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A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma

  • Hao Xie
  • Jun Yin
  • Manisha H. Shah
  • Michael E. Menefee
  • Keith C. Bible
  • Diane Reidy-Lagunes
  • Madeleine A. Kane
  • David I. Quinn
  • David R. Gandara
  • Charles Erlichman
  • Alex A. AdjeiEmail author
PHASE II STUDIES

Summary

Background Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.

Keywords

Adrenal cortical carcinoma AT-101 Gossypol Apoptosis 

Notes

Funding

This study is supported by The Phase 2 Consortium (P2C) through its contract with the National Cancer Institute (N01 CM17104).

Compliance with ethical standards

Conflict of interest

Hao Xie declares that he has no conflict of interest. Jun Yin declares that she has no conflict of interest. Manisha H. Shah declares that she has no conflict of interest related to AT-101 except research funding from Bristol-Myers Squibb for a clinical trial in last 2 years. Michael E. Menefee declares that he has no conflict of interest. Keith C. Bible declares that he has no conflict of interest. Diane Reidy-Lagunes declares that she receives research funds from Novartis, Ipsen, and Merck, and is on the advisory board for Novartis, Ipsen, AAA, and Lexicon. Madeleine A. Kane declares that she has no conflict of interest. David I. Quinn declares that he has no conflict of interest. David R. Gandara declares that he has no conflict of interest. Charles Erlichman declares that he has no conflict of interest. Alex A. Adjei declares that he has no conflict of interest.

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. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Hao Xie
    • 1
  • Jun Yin
    • 1
  • Manisha H. Shah
    • 2
  • Michael E. Menefee
    • 3
  • Keith C. Bible
    • 1
  • Diane Reidy-Lagunes
    • 4
  • Madeleine A. Kane
    • 5
  • David I. Quinn
    • 6
  • David R. Gandara
    • 7
  • Charles Erlichman
    • 1
  • Alex A. Adjei
    • 1
    Email author
  1. 1.Mayo Clinic Cancer CenterRochesterUSA
  2. 2.Division of Medical Oncology, Department of Internal MedicineThe Ohio State University Comprehensive Cancer CenterColumbusUSA
  3. 3.FDASilver SpringUSA
  4. 4.Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  5. 5.Department of Medicine and Division of Medical OncologyUniversity of ColoradoAuroraUSA
  6. 6.University of Southern California Norris Comprehensive Cancer Center, Hospital and ClinicsLos AngelesUSA
  7. 7.UC Davis Comprehensive Cancer CenterSacramentoUSA

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