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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

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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 Investigational New Drugs (2019) 37:755–762 https://doi.org/10.1007/s10637-019-00797-1 PHASE II STUDIES 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 Xie1 & Jun Yin1 & Manisha H. Shah2 & Michael E. Menefee3 & Keith C. Bible1 & Diane Reidy-Lagunes4 & Madeleine A. Kane5 & David I. Quinn6 & David R. Gandara7 & Charles Erlichman1 & Alex A. Adjei1 Received: 7 March 2019 /Accepted: 22 May 2019 /Published online: 6 June 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 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 Introduction Adrenal cortical carcinoma (ACC) is a rare cancer that is best * Alex A. Adjei initially managed with surgical resection even when [email protected] oligometastatic. [1, 2] Although the chances of disease recur- rence are attenuated in patients treated with adjuvant mitotane, 1 Mayo Clinic Cancer Center, 200 First St. SW, Rochester, MN 55905, USA the majority of patients undergoing curative-intention resec- tion ultimately later develop widespread metastases. [3] 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Moreover, many patients have either unresectable or widely Columbus, OH, USA metastatic disease at the time of diagnosis. In metastatic dis- 3 FDA, Silver Spring, MD 20993, USA ease, chemotherapy combining cisplatin, etoposide, and doxo- rubicin provides the greatest first-line efficacy. [4] However, 4 Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA in a recent phase 3 clinical trial, the objective response rate (ORR) was only 23%, progression-free survival (PFS) was 5 Department of Medicine and Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO, only 5 months, and overall survival 14.8 months, suggesting USA benefit, but critical need for improved and additional systemic 6 University of Southern California Norris Comprehensive Cancer therapeutic approaches. [5] Unfortunately, subsequent lines of Center, Hospital and Clinics, Los Angeles, CA 90033, USA therapy evaluated in clinical trials including streptozocin, oth- 7 UC Davis Comprehensive Cancer Center, Sacramento, CA, USA er chemotherapy regimens, and targeted agents have response 756 Invest New Drugs (2019) 37:755–762 rates about 10%, limited durations of response, and do not was any prior therapy exclusionary. Patients were required to definitively improve survival. [5–9] Additional systemic ap- have an anticipated ≥12-week life expectancy, ECOG perfor- proaches are therefore sorely needed to improve a low 5-year mance status of 0 to 2, normal organ and bone marrow function survival of 13%. [10, 11] defined as leukocytes ≥3000/mm3, absolute neutrophil count Dysregulation of apoptosis is crucial to carcinogenesis and ≥1500/mm3, platelets ≥100,000/mm3, total bilirubin <1.5 mg/ cancer progression and associated with resistance to standard dL, AST ≤2.5 upper limit of normal (ULN), ALT ≤2.5 ULN, therapy. Thus, targeting these pathways is potentially attrac- and serum creatinine ≤1.7 mg/dL (or creatinine clearance tive. In particular, the B cell lymphoma 2 (BCL2) family of ≥40 mL/min). Patients were required to be able to take oral apoptosis-related genes is often differentially expressed in a medications and to provide written informed consent. Patients wide variety of malignancies. Although this family of genes with symptomatic or progressive brain metastases, presence of has not been extensively studied in ACC, [12] Preclinical a second malignancy or uncontrolled inter-current illnesses evidence suggested that the loss of apoptosis regulating gene were exclusionary. The protocol was conducted under the aus- bax was associated with adrenocortical cancers compared to pices of the Mayo Phase II Consortium, and approved by the benign adrenal tumors. [13] Hence, modulation of this apo- Institutional Review Boards of all participating institutions. ptotic pathway appeared worthy of pursuit in ACC. In this context, we became interested in R-(−)-gossypol Treatment plan acetic acid (AT-101), the levorotatory enantiomer of gossypol, a natural substance found in cottonseed oil. AT-101 is a BCL2 AT-101 (NSC 726190) was supplied by the National Cancer homology domain 3 (BH3) mimetic that inhibits the Institute Cancer Therapy Evaluation Program as 10 mg tablets. heterodimerization and impairs function of BCL-xL, BCL-2, Patients took two 10-mg tablets (total dose, 20 mg) of AT-101 BCL-w, and myeloid cell leukemia 1 (MCL-1). Its racemic orally, daily 21 out of 28 days. Treatment cycle was continued form has been evaluated in several cancer types including until: 1) the cancer was determined amenable to surgical resec- glioma, ACC, breast, colorectal and lung cancers. [14–16] tion after achieving an objective response to therapy; 2) disease Treatment has been well tolerated in these studies, and partial progression; 3) development of inter-current illness that responses or stable disease were noted. In the initial phase I prevented further treatment administration; 4) occurrence of se- study investigating AT-101 in patients with advanced malig- vere adverse events; 5) self-elected withdraw from the study. nancies, dose limiting toxicities included transaminitis, nau- Patients were monitored for cardiac function including 12-lead sea, and vomiting, with recommended phase II dose of 20 mg ECG and serum troponin level at baseline, and serum troponin daily for 21 days of a 28-day cycle. [16, 17] In a study of 21 level only after the last dose of AT-101 in each cycle of treatment. patients with metastatic adrenal cancer who received oral gos- Upon discontinuation of treatment, patients were followed every sypol after disease progression on chemotherapeutic agents, 3 months for up to 2 years from off-treatment date. In the event three of them had partial responses for over a year, and one of an adverse event at least possibly related to AT-101, the dose attained a minor response to allow surgical resection. [15] of AT-101 was reduced to 10 mg once daily based on predefined AT-101 is 3 to 4 times more potent than its racemic form in criteria for dose modification and treatment delay. Patients who in vitro anti-proliferation assays and animal models of human required additional dose reduction were taken off study. cancer. [18] Despite the limited clinical benefit of AT-101 observed in other cancer types in prostate and small cell lung Study design and statistical analyses cancer, [19, 20] given demonstrated activity of gossypol in ACC, we conducted a phase II study of AT-101 to evaluate A two-stage phase II study design based on the proportion of its clinical activity in patients with advanced ACC. patients who have an objective response to treatment, was used, also assessing toxicity and survival. The primary effica- cy endpoint evaluated in this trial is the objective response rate Patients and methods (ORR), defined as the proportion of patients who achieve a confirmed objective response to treatment, either partial or Patient selection complete (i.e. PR or CR), defined by the RECIST criteria. Based on prior clinical trials of either single or multiple cyto- Eligible adult patients had histologically or cytologically con- toxic agents in advanced ACC, a true ORR of 25% or greater firmed recurrent, metastatic, or primary unresectable ACC with was selected as an indicator that this regimen warrants further measurable disease per the Response Evaluation Criteria in investigation with a null hypothesis being that the true ORR is Solid Tumors (RECIST) criteria [21]andwere≥ 4 weeks from at most 10%. The decision criteria used a Fleming multi-stage completing their last prior therapies. Prior and concomitant use design with 10% Type I error and 90% power. [22] Stage 1: of mitotane and/or ketoconazole were allowed for patients with Enroll 21 patients. If at least 2 of these 21 evaluable patients hormonal excess. No specific prior therapy was required, nor have a confirmed response that started in the first 4 cycles of Invest New Drugs (2019) 37:755–762 757 therapy, accrual would continue. Otherwise, the trial will be Table 1 Patient baseline characteristics terminated. Stage 2: Enroll an additional 19 patients, for a total Total (N =29) of 40 evaluable patients. If at least 7 of these 40 patients are confirmed objective responders, then the treatment regimen Age – would be deemed to warrant further investigation.
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