Abstract 2762: Phase I study of pazopanib and ixabepilone in patients with solid tumors

Abstract

Abstract Background: Pazopanib is a tyrosine kinase inhibitor targeting multiple receptors including vascular endothelial growth factor receptor, platelet derived growth factor receptor, and C-KIT and acts by inhibiting angiogenesis and tumor growth. Ixabepilone is a semi-synthetic analog of epothilone B and promotes microtubule stabilization inducing tumor cell apoptosis. The purpose of this study was to determine the optimal tolerated regimen (OTR) of combination pazopanib and ixabepilone during the first cycle of therapy for the treatment of advanced, previously treated solid tumor malignancies. Methods: Treatment was given until disease progression, unacceptable toxicity, or patient refusal. Ixabepilone was administered intravenously on day 1 of a 21-day cycle. Dose escalation started at 32 mg/m2 and increased to 40mg/m2. Pazopanib was administered orally once daily beginning on day 1 at a starting dose of 400mg and escalating at 200mg increments up to 800mg. Toxicity was assessed by using the Common Terminology Criteria for Adverse Events (version 3.0). Disease assessment was done every 2 cycles. Results: Twenty-eight patients (17 male and 11 female) with ECOG PS of 0 or 1 were enrolled from December 2009 to September 2011.The median age was 58 years (range 30-72). Primary tumor sites included lung (8), colon (9), skin (2), gallbladder (1), cholangiocarcinoma (1), neuroendocrine (1), head and neck (3), esophagus (1), small cell cancer (1), and leimyosarcoma (1). A total of 120 cycles of chemotherapy was administered with a median number of cycles per patient of 4 (range 1-13). Two dose-limiting toxicities (DLT) were seen including grade 4 neutropenia at dose level 2 (ixabepilone 40 mg/m2 and pazopanib 400 mg) and grade 4 thrombocytopenia with proteinuria at dose level 4 (ixabepilone 32 mg/m2 and pazopanib 800 mg). Dose level 2a was added to the study to confirm the safety of the proposed ixabepilone dose (32 mg/m2) before escalating the dose of pazopanib to levels 3 and 4. Dose level 3 was determined to be the optimal tolerated regimen (pazopanib 600 mg and ixabepilone 32 mg/m2). Grade 3-4 hematologic toxicities included neutropenia (14), febrile neutropenia (1), thrombocytopenia (2), and anemia (1). Grade 3-4 non-hematologic toxicities included weakness (1), dehydration (1), transaminitis (1), and fatigue (1). One patient withdrew from the study due to toxicity. Median time to progression during the study period was 3 months. Disease stabilization was seen in 11 patients and partial response in 5 patients. Conclusions: We were able to establish the OTR for combination of pazopanib and ixabepilone. Progression-free survival seen in patients with a variety of previously treated, advanced solid tumors warrants further investigation of this regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2762. doi:1538-7445.AM2012-2762