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Investigational New Drugs

, Volume 32, Issue 5, pp 976–984 | Cite as

A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors

  • Gordana VlahovicEmail author
  • Vassiliki Karantza
  • Ding Wang
  • David Cosgrove
  • Nikita Rudersdorf
  • Jianning Yang
  • Hao Xiong
  • Todd Busman
  • Mack Mabry
PHASE I STUDIES

Summary

Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.

Keywords

ABT-263 Carboplatin Paclitaxel Phase I 

Notes

Acknowledgments

Statistical analyses were performed by Min Tian and Joseph Beason and medical writing assistance was provided by Keith J. Gaddie, Ph.D.; all are AbbVie employees.

Disclosures

The design, study conduct, and analysis of the clinical trial were provided by AbbVie. AbbVie provided the financial support and participated in the interpretation of data, review, and approval of the manuscript.

Conflict of interest

Gordana Vlahovic is on the speaker bureau for Genentech and Pfizer. Vassiliki Karantza, Ding Wang, and David Cosgrove have no conflict of interests to declare. Nikita Rudersdorf, Jianning Yang, Hao Xiong, Todd Busman, and Mack Mabry are employees and stock owners of AbbVie.

References

  1. 1.
    Moffitt KL, Martin SL, Walker B (2010) From sentencing to execution–the processes of apoptosis. J Pharm Pharmacol 62:547–562CrossRefPubMedGoogle Scholar
  2. 2.
    Fulda S (2009) Tumor resistance to apoptosis. Int J Cancer 124:511–515CrossRefPubMedGoogle Scholar
  3. 3.
    Fulda S (2010) Evasion of apoptosis as a cellular stress response in cancer. Int J Cell Biol 2010:370835PubMedCentralPubMedGoogle Scholar
  4. 4.
    Del Gaizo MV, Letai A (2008) Rational design of therapeutics targeting the BCL-2 family: are some cancer cells primed for death but waiting for a final push? Adv Exp Med Biol 615:159–175CrossRefGoogle Scholar
  5. 5.
    Azmi AS, Mohammad RM (2009) Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol 218:13–21PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Leibowitz B, Yu J (2010) Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther 9:417–422PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Tse C, Shoemaker AR, Adickes J et al (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68:3421–3428CrossRefPubMedGoogle Scholar
  9. 9.
    Gandhi L, Camidge DR, Ribeiro de Oliveira M (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29:909–916CrossRefPubMedGoogle Scholar
  10. 10.
    Roberts AW, Seymour JF, Brown JR et al (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30:488–496CrossRefPubMedGoogle Scholar
  11. 11.
    Rudin CM, Hann CL, Garon EB et al (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18:3163–3169PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Wilson WH, O'Connor OA, Czuczman MS et al (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11:1149–1159PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Ackler S, Mitten MJ, Foster K et al (2010) The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother Pharmacol 66:869–880CrossRefPubMedGoogle Scholar
  14. 14.
    Belmont L, Tan N, Wong M, et al.: Predicting synergy: Drug combination screening to identify predictive biomarkers for combination drug therapy. Mol Biol Cell 22, 2011Google Scholar
  15. 15.
    Chen J, Jin S, Abraham V et al (2011) The Bcl-2/Bcl-X (L)/Bcl-w inhibitor, navitoclax, enhances the activity of chemotherapeutic agents in vitro and in vivo. Mol Cancer Ther 10:2340–2349CrossRefPubMedGoogle Scholar
  16. 16.
    Sakuma Y, Tsunezumi J, Nakamura Y et al (2011) ABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikis. Oncol Rep 25:661–667CrossRefPubMedGoogle Scholar
  17. 17.
    Wong M, Tan N, Kassees R, et al.: Navitoclax enhances the activity of chemo-therapeutic and targeted agents across a large panel of epithelial cancer cell lines. Cancer Res 71, 2011Google Scholar
  18. 18.
    Wong M, Tan N, Zha J et al (2012) Navitoclax (ABT-263) reduces Bcl-x (L)-mediated chemo resistance in ovarian cancer models. Mol Cancer Ther 11:1026–1035CrossRefPubMedGoogle Scholar
  19. 19.
    Wheate NJ, Walker S, Craig GE et al (2010) The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans 39:8113–8127CrossRefPubMedGoogle Scholar
  20. 20.
    Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265CrossRefPubMedGoogle Scholar
  21. 21.
    Voss MH, Feldman DR (2011) Paclitaxel, ifosfamide and cisplatin (TIP) beyond its original indication for salvage treatment of germ cell tumors. Onkologie 34:410–411CrossRefPubMedGoogle Scholar
  22. 22.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada. J Natl Cancer Inst 92:205–216Google Scholar
  23. 23.
    Oken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of the Eastern cooperative oncology group. Am J Clin Oncol 5:649–655CrossRefPubMedGoogle Scholar
  24. 24.
    National Cancer Institute: Common Terminology Criteria for Adverse Events, Version 3.0, 2006Google Scholar
  25. 25.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Gordana Vlahovic
    • 1
    Email author
  • Vassiliki Karantza
    • 2
  • Ding Wang
    • 3
  • David Cosgrove
    • 4
  • Nikita Rudersdorf
    • 5
  • Jianning Yang
    • 5
  • Hao Xiong
    • 5
  • Todd Busman
    • 5
  • Mack Mabry
    • 5
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.The Rutgers Cancer Institute of New JerseyNew BrunswickUSA
  3. 3.Henry Ford Health CenterDetroitUSA
  4. 4.Johns Hopkins University School of MedicineBaltimoreUSA
  5. 5.AbbVie, IncNorth ChicagoUSA

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