A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma
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.
KeywordsAdrenal cortical carcinoma AT-101 Gossypol Apoptosis
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.
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 was obtained from all individual participants included in the study.
- 6.Sperone P, Ferrero A, Daffara F et al (2010) Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second−/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer 17(2):445–453. https://doi.org/10.1677/ERC-09-0281 CrossRefPubMedGoogle Scholar
- 7.Fassnacht M, Berruti A, Baudin E et al (2015) Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol 16(4):426–435. https://doi.org/10.1016/S1470-2045(15)70081-1 CrossRefPubMedGoogle Scholar
- 10.Fassnacht M, Johanssen S, Quinkler M et al (2009) Limited prognostic value of the 2004 International Union against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification. Cancer 115(2):243–250. https://doi.org/10.1002/cncr.24030 CrossRefPubMedGoogle Scholar
- 11.Fassnacht M, Dekkers O, Else T et al (2018) European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 179(4):G1–G46. https://doi.org/10.1530/EJE-18-0608 CrossRefPubMedGoogle Scholar
- 13.Kanauchi H, Wada N, Clark OH, Duh QY (2002) Apoptosis regulating genes, bcl-2 and bax, and human telomerase reverse transcriptase messenger RNA expression in adrenal tumors: possible diagnostic and prognostic importance. Surgery 132(6):1021–1026; discussion 1026-7. https://doi.org/10.1067/msy.2002.128616 CrossRefPubMedGoogle Scholar
- 17.Investigator’s Brochure (2006) AT-101 [R-(−)-gossypol acetic acid]. Ascenta Therapeutics, Inc. Accessed 31 Mar 2006Google Scholar
- 27.Sonpavde G, Matveev V, Burke JM et al (2012) Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol 23(7):1803–1808. https://doi.org/10.1093/annonc/mdr555 CrossRefPubMedGoogle Scholar
- 28.Stein MN, Hussain M, Stadler WM et al (2016) A phase II study of AT-101 to overcome Bcl-2--mediated resistance to androgen deprivation therapy in patients with newly diagnosed castration-sensitive metastatic prostate Cancer. Clin Genitourin Cancer 14(1):22–27. https://doi.org/10.1016/j.clgc.2015.09.010 CrossRefPubMedGoogle Scholar
- 29.Swiecicki PL, Bellile E, Sacco AG et al (2016) A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Investig New Drugs 34(4):481–489. https://doi.org/10.1007/s10637-016-0364-5 CrossRefGoogle Scholar