Altaf
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Faiza Saleem
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Azam Ali Sher
- Department of Epidemiology, Michigan State University, Michigan, USA
| | - Ashiq Ali
- Department of Pathology, University of Agriculture, Faisalabad, Pakistan
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An D, Banerjee S, Lee JM. Recent advancements of antiangiogenic combination therapies in ovarian cancer. Cancer Treat Rev 2021; 98:102224. [PMID: 34051628 PMCID: PMC8217312 DOI: 10.1016/j.ctrv.2021.102224] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 12/19/2022]
Abstract
Ovarian cancer is a deadly malignancy with a growing therapeutic armamentarium, though achieving sustained benefit in the clinic remains largely elusive. Through biomarker and genetic analysis, several pathways of resistance and sensitivity to commonly used therapeutics have been identified, expanding the potential of identifying unique drug combinations and indicating new directions for improving clinical outcomes. Here, we review the mechanisms of angiogenic response and antiangiogenic therapy in ovarian cancer, as well as the interactions it exhibits with the immune and DNA damage response pathways. We discuss results from clinical trials examining the combinations of antiangiogenics, PARP inhibitors, and immune checkpoint inhibitors are also discussed, as well as several ongoing trials.
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Affiliation(s)
- Daniel An
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Susana Banerjee
- Gynaecology Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK
| | - Jung-Min Lee
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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12
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13
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Cohen JW, Widemann BC, Derdak J, Dombi E, Goodwin A, Dompierre J, Onukwubiri U, Steinberg SM, O'Sullivan Coyne G, Kummar S, Chen AP, Glod J. Cediranib phase-II study in children with metastatic alveolar soft-part sarcoma (ASPS). Pediatr Blood Cancer 2019; 66:e27987. [PMID: 31502400 PMCID: PMC6803032 DOI: 10.1002/pbc.27987] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/03/2019] [Accepted: 08/22/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Alveolar soft-part sarcoma (ASPS), a rare vascular sarcoma with a clinically indolent course, frequently presents with metastases. Vascular endothelial growth factor (VEGF) is a promising therapeutic target. In a phase-II trial of the VEGF receptor inhibitor cediranib for adults with ASPS, the partial response (PR) rate (response evaluation criteria in solid tumors [RECIST] v1.0) was 35% (15/43; 95% confidence interval: 21-51%). We evaluated cediranib in the pediatric population. PROCEDURE Patients <16 years old with metastatic, unresectable ASPS received cediranib at the pediatric maximum tolerated dose of 12 mg/m2 (≈70% of the fixed adult phase-II dose orally daily). Tumor response was assessed every two cycles (RECIST v1.0). A Simon two-stage optimal design (target response rate 35%, rule out 5%) was used. RESULTS Seven patients (four females), with a median age of 13 years, (range 9-15), were enrolled on stage 1. The most frequent grade 2 or 3 adverse events were neutropenia, diarrhea, hypertension, fatigue, and proteinuria. The best response was stable disease (SD) (median cycle number = 34). Three patients were removed from the study treatment for disease progression (cycles 4, 5, and 36). Five of seven patients had SD for ≥14 months. Two patients with SD remain on study (34-57+ cycles). CONCLUSIONS Cediranib did not reach the target response rate in this small pediatric cohort, in contrast to the adult 35% PR rate. The pediatric dosing was 30% lower compared to the adult dosing, which may have contributed to response differences. Prolonged SD was observed in five patients, but given the indolent nature of ASPS, SD cannot be clearly attributed to cediranib. Cediranib has an acceptable safety profile.
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Affiliation(s)
- Julia W Cohen
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | | | - Joanne Derdak
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - Eva Dombi
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - Anne Goodwin
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - Jessica Dompierre
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - Uzoma Onukwubiri
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, Bethesda, Maryland
| | | | - Shivaani Kummar
- Phase I Clinical Research Program, Division of Oncology, Stanford School of Medicine, Stanford, California
| | - Alice P Chen
- Developmental Therapeutics Clinic, National Cancer Institute, Bethesda, Maryland
| | - John Glod
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland
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14
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Wilding CP, Elms ML, Judson I, Tan AC, Jones RL, Huang PH. The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib. Expert Rev Anticancer Ther 2019; 19:971-991. [PMID: 31665941 PMCID: PMC6882314 DOI: 10.1080/14737140.2019.1686979] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/28/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.Areas covered: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.Expert opinion: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease.
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Affiliation(s)
| | - Mark L Elms
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Ian Judson
- Department of Medical Oncology, Sarcoma Unit, The Royal Marsden Hospital, London, UK
| | - Aik-Choon Tan
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Robin L Jones
- Department of Medical Oncology, Sarcoma Unit, The Royal Marsden Hospital, London, UK
| | - Paul H Huang
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
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15
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Zhou C, Taylor S, Tugwood J, Simpson K, Jayson GC, Symonds P, Paul J, Davidson S, Carty K, McCartney E, Rai D, Dive C, West C. Dynamics of circulating vascular endothelial growth factor-A predict benefit from antiangiogenic cediranib in metastatic or recurrent cervical cancer patients. Br J Clin Pharmacol 2019; 85:1781-1789. [PMID: 30980733 PMCID: PMC6624436 DOI: 10.1111/bcp.13965] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 03/04/2019] [Accepted: 03/27/2019] [Indexed: 02/04/2023] Open
Abstract
AIMS There is a need for predictive and surrogate response biomarkers to support treatment with antiangiogenic vascular endothelial growth factor (VEGF) inhibitors. We aimed to identify a minimally-invasive biomarker predicting benefit from cediranib pretreatment or early during treatment in patients with recurrent or metastatic cervical cancer. METHODS Blood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF-A, VEGF-receptor 2, Ang1 and Tie2 were measured using multiplex enzyme-linked immunosorbent assay. Pretreatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis. RESULTS Samples (n = 556) from 52 patients were analysed. VEGF-receptor 2 (P = .0006) and Tie2 (P = .04) were downregulated following cediranib, while VEGF-A (P = .0025) was upregulated. High Eastern Cooperative Oncology Group performance status (P = .02, hazard ratio [HR] = 2.15, 95% confidence interval [CI] 1.13-4.09) and low pretreatment Tie2 concentrations (P = .003, HR = 0.57, 95%CI 0.39-0.83) were independent prognostic factors associated with reduced progression-free survival. Two patterns of changes in VEGF-A following cediranib were identified. Patients with elevated VEGF-A in the first 3 treatment cycles, regardless of magnitude, had reduced progression-free survival in the placebo arm but improved survival with the addition of cediranib (P = .019, HR = 0.13, 95% CI 0.02-0.71). CONCLUSION Patterns of early elevation in plasma VEGF-A should be studied further as a potential biomarker to predict treatment benefit from cediranib.
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Affiliation(s)
- Cong Zhou
- Division of Cancer SciencesUniversity of Manchester, Manchester Academic Health Science CentreManchesterUK
- Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute and Manchester Centre for Cancer Biomarker SciencesUniversity of ManchesterUK
| | - Sarah Taylor
- Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute and Manchester Centre for Cancer Biomarker SciencesUniversity of ManchesterUK
| | - Jonathan Tugwood
- Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute and Manchester Centre for Cancer Biomarker SciencesUniversity of ManchesterUK
| | - Kathryn Simpson
- Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute and Manchester Centre for Cancer Biomarker SciencesUniversity of ManchesterUK
| | - Gordon C. Jayson
- Division of Cancer SciencesUniversity of Manchester, Christie Hospital NHS Foundation Trust, Manchester Academic Health Science CentreManchesterUK
| | - Paul Symonds
- Department of Cancer StudiesUniversity of LeicesterLeicesterUK
| | - James Paul
- Cancer Research UK Clinical Trials Unit, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | | | - Karen Carty
- Cancer Research UK Clinical Trials Unit, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Elaine McCartney
- Cancer Research UK Clinical Trials Unit, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Debbie Rai
- Cancer Research UK Clinical Trials Unit, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Caroline Dive
- Clinical & Experimental Pharmacology Group, Cancer Research UK Manchester Institute and Manchester Centre for Cancer Biomarker SciencesUniversity of ManchesterUK
| | - Catharine West
- Division of Cancer SciencesUniversity of Manchester, Christie Hospital NHS Foundation Trust, Manchester Academic Health Science CentreManchesterUK
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16
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Zormpas-Petridis K, Jerome NP, Blackledge MD, Carceller F, Poon E, Clarke M, McErlean CM, Barone G, Koers A, Vaidya SJ, Marshall LV, Pearson ADJ, Moreno L, Anderson J, Sebire N, McHugh K, Koh DM, Yuan Y, Chesler L, Robinson SP, Jamin Y. MRI Imaging of the Hemodynamic Vasculature of Neuroblastoma Predicts Response to Antiangiogenic Treatment. Cancer Res 2019; 79:2978-2991. [PMID: 30877107 PMCID: PMC6558276 DOI: 10.1158/0008-5472.can-18-3412] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/25/2019] [Accepted: 03/12/2019] [Indexed: 12/14/2022]
Abstract
Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate R 2* (second-1) and fractional blood volume (fBV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma. SIGNIFICANCE: This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.
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Affiliation(s)
- Konstantinos Zormpas-Petridis
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Neil P Jerome
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Clinic of Radiology and Nuclear Medicine, St. Olavs Hospital, Trondheim, Norway
| | - Matthew D Blackledge
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Fernando Carceller
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Evon Poon
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Matthew Clarke
- Division of Molecular Pathology, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Ciara M McErlean
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Giuseppe Barone
- Department of Pediatric Oncology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Alexander Koers
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Sucheta J Vaidya
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Lynley V Marshall
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Andrew D J Pearson
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Lucas Moreno
- Clinical Research Unit, Pediatric Oncology, Hematology and Stem Cell Transplant Department, Hospital Infantil Universitario Ninõ Jesús, Madrid, Spain
| | - John Anderson
- Department of Pediatric Oncology, Great Ormond Street Hospital for Children, London, United Kingdom
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Neil Sebire
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Department of Histopathology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Kieran McHugh
- Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Dow-Mu Koh
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Yinyin Yuan
- Division of Molecular Pathology, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Louis Chesler
- Division of Clinical Studies, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Simon P Robinson
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom
| | - Yann Jamin
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.
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Sun Y, Yang L, Hao X, Liu Y, Zhang J, Ning Z, Shi Y. Phase I dose-escalation study of chiauranib, a novel angiogenic, mitotic, and chronic inflammation inhibitor, in patients with advanced solid tumors. J Hematol Oncol 2019; 12:9. [PMID: 30642372 PMCID: PMC6332596 DOI: 10.1186/s13045-018-0695-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/27/2018] [Indexed: 02/03/2023] Open
Abstract
Background Chiauranib is a novel orally active multi-target inhibitor that simultaneously inhibits the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit), mitosis-related kinase Aurora B, and chronic inflammation-related kinase CSF-1R. This phase I dose-escalation study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor activity of chiauranib in patients with refractory advanced solid tumor and lymphoma. Methods Eighteen patients were treated with continuous dosing of chiauranib from 10 to 65 mg once daily in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Pharmacokinetic profile of plasma chiauranib was analyzed in both single and multiple dose studies. Results Dose-limiting toxicity (DLT) as of grade 3 hypertension occurred in two patients at 65 mg/day, and one dose level below as MTD was 50 mg/day. The most common treatment-related adverse events included fatigue (61.1%), proteinuria (44.4%), hematuria (38.9%), hypothyroidism (38.9%), hypertriglyceridemia (33.3%), and hypertension (33.3%). A linear and dose-dependent pharmacokinetic profile of chiauranib was characterized with rapid absorption and slow elimination feature in both single and multiple dose studies. The accumulative exposure of chiauranib reached the steady state within 8 days and was approximately increased by twofold as those in the single dose study. No complete or partial response was observed, and 12 patients (66.7%) achieved stable disease (SD). Conclusions Chiauranib demonstrated an acceptable safety and favorable pharmacokinetic profile with potential antitumor activity. Several phase Ib/II clinical studies are currently under further investigation. Trial registration NCT, NCT02122809. Registered 25 April 2014
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Affiliation(s)
- Yongkun Sun
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Lin Yang
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xuezhi Hao
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yutao Liu
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Jinwen Zhang
- Shenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, 518057, Guangdong, China
| | - Zhiqiang Ning
- Shenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, 518057, Guangdong, China
| | - Yuankai Shi
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
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18
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Abstract
Unlike for adenocarcinomas of the lung, no molecular targeted therapies have yet been developed for squamous cell lung cancers, because targetable oncogenic aberrations are scarce in this tumor type. Recent discoveries have established that the fibroblast growth factor (FGF) signaling pathway plays a fundamental role in cancer development by supporting tumor angiogenesis and cancer cell proliferation via different mechanisms. Through comprehensive genomic studies, aberrations in the FGF pathway have been identified in various tumor types, including squamous cell lung cancer, making FGF receptor (FGFR) a potentially druggable target in this malignancy. Several multi-targeted tyrosine kinase inhibitors include FGFR in their target spectrum and a number of these compounds have been approved for clinical use in different cancers. Novel agents selectively targeting FGFRs have been developed and are currently under investigation in clinical trials, showing promising results. This article reviews FGFR aberrations and the clinical data involving selective and multikinase FGFR inhibitors in squamous cell lung cancer.
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19
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Backen AC, Lopes A, Wasan H, Palmer DH, Duggan M, Cunningham D, Anthoney A, Corrie PG, Madhusudan S, Maraveyas A, Ross PJ, Waters JS, Steward WP, Rees C, McNamara MG, Beare S, Bridgewater JA, Dive C, Valle JW. Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial. Br J Cancer 2018; 119:27-35. [PMID: 29925934 PMCID: PMC6035166 DOI: 10.1038/s41416-018-0132-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 03/28/2018] [Accepted: 05/03/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes. METHODS Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). RESULTS Samples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P < 0.001 and P = 0.02, respectively). CONCLUSIONS Rising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.
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Affiliation(s)
- Alison C Backen
- Centre for Cancer Biomarker Sciences, Cancer Research UK Manchester Institute, Manchester, M20 4BX, UK
| | - Andre Lopes
- Cancer Research UK & University College London Cancer Trials Center, London, W1T 4TJ, UK
| | - Harpreet Wasan
- Hammersmith Hospital, Imperial College Healthcare Trust, London, W12 0HS, UK
| | - Daniel H Palmer
- Liverpool Experimental Cancer Medicine Centre, University of Liverpool Cancer Research UK Center, Liverpool, L69 3GL, UK
| | - Marian Duggan
- Cancer Research UK & University College London Cancer Trials Center, London, W1T 4TJ, UK
| | | | - Alan Anthoney
- Leeds Cancer Research UK Clinical Center, Leeds, LS2 9JT, UK
| | - Pippa G Corrie
- Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Srinivasan Madhusudan
- Division of Cancer & Stem Cells, University of Nottingham, Nottingham University Hospitals, Nottingham, NG7 2UH, UK
| | | | - Paul J Ross
- Department of Oncology, King's College Hospital, London, SE5 9RS, UK
| | | | | | - Charlotte Rees
- University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
- Hampshire Hospitals NHS Foundation Trust, Basingstoke, RG24 9NA, UK
| | - Mairéad G McNamara
- Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Sandy Beare
- Cancer Research UK & University College London Cancer Trials Center, London, W1T 4TJ, UK
| | | | - Caroline Dive
- Centre for Cancer Biomarker Sciences, Cancer Research UK Manchester Institute, Manchester, M20 4BX, UK
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK.
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK.
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20
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Morotti M, Dass PH, Harris AL, Lord S. Pharmacodynamic and Pharmacokinetic Markers For Anti-angiogenic Cancer Therapy: Implications for Dosing and Selection of Patients. Eur J Drug Metab Pharmacokinet 2018; 43:137-153. [PMID: 29019020 DOI: 10.1007/s13318-017-0442-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is integral to tumour growth and invasion, and is a key target for cancer therapeutics. However, for many of the licensed indications, only a modest clinical benefit has been observed for both monoclonal antibody and small-molecule tyrosine kinase inhibitor anti-angiogenic therapy. Pre-clinical and clinical studies have attempted to evaluate circulating, imaging, genomic, pharmacokinetic, and pharmacodynamic markers that may aid both the selection of patients for treatment and define dosing. Correct dosing is likely to be critical in the context of vascular normalization to allow better delivery of concomitant anti-cancer therapy and novel imaging techniques hold much promise in the early evaluation of pharmacodynamic response to improve efficacy.
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Affiliation(s)
- Matteo Morotti
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
- Department of Gynaecology Oncology, University of Oxford, Oxford, UK.
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK.
| | - Prashanth Hari Dass
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Adrian L Harris
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Simon Lord
- Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
- Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK
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21
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Yehya AHS, Asif M, Petersen SH, Subramaniam AV, Kono K, Majid AMSA, Oon CE. Angiogenesis: Managing the Culprits behind Tumorigenesis and Metastasis. MEDICINA (KAUNAS, LITHUANIA) 2018; 54:E8. [PMID: 30344239 PMCID: PMC6037250 DOI: 10.3390/medicina54010008] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 03/22/2018] [Accepted: 03/22/2018] [Indexed: 12/14/2022]
Abstract
Deregulated angiogenesis has been identified as a key contributor in a number of pathological conditions including cancer. It is a complex process, which involves highly regulated interaction of multiple signalling molecules. The pro-angiogenic signalling molecule, vascular endothelial growth factor (VEGF) and its cognate receptor 2 (VEGFR-2), which is often highly expressed in majority of human cancers, plays a central role in tumour angiogenesis. Owing to the importance of tumour vasculature in carcinogenesis, tumour blood vessels have emerged as an excellent therapeutic target. The anti-angiogenic therapies have been shown to arrest growth of solid tumours through multiple mechanisms, halting the expansion of tumour vasculature and transient normalization of tumour vasculature which help in the improvement of blood flow resulting in more uniform delivery of cytotoxic agents to the core of tumour mass. This also helps in reduction of hypoxia and interstitial pressure leading to reduced chemotherapy resistance and more uniform delivery of cytotoxic agents at the targeted site. Thus, complimentary combination of different agents that target multiple molecules in the angiogenic cascade may optimize inhibition of angiogenesis and improve clinical benefit in the cancer patients. This review provides an update on the current trend in exploitation of angiogenesis pathways as a strategy in the treatment of cancer.
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Affiliation(s)
- Ashwaq Hamid Salem Yehya
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Muhammad Asif
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan.
| | - Sven Hans Petersen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117543, Singapore.
| | - Ayappa V Subramaniam
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia.
| | - Koji Kono
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117543, Singapore.
- Department of Surgery, National University of Singapore, Singapore 117543, Singapore.
- School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.
| | - Amin Malik Shah Abdul Majid
- EMAN Testing and Research Laboratories, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Acton 0200, Australia.
| | - Chern Ein Oon
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia.
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Abstract
Cediranib potently and selectively inhibits all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), and clinical studies have shown that it is effective in patients with ovarian cancer at a dose of 20 mg/day. Cediranib is absorbed moderately slowly; a high-fat meal reduced the cediranib area under the plasma concentration-time curve (AUC) by 24% and maximum plasma concentration (C max) by 33%. Cediranib binds to serum albumin and α1-acid glycoprotein; protein binding in human plasma is approximately 95%. The cediranib AUC and C max increase proportionally with dose from 0.5 to 60 mg, and cediranib has linear pharmacokinetics (PK) over time. Cediranib is metabolized via flavin-containing monooxygenase 1 and 3 (FMO1, FMO3) and uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4. Cediranib and its metabolites are mainly excreted in faeces (59%), with <1% of unchanged drug being excreted in urine. The apparent oral clearance is moderate and the mean terminal half-life is 22 h. Cediranib is a substrate of multidrug resistance-1 (MDR1) protein (also known as P-glycoprotein [P-gp]). Coadministration with ketoconazole, a potent P-gp inhibitor, increases cediranib AUC at steady-state (AUCss) in patients by 21%, while coadministration with rifampicin, a potent inducer of P-gp, decreases cediranib AUCss by 39%. Administration of cediranib with chemotherapies demonstrated minimal PK impact on each other. No dose adjustment is recommended for patients with mild or moderate hepatic or renal impairment, and no dose adjustment is needed on the basis of age and body weight. A pooled analysis at doses of 0.5-60 mg showed no significant increase in QTc intervals. Increases in blood pressure and the incidence of diarrhoea were associated with increased cediranib dose and systemic exposure.
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Little RA, Barjat H, Hare JI, Jenner M, Watson Y, Cheung S, Holliday K, Zhang W, O'Connor JPB, Barry ST, Puri S, Parker GJM, Waterton JC. Evaluation of dynamic contrast-enhanced MRI biomarkers for stratified cancer medicine: How do permeability and perfusion vary between human tumours? Magn Reson Imaging 2018; 46:98-105. [PMID: 29154898 DOI: 10.1016/j.mri.2017.11.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/08/2017] [Accepted: 11/13/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Solid tumours exhibit enhanced vessel permeability and fenestrated endothelium to varying degree, but it is unknown how this varies in patients between and within tumour types. Dynamic contrast-enhanced (DCE) MRI provides a measure of perfusion and permeability, the transfer constant Ktrans, which could be employed for such comparisons in patients. AIM To test the hypothesis that different tumour types exhibit systematically different Ktrans. MATERIALS AND METHODS DCE-MRI data were retrieved from 342 solid tumours in 230 patients. These data were from 18 previous studies, each of which had had a different analysis protocol. All data were reanalysed using a standardised workflow using an extended Tofts model. A model of the posterior density of median Ktrans was built assuming a log-normal distribution and fitting a simple Bayesian hierarchical model. RESULTS 12 histological tumour types were included. In glioma, median Ktrans was 0.016min-1 and for non-glioma tumours, median Ktrans ranged from 0.10 (cervical) to 0.21min-1 (prostate metastatic to bone). The geometric mean (95% CI) across all the non-glioma tumours was 0.15 (0.05, 0.45)min-1. There was insufficient separation between the posterior densities to be able to predict the Ktrans value of a tumour given the tumour type, except that the median Ktrans for gliomas was below 0.05min-1 with 80% probability, and median Ktrans measurements for the remaining tumour types were between 0.05 and 0.4min-1 with 80% probability. CONCLUSION With the exception of glioma, our hypothesis that different tumour types exhibit different Ktrans was not supported. Studies in which tumour permeability is believed to affect outcome should not simply seek tumour types thought to exhibit high permeability. Instead, Ktrans is an idiopathic parameter, and, where permeability is important, Ktrans should be measured in each tumour to personalise that treatment.
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Affiliation(s)
- Ross A Little
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK.
| | - Hervé Barjat
- Formerly AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
| | - Jennifer I Hare
- IMED Oncology, AstraZeneca, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
| | - Mary Jenner
- Formerly AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Yvonne Watson
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK.
| | - Susan Cheung
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK.
| | - Katherine Holliday
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK.
| | - Weijuan Zhang
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK.
| | - James P B O'Connor
- Division of Cancer Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PL, UK. James.O'
| | - Simon T Barry
- IMED Oncology, AstraZeneca, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
| | - Sanyogitta Puri
- AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
| | - Geoffrey J M Parker
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK; Bioxydyn Ltd., Rutherford House, Manchester M15 6SZ, UK.
| | - John C Waterton
- Centre for Imaging Sciences, Division of Informatics Imaging & Data Sciences, School of Health Sciences, Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK; Formerly AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK; Bioxydyn Ltd., Rutherford House, Manchester M15 6SZ, UK.
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Al-Huniti N, Petersson K, Tang W, Masson E, Li J. Population exposure-safety analysis of cediranib for Phase I and II studies in patients with cancer. Br J Clin Pharmacol 2018; 84:726-737. [PMID: 29274100 DOI: 10.1111/bcp.13495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 11/29/2017] [Accepted: 12/11/2017] [Indexed: 01/08/2023] Open
Abstract
AIMS A multistudy analysis of cediranib, a potent, selective inhibitor of all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), was conducted to establish population exposure-safety models for the relationship of cediranib exposure to the safety endpoints, diastolic and systolic blood pressure (DBP and SBP) and diarrhoea in cancer patients. These models were applied to predict safety outcomes for different cediranib dose regimens. METHODS Models for hypertension and diarrhoea were constructed based on data from 10 Phase I and three Phase II studies comprising 631 cancer patients following cediranib once-daily oral dosing. Daily DBP and SBP were simultaneously characterized using indirect response models for predicted cediranib concentration-time courses, while daily diarrhoea events were modelled as ordered categorical variables with a proportional odds model with a Markov element for predicted average cediranib concentrations. RESULTS For 20 mg cediranib once-daily oral administration, the mean increase in DBP and SBP was predicted to be 7 (95% CI 3-13) and 8 mmHg (95% CI 3-16), respectively, while the probability of mild diarrhoea, but not the severity, was predicted to increase over time. Severe diarrhoea was predicted to be resolved rapidly upon discontinuation of cediranib treatment. CONCLUSIONS Maximum blood pressure increase was observed within the first few days of cediranib treatment, consistent with the pharmacokinetic profile of cediranib reaching steady state in about 5 days. The probability of diarrhoea increased with cediranib concentration but was far more dependent on the status of diarrhoea predicted on the previous day.
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Affiliation(s)
- Nidal Al-Huniti
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, MA, USA
| | | | - Weifeng Tang
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, MA, USA
| | - Eric Masson
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, MA, USA
| | - Jianguo Li
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, MA, USA
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Kimura Y, Chisaki Y, Saki T, Matsumura C, Motohashi H, Onoue M, Yano Y. Prediction of Apparent Oral Clearance of Small-Molecule Inhibitors in Pediatric Patients. J Pharm Sci 2017; 107:949-956. [PMID: 29133236 DOI: 10.1016/j.xphs.2017.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 10/14/2017] [Accepted: 11/01/2017] [Indexed: 11/15/2022]
Abstract
The purpose of this study was to build regression models for the prediction of apparent oral clearance (CL/F) for small-molecule inhibitors in the pediatric population using data obtained from adults. Two approaches were taken; a simple allometric regression model which considers no interdrug or interindividual variability and an allometric regression model with mixed-effects modeling where some variability parameters are included in the model. Average CL/F values were obtained for 15 drugs at various dosages from 31 literatures (a total of 139 data sets) conducted in adults and for 15 drugs from 26 literatures (62 data sets) conducted in children. Data were randomly separated into the "modeling" or "validation" data set, and the 2 allometric regression models were applied to the modeling data set. The predictive ability of the models was examined by comparing the observed and model-predicted CL/F in children using the validation data set. The percentage root mean square error was 17.2% and 26.3% in the simple allometric regression model and the allometric regression model with mixed-effects modeling, respectively. The predictive ability of the 2 models seems acceptable, suggesting that they could be useful for predicting the CL/F of new small-molecule inhibitors and for determining adequate doses in clinical pharmacotherapy for children.
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Affiliation(s)
- Yoshihiko Kimura
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan; Department of Pharmacy, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka, 530-8480, Japan
| | - Yugo Chisaki
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Tomohiko Saki
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Chikako Matsumura
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Hideyuki Motohashi
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Masahide Onoue
- Department of Pharmacy, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka, 530-8480, Japan
| | - Yoshitaka Yano
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
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Orbegoso C, Marquina G, George A, Banerjee S. The role of Cediranib in ovarian cancer. Expert Opin Pharmacother 2017; 18:1637-1648. [DOI: 10.1080/14656566.2017.1383384] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Cecilia Orbegoso
- Gynaecology Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - Gloria Marquina
- Gynaecology Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - Angela George
- Gynaecology Unit, Royal Marsden NHS Foundation Trust, London, UK
| | - Susana Banerjee
- Gynaecology Unit, Royal Marsden NHS Foundation Trust, London, UK
- Division of Clinical Studies, The Institiute of Cancer Research, London, UK
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Lee JM, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, Cao L, Harrell MI, Swisher EM, Houston N, Botesteanu DA, Taube JM, Thompson E, Ogurtsova A, Xu H, Nguyen J, Ho TW, Figg WD, Kohn EC. Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. J Clin Oncol 2017; 35:2193-2202. [PMID: 28471727 DOI: 10.1200/jco.2016.72.1340] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.
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Affiliation(s)
- Jung-Min Lee
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Ashley Cimino-Mathews
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Cody J Peer
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Alexandra Zimmer
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Stanley Lipkowitz
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Christina M Annunziata
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Liang Cao
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Maria I Harrell
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Elizabeth M Swisher
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Nicole Houston
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Dana-Adriana Botesteanu
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Janis M Taube
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Elizabeth Thompson
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Aleksandra Ogurtsova
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Haiying Xu
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Jeffers Nguyen
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Tony W Ho
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - William D Figg
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
| | - Elise C Kohn
- Jung-Min Lee, Cody J. Peer, Alexandra Zimmer, Stanley Lipkowitz, Christina M. Annunziata, Liang Cao, Nicole Houston, Dana-Adriana Botesteanu, Jeffers Nguyen, William D. Figg, and Elise C. Kohn, Center for Cancer Research, National Cancer Institute, Bethesda; Ashley Cimino-Mathews, Janis M. Taube, Elizabeth Thompson, Aleksandra Ogurtsova, and Haiying Xu, The Johns Hopkins Medical Institution, Baltimore; and Tony W. Ho, AstraZeneca, Gaithersburg, MD; and Maria I. Harrell and Elizabeth M. Swisher, University of Washington, Seattle, WA
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Li J, Al-Huniti N, Henningsson A, Tang W, Masson E. Population pharmacokinetic and exposure simulation analysis for cediranib (AZD2171) in pooled Phase I/II studies in patients with cancer. Br J Clin Pharmacol 2017; 83:1723-1733. [PMID: 28213941 DOI: 10.1111/bcp.13266] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 01/25/2017] [Accepted: 02/10/2017] [Indexed: 01/22/2023] Open
Abstract
AIMS A population pharmacokinetic (PK) model was developed for cediranib to simulate cediranib exposure for different doses, including comedication with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin, in cancer patients. METHODS Plasma concentrations and covariates from 625 cancer patients after single or multiple oral cediranib administrations ranging from 0.5 to 90 mg in 19 Phase I and II studies were included in the analysis. Stepwise covariate modelling was used to develop the population PK model. The final model was used to simulate cediranib exposure in cancer patients to evaluate cediranib target coverage and the need for dose adjustment for covariates or coadministration with rifampicin. RESULTS A two-compartment model with sequential zero- and first-order absorption and first-order elimination adequately described the cediranib concentration-time courses. Body weight and age were identified as having statistically significant impact on cediranib PK, but only <21% impact on AUC and maximum concentrations. Simulated lower bounds of 90% prediction interval or median of unbound cediranib concentrations after cediranib 15 or 20 mg exceeded the IC50 for vascular endothelial growth factor receptors-1, -2 and -3. Exposures of cediranib 20 or 30 mg with coadministration of rifampicin were comparable to those of 15 or 20 mg, respectively, without coadministration. CONCLUSIONS No covariate was identified to require dose adjustment for cediranib. Cediranib exposure following 15 or 20 mg daily dose administration is adequate overall for inhibition of in vitro estimated vascular endothelial growth factor receptor-1, -2 and -3 activities. An increase in cediranib dose may be needed for cediranib coadministered with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin.
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Affiliation(s)
- Jianguo Li
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA
| | - Nidal Al-Huniti
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA
| | | | - Weifeng Tang
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA
| | - Eric Masson
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA
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O'Connor JPB, Aboagye EO, Adams JE, Aerts HJWL, Barrington SF, Beer AJ, Boellaard R, Bohndiek SE, Brady M, Brown G, Buckley DL, Chenevert TL, Clarke LP, Collette S, Cook GJ, deSouza NM, Dickson JC, Dive C, Evelhoch JL, Faivre-Finn C, Gallagher FA, Gilbert FJ, Gillies RJ, Goh V, Griffiths JR, Groves AM, Halligan S, Harris AL, Hawkes DJ, Hoekstra OS, Huang EP, Hutton BF, Jackson EF, Jayson GC, Jones A, Koh DM, Lacombe D, Lambin P, Lassau N, Leach MO, Lee TY, Leen EL, Lewis JS, Liu Y, Lythgoe MF, Manoharan P, Maxwell RJ, Miles KA, Morgan B, Morris S, Ng T, Padhani AR, Parker GJM, Partridge M, Pathak AP, Peet AC, Punwani S, Reynolds AR, Robinson SP, Shankar LK, Sharma RA, Soloviev D, Stroobants S, Sullivan DC, Taylor SA, Tofts PS, Tozer GM, van Herk M, Walker-Samuel S, Wason J, Williams KJ, Workman P, Yankeelov TE, Brindle KM, McShane LM, Jackson A, Waterton JC. Imaging biomarker roadmap for cancer studies. Nat Rev Clin Oncol 2017; 14:169-186. [PMID: 27725679 PMCID: PMC5378302 DOI: 10.1038/nrclinonc.2016.162] [Citation(s) in RCA: 739] [Impact Index Per Article: 92.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.
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Affiliation(s)
- James P B O'Connor
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Manchester, Manchester, UK
| | - Eric O Aboagye
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Judith E Adams
- Department of Clinical Radiology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Hugo J W L Aerts
- Department of Radiation Oncology, Harvard Medical School, Boston, MA
| | - Sally F Barrington
- CRUK and EPSRC Comprehensive Imaging Centre at KCL and UCL, Kings College London, London, UK
| | - Ambros J Beer
- Department of Nuclear Medicine, University Hospital Ulm, Ulm, Germany
| | - Ronald Boellaard
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands
| | - Sarah E Bohndiek
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Cambridge, Cambridge, UK
| | - Michael Brady
- CRUK and EPSRC Cancer Imaging Centre, University of Oxford, Oxford, UK
| | - Gina Brown
- Radiology Department, Royal Marsden Hospital, London, UK
| | - David L Buckley
- Division of Biomedical Imaging, University of Leeds, Leeds, UK
| | | | | | | | - Gary J Cook
- CRUK and EPSRC Comprehensive Imaging Centre at KCL and UCL, Kings College London, London, UK
| | - Nandita M deSouza
- CRUK Cancer Imaging Centre, The Institute of Cancer Research, London, UK
| | - John C Dickson
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Caroline Dive
- Clinical and Experimental Pharmacology, CRUK Manchester Institute, Manchester, UK
| | | | - Corinne Faivre-Finn
- Radiotherapy Related Research Group, University of Manchester, Manchester, UK
| | - Ferdia A Gallagher
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Cambridge, Cambridge, UK
| | - Fiona J Gilbert
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Cambridge, Cambridge, UK
| | | | - Vicky Goh
- CRUK and EPSRC Comprehensive Imaging Centre at KCL and UCL, Kings College London, London, UK
| | - John R Griffiths
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Cambridge, Cambridge, UK
| | - Ashley M Groves
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Steve Halligan
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Adrian L Harris
- CRUK and EPSRC Cancer Imaging Centre, University of Oxford, Oxford, UK
| | - David J Hawkes
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Otto S Hoekstra
- Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands
| | - Erich P Huang
- Biometric Research Program, National Cancer Institute, Bethesda, MD
| | - Brian F Hutton
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Edward F Jackson
- Department of Medical Physics, University of Wisconsin, Madison, WI
| | - Gordon C Jayson
- Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Andrew Jones
- Medical Physics, The Christie Hospital NHS Foundation Trust, Manchester, UK
| | - Dow-Mu Koh
- CRUK Cancer Imaging Centre, The Institute of Cancer Research, London, UK
| | | | - Philippe Lambin
- Department of Radiation Oncology, University of Maastricht, Maastricht, Netherlands
| | - Nathalie Lassau
- Department of Imaging, Gustave Roussy Cancer Campus, Villejuif, France
| | - Martin O Leach
- CRUK Cancer Imaging Centre, The Institute of Cancer Research, London, UK
| | - Ting-Yim Lee
- Imaging Research Labs, Robarts Research Institute, London, Ontario, Canada
| | - Edward L Leen
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yan Liu
- EORTC Headquarters, EORTC, Brussels, Belgium
| | - Mark F Lythgoe
- Centre for Advanced Biomedical Imaging, University College London, London, UK
| | - Prakash Manoharan
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Manchester, Manchester, UK
| | - Ross J Maxwell
- Northern Institute for Cancer Research, Newcastle University, Newcastle, UK
| | - Kenneth A Miles
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Bruno Morgan
- Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK
| | - Steve Morris
- Institute of Epidemiology and Health, University College London, London, UK
| | - Tony Ng
- CRUK and EPSRC Comprehensive Imaging Centre at KCL and UCL, Kings College London, London, UK
| | - Anwar R Padhani
- Paul Strickland Scanner Centre, Mount Vernon Hospital, London, UK
| | - Geoff J M Parker
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Manchester, Manchester, UK
| | - Mike Partridge
- CRUK and EPSRC Cancer Imaging Centre, University of Oxford, Oxford, UK
| | - Arvind P Pathak
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew C Peet
- Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
| | - Shonit Punwani
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Andrew R Reynolds
- Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
| | - Simon P Robinson
- CRUK Cancer Imaging Centre, The Institute of Cancer Research, London, UK
| | | | - Ricky A Sharma
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Dmitry Soloviev
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Cambridge, Cambridge, UK
| | - Sigrid Stroobants
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium
| | - Daniel C Sullivan
- Department of Radiology, Duke University School of Medicine, Durham, NC
| | - Stuart A Taylor
- CRUK and EPSRC Cancer Imaging Centre at KCL and UCL, University College London, London, UK
| | - Paul S Tofts
- Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Gillian M Tozer
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Marcel van Herk
- Radiotherapy Related Research Group, University of Manchester, Manchester, UK
| | - Simon Walker-Samuel
- Centre for Advanced Biomedical Imaging, University College London, London, UK
| | | | - Kaye J Williams
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Manchester, Manchester, UK
| | - Paul Workman
- CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK
| | - Thomas E Yankeelov
- Institute of Computational Engineering and Sciences, The University of Texas, Austin, TX
| | - Kevin M Brindle
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Cambridge, Cambridge, UK
| | - Lisa M McShane
- Biometric Research Program, National Cancer Institute, Bethesda, MD
| | - Alan Jackson
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Manchester, Manchester, UK
| | - John C Waterton
- CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, University of Manchester, Manchester, UK
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Jiang W, Liu P, Li X, Wang P. Identification of target genes of cediranib in alveolar soft part sarcoma using a gene microarray. Oncol Lett 2017; 13:2623-2630. [PMID: 28454442 PMCID: PMC5403492 DOI: 10.3892/ol.2017.5779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 01/04/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to identify the target genes of cediranib and the associated signaling pathways in alveolar soft part sarcoma (ASPS). A microarray dataset (GSE32569) was obtained from the Gene Expression Omnibus database. The R software package was used for data normalization and screening of differentially expressed genes (DEGs). The Database for Annotation, Visualization and Integrated Discovery was used to perform Gene Ontology analysis. Gene Set Enrichment Analysis was performed to obtain the up- and downregulated pathways in ASPS. The Distant Regulatory Elements of co-regulated genes database was used to identify the transcription factors (TFs) that were enriched in the signaling pathways. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database and was visualized using Cytoscape software. A total of 71 DEGs, including 59 upregulated genes and 12 downregulated genes, were identified. Gene sets associated with ASPS were enriched primarily in four signaling pathways: The phenylalanine metabolism pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, the taste transduction pathway and the intestinal immune network for the production of immunoglobulin A. Furthermore, 107 TFs were identified to be enriched in the MAPK signaling pathway. Certain genes, including those coding for Fms-like tyrosine kinase 1, kinase insert domain receptor, E-selectin and platelet-derived growth factor receptor D, that were associated with other genes in the PPI network, were identified. The present study identified certain potential target genes and the associated signaling pathways of cediranib action in ASPS, which may be helpful in understanding the efficacy of cediranib and the development of new targets for cediranib.
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Affiliation(s)
- Wenhua Jiang
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Sino-US Center of Lymphoma and Leukemia, Tianjin 300060, P.R. China.,Department of Radiotherapy, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Pengfei Liu
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Sino-US Center of Lymphoma and Leukemia, Tianjin 300060, P.R. China
| | - Xiaodong Li
- Department of Radiotherapy, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Ping Wang
- Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Sino-US Center of Lymphoma and Leukemia, Tianjin 300060, P.R. China
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Tampellini M, La Salvia A, Scagliotti GV. Novel investigational therapies for treating biliary tract carcinoma. Expert Opin Investig Drugs 2016; 25:1423-1436. [PMID: 27771967 DOI: 10.1080/13543784.2016.1252330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is an epithelial cell malignancy arising from bile ducts and/or peribiliary glands. Even though it is considered as a rare neoplasm, its incidence is raising, particularly in developed countries. Prognosis is generally poor with few patients who present the inclusion criteria for surgery (the mainstay treatment for this tumour). Several genetic alterations potentially driving tumour progression have been described, representing a possible target for new compounds. Areas covered: A clinical trial search in Clinicaltrials.gov encompassing a literature search in PubMed and ASCO/ESMO Websites was undertaken in March 2016. Expert opinion: Notwithstanding a large number of drug tested, results are still disappointing. The main reasons could be the low number of patients enrolled in trials, and the lack of a patient selection based on the biological profile of the tumours. Potential active drugs could have been discharged simply because beneficial in a particular subgroup of patients and not in un unselected population. The future direction of the research should consider biomarker evaluation in order to describe the genetic alteration/s that drive tumour progression and aggressiveness and the mechanisms of drug resistance. Finally, it will be of great interest to consider the results of immunotherapy whenever available.
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Affiliation(s)
- M Tampellini
- a Department of Oncology, AOU San Luigi di Orbassano , University of Turin , Torino , Italy
| | - A La Salvia
- a Department of Oncology, AOU San Luigi di Orbassano , University of Turin , Torino , Italy
| | - G V Scagliotti
- a Department of Oncology, AOU San Luigi di Orbassano , University of Turin , Torino , Italy
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Abstract
Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR-TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug-drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.
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Bordinhão ALR, Evangelista AF, Oliveira RJS, Macedo T, Silveira HC, Reis RM, Marques MM. MicroRNA profiling in human breast cancer cell lines exposed to the anti-neoplastic drug cediranib. Oncol Rep 2016; 36:3197-3206. [PMID: 27748845 DOI: 10.3892/or.2016.5153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 03/15/2016] [Indexed: 11/06/2022] Open
Abstract
Cediranib, a pan-tyrosine kinase inhibitor is showing promising results for the treatment of several solid tumours. In breast cancer, its effects remain unclear, and there are no predictive biomarkers. Several studies have examined the expression profiles of microRNAs (miRNAs) in response to different chemotherapy treatments and found that the expression patterns may be associated with the treatment response. Therefore, our aim was to evaluate the cellular behaviour and differential expression profiles of miRNAs in breast cancer cell lines exposed to cediranib. The biological effect of this drug was measured by viability, migration, invasion and cell death in in vitro assays. Signaling pathways were assessed using a human phospho-receptor tyrosine kinase array. Furthermore, using a miRNA array and quantitative real-time PCR (qRT‑PCR), we assessed the relative expression of miRNAs following cediranib treatment. The breast cancer cell lines exhibited a distinct cytotoxic response to cediranib treatment. Cediranib exposure resulted in a decrease in the cell migration and invasion of all the breast cancer cell lines. Treatment with cediranib appeared to be able to modulate the activation of several RTKs that are targets of cediranib such as EGFR and a new potential target ROR2. Furthermore, this drug was able to modulate the expression profile of different microRNAs such as miR-494, miR-923, miR-449a, miR-449b and miR-886-3 in breast cancer cell lines. These miRNAs are reported to regulate genes involved in important molecular processes, according to bioinformatics prediction tools.
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Affiliation(s)
- A L R Bordinhão
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - A F Evangelista
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - R J S Oliveira
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - T Macedo
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - H C Silveira
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - R M Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - M M Marques
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
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Liu Y, Peng X, Guan X, Lu D, Xi Y, Jin S, Chen H, Zeng L, Ai J, Geng M, Hu Y. Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors. Eur J Med Chem 2016; 126:122-132. [PMID: 27750146 DOI: 10.1016/j.ejmech.2016.10.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/01/2016] [Accepted: 10/01/2016] [Indexed: 11/29/2022]
Abstract
FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50-100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.
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Affiliation(s)
- Yang Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Xia Peng
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Xiaocong Guan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Dong Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Yong Xi
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Shiyu Jin
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Hui Chen
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Limin Zeng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China
| | - Jing Ai
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
| | - Meiyu Geng
- Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
| | - Youhong Hu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
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Ethier JL, Lheureux S, Oza A. The role of cediranib in ovarian cancer: current status and further investigation. Expert Opin Orphan Drugs 2016. [DOI: 10.1080/21678707.2016.1196130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Deray G, Janus N, Aloy B, Launay-Vacher V. [Renovascular effects of antiangiogenic drugs]. Bull Cancer 2016; 103:662-6. [PMID: 27318610 DOI: 10.1016/j.bulcan.2016.05.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 03/31/2016] [Accepted: 05/13/2016] [Indexed: 11/24/2022]
Abstract
During the last decade, inhibitors of the vascular endothelial growth factor (VEGF) were developed for the treatment of cancer. Many anti-VEGF are available but the issue is still the same: to inhibit the effect of the VEGF on their receptors. There are two main classes, depending on the mechanism of action by blocking the binding of the ligand on the receptor (VEGF trap or monoclonal antibody) or by affecting directly the receptor (tyrosine kinase inhibitor [TKI], monoclonal antibody directed against the VEGF receptor). These selective agents are safe. Nevertheless, side effects were described, in particular renal and vascular effects. In this article, we analyze the frequency of these renovascular complications, their clinical aspects and the interest of these indexes as a marker of treatment efficacy.
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Affiliation(s)
- Gilbert Deray
- Groupe hospitalier Pitié-Salpêtrière, service ICAR, 83, boulevard de l'Hôpital, 75013 Paris, France; Groupe hospitalier Pitié-Salpêtrière, service de néphrologie, 83, boulevard de l'Hôpital, 75013 Paris, France
| | - Nicolas Janus
- Groupe hospitalier Pitié-Salpêtrière, service ICAR, 83, boulevard de l'Hôpital, 75013 Paris, France; Groupe hospitalier Pitié-Salpêtrière, service de néphrologie, 83, boulevard de l'Hôpital, 75013 Paris, France.
| | - Blandine Aloy
- Groupe hospitalier Pitié-Salpêtrière, service ICAR, 83, boulevard de l'Hôpital, 75013 Paris, France; Groupe hospitalier Pitié-Salpêtrière, service de néphrologie, 83, boulevard de l'Hôpital, 75013 Paris, France
| | - Vincent Launay-Vacher
- Groupe hospitalier Pitié-Salpêtrière, service ICAR, 83, boulevard de l'Hôpital, 75013 Paris, France; Groupe hospitalier Pitié-Salpêtrière, service de néphrologie, 83, boulevard de l'Hôpital, 75013 Paris, France
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Orton MR, Messiou C, Collins D, Morgan VA, Tessier J, Young H, deSouza N, Leach MO. Diffusion-weighted MR imaging of metastatic abdominal and pelvic tumours is sensitive to early changes induced by a VEGF inhibitor using alternative diffusion attenuation models. Eur Radiol 2016; 26:1412-9. [PMID: 26253255 PMCID: PMC4820470 DOI: 10.1007/s00330-015-3933-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 04/16/2015] [Accepted: 07/20/2015] [Indexed: 01/17/2023]
Abstract
OBJECTIVES To assess the utility of diffusion weighted imaging for monitoring early treatment effects associated with a VEGF inhibitor. MATERIALS AND METHODS Twenty-nine patients with metastatic abdominal and pelvic tumours were recruited and imaged with DW-MRI: twice at baseline, and after 7 and 28 days of treatment with cediranib. Tumour measures were derived using mono-exponential, bi-exponential and stretched-exponential models, and parameter repeatability and treatment effects seen after 7 and 28 days were assessed. Correlations with volume changes and DCE-MRI metrics were also assessed. RESULTS Diffusion coefficient repeatabilities from all models were < 6%; f and D* (bi-exponential) were 22% and 44%; α (stretched-exponential) was 4.2%. Significant increases in the diffusion coefficients from all models were observed at day 28 but not day 7. Significant decreases in D* and f.D* were observed at day 7 and in f at day 28; significant increases in α were observed at both time-points. Weak correlations between DW-MRI changes and volume changes and DCE-MRI changes were observed. CONCLUSION DW-MRI is sensitive to early and late treatment changes caused by a VEGF inhibitor using non-mono-exponential models. Evidence of over-fitting using the bi-exponential model suggests that the stretched-exponential model is best suited to monitor such changes. KEY POINTS • Non-mono-exponential diffusion models widen sensitivity to a broader class of tissue properties. • A stretched-exponential model robustly detects changes after 7 days of VEGF-inhibitor treatment. • There are very weak correlations between DWI-IVIM perfusion and similar DCE-MRI measures. • Diffusion-weighted MRI is a highly informative technique for assessing novel tumour therapies.
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Affiliation(s)
- Matthew R Orton
- CRUK and EPSRC Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
- Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, SM2 5MG, UK.
| | - Christina Messiou
- CRUK and EPSRC Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
- Department of Radiology, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - David Collins
- CRUK and EPSRC Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Veronica A Morgan
- Department of Radiology, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Jean Tessier
- Early Clinical Development, AstraZeneca, Macclesfield, UK
| | - Helen Young
- Early Clinical Development, AstraZeneca, Macclesfield, UK
| | - Nandita deSouza
- CRUK and EPSRC Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
- Department of Radiology, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Martin O Leach
- CRUK and EPSRC Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
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Cidon EU, Alonso P, Masters B. Markers of Response to Antiangiogenic Therapies in Colorectal Cancer: Where Are We Now and What Should Be Next? Clin Med Insights Oncol 2016; 10:41-55. [PMID: 27147901 PMCID: PMC4849423 DOI: 10.4137/cmo.s34542] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/15/2016] [Accepted: 03/13/2016] [Indexed: 12/17/2022] Open
Abstract
Despite advances in the treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the Western world. Angiogenesis is a complex process that involves the formation of new blood vessels from preexisting vessels. It is essential for promoting cancer survival, growth, and dissemination. The inhibition of angiogenesis has been shown to prevent tumor progression experimentally, and several chemotherapeutic targets of tumor angiogenesis have been identified. These include anti-vascular endothelial growth factor (VEGF) treatments, such as bevacizumab (a VEGF-specific binding antibody) and anti-VEGF receptor tyrosine kinase inhibitors, although antiangiogenic therapy has been shown to be effective in the treatment of several cancers, including CRC. However, it is also associated with its own side effects and financial costs. Therefore, the identification of biomarkers that are able to identify patients who are more likely to benefit from antiangiogenic treatment is very important. This article intends to be a concise summary of the potential biomarkers that can predict or prognosticate the benefit of antiangiogenic treatments in CRC, and also what we can expect in the near future.
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Affiliation(s)
- E. Una Cidon
- Department of Medical Oncology, Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK
| | - P. Alonso
- Department of Clinical Oncology, Clinical University Hospital, Valladolid, Spain
| | - B. Masters
- Department of Oncology, Nottingham City Hospital, Nottingham, UK
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Dowlati A, Vlahovic G, Natale RB, Rasmussen E, Singh I, Hwang YC, Rossi J, Bass MB, Friberg G, Pickett CA. A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res 2016; 22:4574-84. [PMID: 27076631 DOI: 10.1158/1078-0432.ccr-15-2145] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 03/18/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor. EXPERIMENTAL DESIGN This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation. RESULTS Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (K(trans)), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease. CONCLUSIONS AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574-84. ©2016 AACR.
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Affiliation(s)
- Afshin Dowlati
- Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland, Ohio.
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Kim YE, Joo B, Park MS, Shin SJ, Ahn JB, Kim MJ. Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Surrogate Biomarker for Bevacizumab in Colorectal Cancer Liver Metastasis: A Single-Arm, Exploratory Trial. Cancer Res Treat 2016; 48:1210-1221. [PMID: 26987390 PMCID: PMC5080817 DOI: 10.4143/crt.2015.374] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 03/08/2016] [Indexed: 12/16/2022] Open
Abstract
Purpose The purpose of this study is to investigate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plasma cytokines and angiogenic factors (CAFs) as pharmacodynamic and prognostic biomarkers of bevacizumab monotherapy in colorectal cancer with liver metastasis (CRCLM). Materials and Methods From July 2011 to March 2012, 28 patients with histologically confirmed CRCLM received bevacizumab monotherapy followed by combined FOLFOX therapy. The mean age of the patients was 57 years (range, 30 to 77 years). DCE-MRI (Ktransand IAUC60) was performed at baseline, first follow-up (3 days after bevacizumab monotherapy), and second follow-up (3 days after combined therapy). CAF levels (vascular endothelial growth factor [VEGF], placental growth factor [PlGF], and interleukin-8) were assessed on the same days. Progression-free survival (PFS) time distributions were summarized using the Kaplan-Meier method and compared using log-rank tests. Results The median PFS period was 11.2 months. Ktrans, IAUC60, VEGF, and PlGF values on the first follow-up day were significantly different compared with baseline values. No differences were observed on the second follow-up day. A > 40% decrease in Ktrans from baseline to first follow-up was associated with a longer PFS (hazard ratio, 0.349; 95% confidence interval, 0.133 to 0.912; p=0.032). Changes in CAFs did not show correlation with PFS time. Conclusion DCE-MRI parameters and CAFs are pharmacodynamic biomarkers of bevacizumab for CRCLM. In our study, change in Ktrans at 3 days after bevacizumab monotherapy was a favorable prognostic factor; however, the value of CAFs as a prognostic biomarker was not found.
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Affiliation(s)
- Yeo-Eun Kim
- Department of Diagnostic Radiology, Seoul Medical Center, Seoul, Korea.,Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Bio Joo
- Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Mi-Suk Park
- Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Joon Shin
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Joong Bae Ahn
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Myeong-Jin Kim
- Department of Diagnostic Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Salem A, O'Connor JPB. Assessment of Tumor Angiogenesis: Dynamic Contrast-enhanced MR Imaging and Beyond. Magn Reson Imaging Clin N Am 2016; 24:45-56. [PMID: 26613875 DOI: 10.1016/j.mric.2015.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Dynamic contrast-enhanced (DCE) MR imaging is used increasingly often to evaluate tumor angiogenesis and the efficacy of antiangiogenic drugs. In clinical practice DCE-MR imaging applications are largely centered on lesion detection, characterization, and localization. In research, DCE-MR imaging helps inform decision making in early-phase clinical trials by showing efficacy and by selecting dose and schedule. However, the role of these techniques in patient selection is uncertain. Future research is required to optimize existing DCE-MR imaging methods and to fully validate these biomarkers for wider use in patient care and in drug development.
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Affiliation(s)
- Ahmed Salem
- Cancer Research UK and EPSRC Cancer Imaging Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - James P B O'Connor
- Cancer Research UK and EPSRC Cancer Imaging Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK. james.o'
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Powles T, Brown J, Larkin J, Jones R, Ralph C, Hawkins R, Chowdhury S, Boleti E, Bhal A, Fife K, Webb A, Crabb S, Geldart T, Hill R, Dunlop J, Hall PE, McLaren D, Ackerman C, Beltran L, Nathan P. A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK). Ann Oncol 2016; 27:880-6. [PMID: 26802156 DOI: 10.1093/annonc/mdw014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/06/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV NCT00942877.
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Affiliation(s)
- T Powles
- Department of Medical Oncology, The Royal Free NHS Foundation Trust, London Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London
| | - J Brown
- Department of Medical Oncology, University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Department of Medical Oncology, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire
| | - J Larkin
- Department of Medical Oncology, The Royal Marsden Hospital, London
| | - R Jones
- The Beatson Cancer Centre, University of Glasgow, Glasgow
| | - C Ralph
- Department of Medical Oncology, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire
| | - R Hawkins
- Department of Medical Oncology, The Christie Hospital, Manchester
| | - S Chowdhury
- Department of Medical Oncology, Guys and St Thomas' NHS Foundation Trust, London
| | - E Boleti
- Department of Medical Oncology, The Royal Free NHS Foundation Trust, London
| | - A Bhal
- Department of Oncology, University Hospital Bristol NHS Foundation trust, Bristol
| | - K Fife
- Addenbrooke's Cancer Centre, University of Cambridge, Cambridge
| | - A Webb
- Department of Medical Oncology, West Sussex Cancer Centre, Brighton
| | - S Crabb
- Cancer Sciences Unit, Southampton NHS Foundation Trust, Southampton
| | - T Geldart
- Department of Medical Oncology, Royal Bournemouth Hospital, Bournemouth
| | - R Hill
- Scottish Clinical Trials Research Unit (SCTRU), Partners in CaCTUS, Edinburgh
| | - J Dunlop
- Scottish Clinical Trials Research Unit (SCTRU), Partners in CaCTUS, Edinburgh
| | - P E Hall
- Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London
| | - D McLaren
- Edinburgh Cancer Centre, Western General Hospital, Edinburgh
| | - C Ackerman
- Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London
| | - L Beltran
- Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London
| | - P Nathan
- Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK
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Cediranib in ovarian cancer: state of the art and future perspectives. Tumour Biol 2016; 37:2833-9. [DOI: 10.1007/s13277-015-4781-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 12/29/2015] [Indexed: 12/24/2022] Open
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44
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Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial. Lung Cancer 2015; 90:288-95. [DOI: 10.1016/j.lungcan.2015.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 09/02/2015] [Accepted: 09/05/2015] [Indexed: 01/10/2023]
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Symonds RP, Gourley C, Davidson S, Carty K, McCartney E, Rai D, Banerjee S, Jackson D, Lord R, McCormack M, Hudson E, Reed N, Flubacher M, Jankowska P, Powell M, Dive C, West CML, Paul J. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol 2015; 16:1515-1524. [PMID: 26474517 PMCID: PMC4705431 DOI: 10.1016/s1470-2045(15)00220-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 07/30/2015] [Accepted: 08/03/2015] [Indexed: 01/25/2023]
Abstract
BACKGROUND Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20-30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer. METHODS In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m(2) by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed. FINDINGS Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9-29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4-8·8]) than in the placebo group (6·7 months [6·2-7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40-0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2-3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group. INTERPRETATION Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). FUNDING Cancer Research UK and AstraZeneca.
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Affiliation(s)
- R Paul Symonds
- Department of Cancer Studies, University of Leicester, Leicester, UK.
| | - Charlie Gourley
- University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, UK
| | | | - Karen Carty
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Elaine McCartney
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Debbie Rai
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Susana Banerjee
- Gynaecology Unit, Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - David Jackson
- Institute of Oncology, Leeds Cancer Centre, St James's University Hospital, Leeds UK
| | - Rosemary Lord
- Clatterbridge Centre for Oncology, University of Liverpool, Liverpool, UK
| | - Mary McCormack
- Oncology Department, University College Hospital, London, UK
| | | | - Nicholas Reed
- Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK
| | | | - Petra Jankowska
- Musgrove Park Hospital, Taunton and Somerset NHS Foundation Trust, Taunton, UK
| | | | - Caroline Dive
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | | | - James Paul
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC. Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan–Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol 2015; 33:3401-8. [DOI: 10.1200/jco.2014.60.7341] [Citation(s) in RCA: 286] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493. Patients and Methods Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off). Results Sixty-five patients were enrolled. The most common treatment-emergent adverse events included hyperphosphatemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), decreased appetite (32%), and dysgeusia (31%). Twenty-seven patients (42%) experienced grade ≥ 3 treatment-emergent adverse events, and one dose-limiting toxicity of grade 3 ALT elevation was observed at 12 mg daily. Maximum-tolerated dose was not defined. Nine milligrams daily was considered as the initial RP2D; however, tolerability was improved with intermittent schedules, and 10 mg administered on a 7-days-on/7-days-off schedule was considered the final RP2D. Pharmacokinetics were linear, dose proportional, and predictable, with a half-life of 50 to 60 hours. Dose-dependent elevations in serum phosphate, a manifestation of pharmacodynamic effect, occurred in all patients starting at 4 mg daily. Among 23 response-evaluable patients with tumor FGFR pathway alterations, four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer (all with FGFR2 or FGFR3 translocations); 16 patients had stable disease. Conclusion JNJ-42756493 administered at 10 mg on a 7-days-on/7-days-off schedule achieved exposures at which clinical responses were observed, demonstrated pharmacodynamic biomarker activity, and had a manageable safety profile.
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Affiliation(s)
- Josep Tabernero
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Rastislav Bahleda
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Rodrigo Dienstmann
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Jeffrey R. Infante
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Alain Mita
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Antoine Italiano
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Emiliano Calvo
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Victor Moreno
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Barbara Adamo
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Anas Gazzah
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Bob Zhong
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Suso J. Platero
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Johan W. Smit
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Kim Stuyckens
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Moitreyee Chatterjee-Kishore
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Jordi Rodon
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Vijay Peddareddigari
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Feng R. Luo
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
| | - Jean-Charles Soria
- Josep Tabernero, Rodrigo Dienstmann, Barbara Adamo, and Jordi Rodon, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona; Emiliano Calvo, START Madrid, Centro Integral Oncológico Clara Campal; Victor Moreno, START Madrid, Hospital Fundación Jiménez Díaz, Madrid, Spain; Rastislav Bahleda, Anas Gazzah, and Jean-Charles Soria, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif; Antoine Italiano, Institut Bergonié, Bordeaux, France; Jeffrey
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Lengel D, Lamm Bergström E, Barthlow H, Oldman K, Musgrove H, Harmer A, Valentin JP, Duffy P, Braddock M, Curwen J. Prevention of fostamatinib-induced blood pressure elevation by antihypertensive agents. Pharmacol Res Perspect 2015; 3:e00176. [PMID: 26516588 PMCID: PMC4618647 DOI: 10.1002/prp2.176] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 08/14/2015] [Accepted: 07/14/2015] [Indexed: 12/15/2022] Open
Abstract
Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase which has completed clinical trials for patients with rheumatoid arthritis. In clinical studies fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between fostamatinib-induced blood pressure elevation and plasma levels of the fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship. Free plasma levels of R940406 produced in these studies (up to 346 nmol/L) span the clinically observed mean peak free plasma concentration of 49 nmol/L. We have demonstrated that the blood pressure elevation induced by fostamatinib dosing can be successfully controlled by a variety of methods, notably simple drug withdrawal or codosing with a range of standard antihypertensive agents such as atenolol, captopril, and nifedipine. These findings support potential methods of maintaining patient safety while on fostamatinib therapy. Furthermore, we have demonstrated, using nifedipine as an example agent, that this blood pressure control was not achieved by reduction in plasma exposure of R940406, suggesting that potential benefits from the pharmacology of the investigational drug can be maintained while blood pressure control is managed by use of standard comedications.
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Affiliation(s)
- Dave Lengel
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Eva Lamm Bergström
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Herb Barthlow
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Karen Oldman
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Helen Musgrove
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Alex Harmer
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | | | - Paul Duffy
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Martin Braddock
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Jon Curwen
- AstraZeneca R&D Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom
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48
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Bender D, Sill MW, Lankes HA, Reyes HD, Darus CJ, Delmore JE, Rotmensch J, Gray HJ, Mannel RS, Schilder JM, Hunter MI, McCourt CK, Samuelson MI, Leslie KK. A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2015; 138:507-12. [PMID: 26186911 PMCID: PMC4642817 DOI: 10.1016/j.ygyno.2015.07.018] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/08/2015] [Accepted: 07/12/2015] [Indexed: 01/17/2023]
Abstract
PURPOSE Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.
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Affiliation(s)
- David Bender
- Gynecologic Oncology Division, University of Iowa, Gyn/Onc Division, Iowa City, IA 52242, United States.
| | - Michael W Sill
- NRG Oncology Statistics & Data Management Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
| | - Heather A Lankes
- NRG Oncology Statistics & Data Management Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
| | - Henry D Reyes
- Gynecologic Oncology Division, University of Iowa, Gyn/Onc Division, Iowa City, IA 52242, United States.
| | - Christopher J Darus
- Division of Gynecologic Oncology, Maine Medical Center, Scarborough, ME 04101, United States.
| | - James E Delmore
- University of Kansas School of Medicine, Wichita CCOP, Wichita, KS 67208, United States.
| | - Jacob Rotmensch
- Division of Gynecologic Oncology, Rush-Presbyterian St. Lukes Medical Center, Chicago, IL 60612, United States.
| | - Heidi J Gray
- Dept. of OB/GYN, University of Washington, Seattle, WA 98195, United States.
| | - Robert S Mannel
- Dept. of OB/GYN, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
| | - Jeanne M Schilder
- Dept. of Gyn/Onc, Indiana University Medical Center, Indianapolis, IN 46202, United States.
| | - Mark I Hunter
- Ellis Fischel Cancer Center, Columbia, MO 65203, United States.
| | - Carolyn K McCourt
- Dept. of Oncology, Women & Infants Hospital, Providence, RI 02905, United States.
| | - Megan I Samuelson
- Gynecologic Oncology Division, University of Iowa, Gyn/Onc Division, Iowa City, IA 52242, United States
| | - Kimberly K Leslie
- Gynecologic Oncology Division, University of Iowa, Gyn/Onc Division, Iowa City, IA 52242, United States.
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49
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A phase I trial and PK study of cediranib (AZD2171), an orally bioavailable pan-VEGFR inhibitor, in children with recurrent or refractory primary CNS tumors. Childs Nerv Syst 2015; 31:1433-45. [PMID: 26188774 PMCID: PMC4561207 DOI: 10.1007/s00381-015-2812-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 07/03/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors. METHODS Children and adolescents <22 years were enrolled into one of two strata: stratum I—those not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum II—those receiving EIACDs. Dose-level selection was based on the continual reassessment method (CRM). RESULTS Thirty-six eligible patients with median age of 12.7 years (range, 5.4-21.7 years) in stratum I (24 males) and 12 patients (7 males) in stratum II with median age of 13.4 years (range, 8.9-19.5 years) were initially assessed over a 4-week DLT evaluation period, modified to 6 weeks during the study. An MTD of 32 mg/m(2)/day was declared; however, excessive toxicities (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) in the expansion cohort treated at this dose suggested that it might not be tolerated over a longer time period. An expansion cohort at 20 mg/m(2)/day also demonstrated poor longer-term tolerability. Diffusion and perfusion MRI and PET imaging variables as well as biomarker analysis were performed and correlated with outcome. At 20 mg/m(2)/day, the median plasma area under the concentration-time curve at steady state was lower than that observed in adults at similar dosages. CONCLUSIONS While the MTD of once daily oral cediranib in children with recurrent or progressive CNS tumors was initially defined as 32 mg/m(2)/day, this dose and 20 mg/m(2)/day were not considered tolerable over a protracted time period.
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50
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Depot delivery of dexamethasone and cediranib for the treatment of brain tumor associated edema in an intracranial rat glioma model. J Control Release 2015; 217:183-90. [PMID: 26285064 DOI: 10.1016/j.jconrel.2015.08.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 08/03/2015] [Accepted: 08/13/2015] [Indexed: 11/22/2022]
Abstract
Treatments of brain tumor associated edema with systemically delivered dexamethasone, the standard of care, and cediranib, a novel anti-edema agent, are associated with systemic toxicities in brain tumor patients. A tunable, reservoir-based drug delivery device was developed to investigate the effects of delivering dexamethasone and cediranib locally in the brain in an intracranial 9L gliosarcoma rat model. Reproducible, sustained releases of both dexamethasone and solid dispersion of cediranib in polyvinylpyrrolidone (AZD/PVP) from these devices were achieved. The water-soluble AZD/PVP, which exhibited similar bioactivity as cediranib, was developed to enhance the release of cediranib from the device. Local and systemic administration of both dexamethasone and cediranib was equally efficacious in alleviating edema but had no effect on tumor growth. Edema reduction led to modest but significant improvement in survival. Local delivery of dexamethasone prevented dexamethasone-induced weight loss, an adverse effect seen in animals treated with systemic dexamethasone. Local deliveries of dexamethasone and cediranib via these devices used only 2.36% and 0.21% of the systemic doses respectively, but achieved similar efficacy as systemic drug deliveries without the side effects associated with systemic administration. Other therapeutic agents targeting brain tumor can be delivered locally in the brain to provide similar improved treatment outcomes.
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