Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1–3 and 8–10,; and gemcitabine 1,000 mg/m2 on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1–3, 8–10, and 15–17; and gemcitabine 1,000 mg/m2 on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m2 for the 21-day schedule. No clinically significant pharmacokinetic drug–drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m2 was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.
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This study was funded by AbbVie, Inc. We thank the study teams at our respective institutions. Medical writing support was provided by Michael J. Theisen, PhD and Jamie L. Kistler, PhD, at Complete Publication Solutions, LLC; this support was funded by AbbVie, Inc. Joseph Beason and Min Tian provided statistical programming support and Keith J. Gaddie, Ph. D provided medical writing support; all are AbbVie employees.
Conflict of interest/disclosure information
James Cleary, Caio Rocha-Lima, Herbert Hurwitz, Alberto J. Montero, Geoffrey Shapiro, and Hope Uronis have no conflict of interests to declare. Jianning Yang, Alison M. Graham, Todd Busman, Kyle Holen, and Mack Mabry are employees and stock owners of AbbVie. *Catherine Franklin is a former employee and stock owner of AbbVie and currently works for Novartis Institutes for Biomedical Research, Inc., Cambridge, MA.
The design, study conduct, analysis, and financial support of the clinical trial were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of this manuscript.
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