Patients had to have histologically proven adenocarcinoma of the prostate. A serum testosterone level ≤ 50 ng/mL was required and patients were required to be maintained on androgen-deprivation therapy with a leuteinizing hormone-releasing (LHRH) agonist or antagonist, unless they had a prior bilateral orchiectomy. Patients were considered eligible if they had progressive CRPC documented by two consecutive PSA increases over a reference value. All PSA values used for eligibility determination must be taken at least 1 week apart, with the last value being ≥ 5 ng/mL. Progressive disease after 4 weeks of flutamide, megestrol, or ketoconazole (6 weeks for bicalutamide or nilutamide) withdrawal was required to exclude an antiandrogen withdrawal response. Radiotherapy and/or samarium must have been completed at least 4 weeks (12 weeks for prior strontium) prior to registration. Bisphosphonate use was allowed in patients with known bone metastasis if initiated prior to registration; however, bisphosphonate therapy was not allowed to be initiated during study treatment. Other inclusion criteria included: Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, adequate hematologic function (absolute neutrophil count ≥ 1,500/μl, hemoglobin ≥ 9 gm/dl, platelet count ≥ 100,000/μ1), liver function (albumin ≥ 2.5 gm/dL, total bilirubin ≥ 1.5 × upper limit of normal, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × upper limit of normal), renal function (serum creatinine ≤ 2.0 mg/dL), and a life-expectancy of ≥ 3 months. No prior cytotoxic chemotherapy was permitted. No concurrent systemic steroids or concurrent therapy for prostate cancer (e.g. immunologic, biologic, investigational, etc) was allowed. All patients gave written informed consent in compliance with state, federal, and institutional guidelines.
The Phase I dose-escalation portion of this study was designed to enroll cohorts of three to six patients, to determine the maximum tolerated dose (MTD) of single-agent AT-101. The MTD was defined as one dose level below that at which 33% of the patients within a cohort experienced a dose-limiting toxicity (DLT). DLTs were defined as any toxicity felt at least possibly related to AT-101, and met the following criteria (using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.022
): grade ≥ 3 non-hematological toxicity (excluding nausea, vomiting or diarrhea unless uncontrolled by maximal antiemetic and/or antidiarrheal therapy), any elevation in serum troponin (outside of the institutional normal range), or any grade ≥ 3 granulocytopenia/thrombocytopenia lasting ≥ 7 days, or any grade thrombocytopenia if associated with bleeding.
At the recommended Phase 2 dose (RP2D), an additional 21 patients were planned to assess preliminary evidence of efficacy with the primary objective being PSA response, as defined by the PSA Working Group Criteria 123
. Secondary objectives included determination of the rate, quality (depth), duration, and time to response, as well as objective tumor responses in patients with measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST)24
AT-101 was supplied as a 10 mg immediate release solid dosage tablet. AT-101 was administered orally, once daily starting at 30 mg, on a daily basis for 21 days of a 28 day cycle, and was taken at the same time each day on an empty stomach (at least one hour before or after a meal). Each patient continued at their assigned dose unless a dose-adjustment was made for safety or toxicity. No intra-patient dose-escalation was permitted. Patients continued treatment until they experienced progressive disease, unacceptable toxicity, or required alternative therapies. Compliance was monitored by counting unused medications during each visit.
Baseline and Treatment Assessments
At study entry, all patients underwent a complete history and physical exam, including a complete blood count, serum chemistries, and disease assessment (bone scan, computed tomography imaging, and PSA). Baseline electrocardiogram (ECG), serum testosterone and troponin level, and urine analysis were obtained as well.
Weekly laboratory assessments including a complete blood count (CBC), serum chemistries (sodium, potassium, chloride, calcium, glucose, BUN, creatinine, and phosphate), and liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin, total protein, and gamma glutamyl transferase) were obtained during the first four weeks of drug administration. Thereafter, physical examinations, complete blood counts, serum chemistries, serum troponin level, ECG, and PSA levels were evaluated every 4 weeks while the patient was on study. Radiographic disease assessments for soft tissue disease were repeated every 8 weeks and bone scans were repeated every 24 weeks, sooner if clinically indicated.
Post-study evaluations were conducted 30 days after the last dose and included a PSA and review of systems.
Toxicity and Dose Modifications
Patients with clinically significant grade 2-3 toxicity had their treatment held (up to 14 days) until the toxicity resolved to grade ≤ 1. Treatment was then restarted at the next lower dose level (20 or 10 mg). Grade 4, or recurrent clinically significant grade 2-3, toxicity required discontinuation of treatment. An elevation of serum troponin levels required discontinuation of therapy.
Although all patients were included in the safety and toxicity analysis, only patients completing at least 8 weeks of AT-101 were considered evaluable (protocol-defined) for the treatment outcome assessment (disease progression prior to week 8 of treatment was counted as a treatment failure). The primary indicator of drug activity was the PSA response rate, defined as a ≥ 50% decrease in PSA from baseline, confirmed by a repeat value 4 weeks later (PSA Working Group Criteria 1). Patients may not have any evidence for clinical or radiographical progression during that time period. PSA progression was defined as a ≥ 25% increase from nadir, confirmed by a second value, with an absolute increase in PSA of at least 5 ng/mL. The radiologic response rate assessment used RECIST, and defined a complete response (CR) as the disappearance of all known disease during two observations at least 4 weeks apart, during which no new lesions develop. For patients with bone only disease, normalization of the bone scan was required. A partial response (PR) was defined as ≥ 30% decrease in sum of the greatest perpendicular tumor diameters of all measurable disease documented for ≥ 4 weeks. No new lesions or increased size of any existing lesion was allowed. Progressive disease included any unequivocal increase ≥ 20% in the size of any existing lesion, or the appearance of any new lesion. Stable disease (SD) was any other condition not met by the criteria outlined in CR, PR, or progression.
The statistical analyses used SAS Version 8 or higher, and continuous variables were summarized with sample size, mean, standard deviation, median, and range values. Time-to-event parameters were summarized using Kaplan-Meier methods. The Phase II portion of the study used PSA response as the primary indicator of efficacy. Sample size was determined assuming that with a null hypothesis of 0.05, that the binomial probability of observing 4 or more responses is 0.019. With a response rate of 25% being of interest, 21 patients were required to achieve an estimate of power to detect 4 or more responses of 0.808. Days to response, duration of response, and time to progression were calculated from the start of therapy. Pretreatment rate of PSA progression was calculated using PSA values prior to, and including, day 1 of AT-101 treatment.