Abstract LB-158: Phase I study of pazopanib and ixabepilone in patients with solid tumors.
Authors: Ganesan Chitra , Obulareddy Sri J. , Bliss Robin L. , Dudek Arkadiusz Z. 
Published: August 2014

Background: Pazopanib (P) is a TKI targeting multiple receptors including VEGF, PDGF, and C-KIT and acts by inhibiting tumor angiogenesis. Ixabepilone (I) 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 P and I in patients with advanced, previously treated solid tumors.

Methods: I was administered intravenously on day 1 of a 21-day cycle. Dose escalation started at 32 mg/m2. P was administered orally once daily beginning on day 1 at a starting dose of 400mg and escalating at 200mg increments up to 800mg. Disease assessment was done every 2 cycles. A correlative study was conducted to evaluate the changes in levels of VEGF, FGF basic, HGF, IL-8, CXCL-10, MCP-1, M-CSF, MIP 1alpha,MIP-1 beta, PDGF-BB, sE-selectin, TNF-alpha, SAA, PIGF-1, SICAM-1,SDF-1 from baseline to pre-cycle 2 using the Luminex™ system. Replicates for levels were averaged and differences in averages were used in proportional hazards models to predict progression-free survival.

Results: Thirty one patients (11 female) 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 (6), esophagus (1), small cell cancer (1), ovary (1) and leiomyosarcoma (1). A total of 120 cycles of chemotherapy was administered with a median number of cycles per patient of 4 (range 1-13). Three patients had dose-limiting toxicities (DLT) including grade 4 neutropenia and fatigue at dose level 2 (I at 40 mg/m2 and P at 400 mg). Dose level 2a was added to the study to confirm the safety of the proposed I dose (32 mg/m2) before escalating the dose of P to levels 3 and 4. One patient had DLT at dose level (I at 32 mg/m2 and P at 800 mg) due to grade 4 thrombocytopenia. Dose level 3 was determined to be the OTR (P at 600 mg and I at 32 mg/m2).

Grade 3-4 hematologic toxicities included neutropenia (5), febrile neutropenia (1), thrombocytopenia (1), and anemia (1). Grade 3-4 non-hematologic toxicities included diarrhea (1) and abdominal pain (1). Disease stabilization was seen in 13 patients and partial response in 8 patients. Progression of disease was seen in 9 patients. There was a significant increase in CXCL10, SAA, and SICAM-1 whereas sE-selectin decreased after the first cycle, but only decrease in sE-selectin was associated with a progression free survival benefit (HR 0.401; 95% CI: 0.168-0.959].

Conclusions: We were able to establish the OTR for combination of P and I. Activity of this regimen was seen in patients with a variety of previously treated solid tumors and it warrants further investigation. We were able to demonstrate significant changes in cytokine levels and correlation of sE-selectin decrease with progression free survival benefit.

Citation Format: Chitra Ganesan, Sri J. Obulareddy, Robin L. Bliss, Arkadiusz Z. Dudek. Phase I study of pazopanib and ixabepilone in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-158. doi:10.1158/1538-7445.AM2013-LB-158