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.

• Authors: James M Cleary, Caio Max S Rocha Lima, Herbert I Hurwitz, Alberto J Montero, Catherine Franklin, Jianning Yang, Alison Graham, Todd Busman, Mack Mabry, Kyle Holen, Geoffrey I Shapiro, Hope Uronis
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 5 Pg. 937-45 (Oct 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24916770 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Deoxycytidine
• navitoclax
• Gemcitabine

Topics

• Adult
• Aged
• Aged, 80 and over
• Aniline Compounds (administration & dosage, adverse effects, blood, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, blood, pharmacokinetics, therapeutic use)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, blood, pharmacokinetics)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (blood, drug therapy)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Sulfonamides (administration & dosage, adverse effects, blood, pharmacokinetics)
• Treatment Outcome
• Gemcitabine