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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.

Publication ,  Journal Article
Cleary, JM; Lima, CMSR; Hurwitz, HI; Montero, AJ; Franklin, C; Yang, J; Graham, A; Busman, T; Mabry, M; Holen, K; Shapiro, GI; Uronis, H
Published in: Invest New Drugs
October 2014

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.

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Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

October 2014

Volume

32

Issue

5

Start / End Page

937 / 945

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Sulfonamides
  • Proto-Oncogene Proteins c-bcl-2
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
  • Gemcitabine
 

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Cleary, J. M., Lima, C. M. S. R., Hurwitz, H. I., Montero, A. J., Franklin, C., Yang, J., … Uronis, H. (2014). A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors. Invest New Drugs, 32(5), 937–945. https://doi.org/10.1007/s10637-014-0110-9
Cleary, James M., Caio Max S Rocha Lima, Herbert I. Hurwitz, Alberto J. Montero, Catherine Franklin, Jianning Yang, Alison Graham, et al. “A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.Invest New Drugs 32, no. 5 (October 2014): 937–45. https://doi.org/10.1007/s10637-014-0110-9.
Cleary JM, Lima CMSR, Hurwitz HI, Montero AJ, Franklin C, Yang J, et al. A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors. Invest New Drugs. 2014 Oct;32(5):937–45.
Cleary, James M., et al. “A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.Invest New Drugs, vol. 32, no. 5, Oct. 2014, pp. 937–45. Pubmed, doi:10.1007/s10637-014-0110-9.
Cleary JM, Lima CMSR, Hurwitz HI, Montero AJ, Franklin C, Yang J, Graham A, Busman T, Mabry M, Holen K, Shapiro GI, Uronis H. A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors. Invest New Drugs. 2014 Oct;32(5):937–945.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

October 2014

Volume

32

Issue

5

Start / End Page

937 / 945

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Sulfonamides
  • Proto-Oncogene Proteins c-bcl-2
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
  • Gemcitabine