Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor
Open Access
- 19 October 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 103 (10), 1554-1561
- https://doi.org/10.1038/sj.bjc.6605941
Abstract
Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60–100 mg twice daily (BID)) and docetaxel (75–100 mg m–2), or CP-868,596 (60 mg BID), docetaxel (75 mg m–2), and VEGFR inhibitor axitinib (5 mg BID). The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m–2 docetaxel (maximum approved dose). Most treatment-emergent AEs were mild–moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3–16) cycles. The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.Keywords
This publication has 82 references indexed in Scilit:
- Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced CancersJournal of Clinical Oncology, 2009
- A Phase II Study of Imatinib Mesylate and Capecitabine in Metastatic Breast Cancer: Southwest Oncology Group Study 0338Clinical Breast Cancer, 2008
- Scan-rescan variability in perfusion assessment of tumors in MRI using both model and data-derived arterial input functionsJournal of Magnetic Resonance Imaging, 2008
- Treatment with imatinib improves drug delivery and efficacy in NSCLC xenograftsBritish Journal of Cancer, 2007
- Expression analysis of the acute phase response in channel catfish (Ictalurus punctatus) after infection with a Gram-negative bacteriumDevelopmental & Comparative Immunology, 2007
- Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenationBritish Journal of Cancer, 2006
- Molecular Identification, Polymorphism, and Expression Analysis of Major Histocompatibility Complex Class IIA and B Genes of Turbot (Scophthalmus maximus)Marine Biotechnology, 2006
- The in vitro effects of CpG oligodeoxynucleotides on the expression of cytokine genes in the common carp (Cyprinus carpio L.) head kidney cellsVeterinary Immunology and Immunopathology, 2006
- Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical ResultsJournal of Clinical Oncology, 2005
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000