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

Abstract

Purpose: To evaluate the safety, MTD, pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 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/m(2); schedule B: 20, 30, or 40 mg/m(2)), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLT) 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 hematologic and nonhematologic adverse events were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response, while 13 patients had stable disease. Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Coadministration 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 the 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 postbaseline.

Conclusions: Coadministration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer. Clin Cancer Res; 22(13); 3209-17. ©2016 AACR.

Figure 1

Study schema

Figure 2

Overall change in tumor size to ixabepilone and sunitinib by schedule. A. Maximum percent change in target lesion size with sunitinib treatment plus either weekly (schedule A) or every three week (schedule B) ixabepilone. Each bar represents one patient. B. Overall change in maximum tumor length.

Figure 3

Impact of sunitinib and ixapebilone on angiogenesis biomarkers and correlation with clinical response. A, correlation between baseline (pre-treatment) Plasma Angiogenic Activity (PAA) and best response (by RECIST criteria) in schedule A and B patients. B, correlation between baseline (pre-treatment) PAA and prolonged clinical benefit, defined by continuing on treatment for > 7 cycles in schedule A and B patients. Levels of PAA are displayed as percent of (no patient plasma) control (see methods section). Each dot represents average values of an individual patient’s PAA (each in triplicate). C, correlation between baseline circulating endothelial cell numbers (cells/microliter) and prolonged benefit (on study > 6 cycles). D, changes in PAA post-baseline (after 1 cycle) in schedule A and B patients. Values are displayed as percent change in PAA at cycle 2 compared to baseline values. Each dot represents the average value of individual patients PAA (in triplicate). E, correlation between changes in PAA after baseline and best response (by RECIST). Each line represents changes in PAA from baseline to after cycle 1 of each individual patient (in triplicate). F, correlation between changes in circulating endothelial precursor cells (EPCs) and best response. Values are displayed as percent change in EPC after cycle 1, compared with baseline. Each line represents an individual patient.

Figure 3

Impact of sunitinib and ixapebilone on angiogenesis biomarkers and correlation with clinical response. A, correlation between baseline (pre-treatment) Plasma Angiogenic Activity (PAA) and best response (by RECIST criteria) in schedule A and B patients. B, correlation between baseline (pre-treatment) PAA and prolonged clinical benefit, defined by continuing on treatment for > 7 cycles in schedule A and B patients. Levels of PAA are displayed as percent of (no patient plasma) control (see methods section). Each dot represents average values of an individual patient’s PAA (each in triplicate). C, correlation between baseline circulating endothelial cell numbers (cells/microliter) and prolonged benefit (on study > 6 cycles). D, changes in PAA post-baseline (after 1 cycle) in schedule A and B patients. Values are displayed as percent change in PAA at cycle 2 compared to baseline values. Each dot represents the average value of individual patients PAA (in triplicate). E, correlation between changes in PAA after baseline and best response (by RECIST). Each line represents changes in PAA from baseline to after cycle 1 of each individual patient (in triplicate). F, correlation between changes in circulating endothelial precursor cells (EPCs) and best response. Values are displayed as percent change in EPC after cycle 1, compared with baseline. Each line represents an individual patient.