Investigational New Drugs

, Volume 32, Issue 5, pp 937–945 | Cite as

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

  • 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. ShapiroEmail author
  • Hope Uronis


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.


ABT-263 Apoptosis Bcl-2 Bcl-xL Gemcitabine Navitoclax 



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.

Funding source

AbbVie Inc.

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • James M. Cleary
    • 1
  • Caio Max S. Rocha Lima
    • 2
  • Herbert I. Hurwitz
    • 3
  • Alberto J. Montero
    • 4
  • Catherine Franklin
    • 5
  • Jianning Yang
    • 5
  • Alison Graham
    • 5
  • Todd Busman
    • 5
  • Mack Mabry
    • 5
  • Kyle Holen
    • 5
  • Geoffrey I. Shapiro
    • 1
    • 6
    Email author
  • Hope Uronis
    • 3
  1. 1.Department of Medical Oncology, Dana-Farber Cancer Institute and Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.University of Miami Sylvester Comprehensive Cancer CenterMiamiUSA
  3. 3.Division of Medical OncologyDuke University Medical CenterDurhamUSA
  4. 4.Cleveland Clinic Taussig Cancer InstituteDepartment of Solid Tumor OncologyClevelandUSA
  5. 5.AbbVie IncNorth ChicagoUSA
  6. 6.Early Drug Development CenterDana-Farber Cancer InstituteBostonUSA

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