Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor

Abstract

Background:Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.Methods: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).Results: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.Conclusions: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. © 2010 Cancer Research UK All rights reserved.