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

Abstract

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.

• Authors: 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 Adjei
• Journal: Investigational new drugs (Invest New Drugs) Vol. 37 Issue 4 Pg. 755-762 (08 2019) ISSN: 1573-0646 [Electronic] United States
• PMID: 31172443 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Phytogenic
• Proto-Oncogene Proteins c-bcl-2
• Gossypol
• gossypol acetic acid

Topics

• Adrenal Cortex Neoplasms (drug therapy)
• Adrenocortical Carcinoma (drug therapy)
• Adult
• Aged
• Antineoplastic Agents, Phytogenic (adverse effects, therapeutic use)
• Female
• Gossypol (adverse effects, analogs & derivatives, therapeutic use)
• Humans
• Male
• Middle Aged
• Proto-Oncogene Proteins c-bcl-2
• Response Evaluation Criteria in Solid Tumors