A Phase I Clinical, Pharmacokinetic and Pharmacodynamic Study of Weekly or Every Three Week Ixabepilone and Daily Sunitinib in Patients with Advanced Solid Tumors

Purpose: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every three weeks in combination with daily sunitinib in patients with advanced solid tumors. Experimental Design: Eligible patients received either weekly (Schedule A) or every 3 weeks (schedule B) Ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m2;; schedule B: 20, 30, or 40 mg/m2), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLTs) were assessed during cycle 1. Results: The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3-4 hematological and non-hematological adverse events (AEs) were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response (PR), while 13 patients had stable disease (SD). Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Co-administration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks Ixabepilone led to a significant decrease in PAA post-baseline. Conclusion: Co-administration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients. The above results warrant further evaluation of this combination.

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