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Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors

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Abstract

Purpose

Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of navitoclax combined with erlotinib in patients with advanced solid tumors.

Patients and methods

An open-label dose escalation study included an arm evaluating navitoclax combined with erlotinib, which included a dose escalation cohort and a planned safety expansion cohort. Patients with documented cancers for whom erlotinib therapy was appropriate received erlotinib 150 mg orally once daily plus navitoclax 150 mg orally once daily, with navitoclax dose escalation via a continuous reassessment method model.

Results

Eleven patients were enrolled, including six patients with nonsmall cell lung cancer. Dose-limiting toxicities, most commonly diarrhea, were observed in 4 patients. Navitoclax dosing remained at 150 mg/day because the maximum tolerated dose was exceeded at this starting dose. The planned dose escalation did not occur; no recommended phase II dose (RPTD) was identified, and there was no safety expansion cohort. The most common treatment-related adverse events were diarrhea, nausea, vomiting, and decreased appetite. Pharmacokinetic analysis showed no apparent interactions between co-administered navitoclax and erlotinib. No objective responses were observed; the disease control rate was 27 % (95 % CI, 6–61 %).

Conclusion

At the erlotinib and navitoclax doses administered, RPTD was not reached, but the safety profile of the combination was consistent with data from monotherapy studies. There were no apparent pharmacokinetic interactions between erlotinib and navitoclax. Three patients had stable disease.

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Acknowledgments

We acknowledge the patients and their caregivers for their participation in this study. We also acknowledge medical writing assistance from Amy Zanikos, PhD, and Tiffany Brake, PhD, which was supported by AbbVie Inc. This study was funded by AbbVie Inc and Genentech.

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Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA

    Anthony W. Tolcher

  2. Yale University, New Haven, CT, USA

    Patricia LoRusso

  3. AbbVie Inc., North Chicago, IL, USA

    Jennifer Arzt, Todd A. Busman, Guinan Lian, Niki S. Rudersdorf, Carol Ann Vanderwal & Kyle D. Holen

  4. AbbVie Biotherapeutics Inc., Redwood City, CA, USA

    Whitney Kirschbrown

  5. Division of Hematology-Oncology, University of California Los Angeles, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA

    Lee S. Rosen

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  1. Anthony W. Tolcher
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Corresponding author

Correspondence to Lee S. Rosen.

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Conflict of interest

Anthony W. Tolcher has advisory/consulting agreements with AbbVie, Akebia, AP Pharma, ArQule, Inc., Asana, Astex, Avid Biologics, Bayer HealthCare, Bind Therapeutics, BioMed Valley Discoveries, Blend Therapeutics, Bristol-Myers Squibb Japan, Celator, Clovis, Curis, De Novo Sciences, Dicerna, Eisai, Endo, Genentech, Heron, Janssen, Lilly MedImmune, Mersana, Merus, Nanobiotix S.A., Nektar, Neumedicines, Novartis, Pfizer, Pharmacyclics, Pierre Fabre, Proimagen, Sanofi-Aventis, Symphogen, Vaccinex, Valent Technologies, and Zyngenia. Patricia LoRusso has no conflicts to disclose. Lee S. Rosen receives research funding from Abbott/AbbVie Inc. Jennifer Arzt, Todd A. Busman, Guinan Lian, Niki S. Rudersdorf, Carol Ann Vanderwal, Whitney Kirschbrown, and Kyle D. Holen are employees of and may own stock in AbbVie Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Tolcher, A.W., LoRusso, P., Arzt, J. et al. Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors. Cancer Chemother Pharmacol 76, 1025–1032 (2015). https://doi.org/10.1007/s00280-015-2883-8

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  • DOI: https://doi.org/10.1007/s00280-015-2883-8

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