A phase I study of sunitinib malate (S) and gemcitabine (G) in solid tumors.

Abstract

3046 Background: Continuous daily dosing (CDD) of S with G is a novel regimen that may have broad clinical activity. Methods: Eligible patients had no curative therapy options, adequate organ function, and no prior antiangiogenic treatments. A 3+3 dose escalation design was followed with expansion of the recommended phase II dose (RP2D) to 10 patients. G was administered as a standard 30-minute IV infusion. G was initiated at 800 mg/m2 days 1, 8, 15 of each 28-day cycle, with escalating once-daily oral doses of S. Treatment-related grade (gr) 4 toxicity, gr 3 cardiac or venous thrombosis, unresolved noncardiac gr 3 event, or uncontrolled hypertension in cycle 1 was defined as DLT. Results: 31 patients were treated (most common tumor type: pancreatic adenocarcinoma, n=9). DLTs are shown in the TableTable. Dose level 1 was expanded to 10 patients after the occurrence of 2 DLTs at dose level 2 and was found to be tolerable. Four patients at dose level 1 did not receive the three planned doses of G due to toxicity. The study was amended to evaluate day 1 and day 8 G every 21 days with continuous daily S. Excessive DLT occurred at dose levels -1a and -1. Of the 8 patients enrolled to dose level -2, all received the full dose of G and S for cycle 1. Four patients had a confirmed PR: 2 with pancreatic adenocarcinoma (dose level 1), 1 with pancreatic neuroendocrine cancer (dose level -2) and 1 with thymic carcinoma (dose level -2). 9 patients had stable disease (median 20 weeks, range 14-49 weeks). Conclusions: The MTD of weekly G + daily S is 800 mg/m2 G on days 1, 8, and 15 every 28 days with 25 mg daily S. The RP2D is 675 mg/m2 G on days 1 and 8 every 21 days with 25 mg daily S. This clinically active and well-tolerated regimen warrants further investigation. Supported by NIH/Cancer Therapy Evaluation Program U01 CA62502. Dose level S mg daily G mg/m2; days of G;days/cycle N # subjects with DLT/type of DLT 1 25 800; 1,8,15; 28 10 1/gr 4 ANC 2 37.5 800; 1,8,15; 28 5 2/gr 4 ANC and gr 4 platelet −1a 37.5 800; 1,8; 21 3 2/gr 4 platelet −1 25 800; 1,8; 21 5 2/gr 4 platelet and gr 3 cardiac LV systolic dysfunction −2 25 675; 1,8; 21 8 1/gr 3 hemorrhage Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, ImClone Systems, Merck, Pfizer, sanofi-aventis, Wyeth