Open AccessA phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma
Author(s) -
Hao Xie,
Jun Yin,
Manisha H. Shah,
Michael E. Menefee,
Keith C. Bible,
Diane ReidyLagunes,
Madeleine A. Kane,
David I. Quinn,
David R. Gandara,
Charles Erlichman,
Alex A. Adjei
Publication year - 2019
Publication title -
investigational new drugs
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 87
eISSN - 1573-0646
pISSN - 0167-6997
DOI - 10.1007/s10637-019-00797-1
Subject(s) - medicine , clinical endpoint , clinical trial , cancer , gastroenterology , response evaluation criteria in solid tumors , oncology , toxicity , phases of clinical research , surgery
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.