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A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.

Abstract：

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/m(2) 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/m(2) 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/m(2) 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/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.

journal_name

Invest New Drugs

journal_title

Investigational new drugs

authors

Cleary JM,Lima CM,Hurwitz HI,Montero AJ,Franklin C,Yang J,Graham A,Busman T,Mabry M,Holen K,Shapiro GI,Uronis H

doi

10.1007/s10637-014-0110-9

subject

Has Abstract

pub_date

2014-10-01 00:00:00

pages

937-45

issue

eissn

0167-6997

issn

1573-0646

journal_volume

pub_type

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A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.