This was a first-in-man phase I, dose-escalation study of BMS-641988 in castration-resistant prostate cancer (CRPC). The US study (CA185-002) was conducted at: Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA; University of Wisconsin, Madison, Wisconsin, USA; and Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA. Seventy-seven patients were enrolled in the US, and 54 were treated from February 6, 2006, through March 31, 2009. The companion study, CA185-005, was conducted across multiple institutions in Japan and enrolled a total of eight patients, with seven receiving treatment. The study was approved by the institutional review board at each site. All patients signed an institutional review board–approved written informed consent before the conduct of any study procedures and after a full explanation of the study.
Eligible patients had histologically confirmed prostate cancer and progressive castration-resistant disease, defined by the combination of castrate levels of testosterone (<50 ng/mL) and a rising prostate-specific antigen (PSA) level, with or without detectable metastases. The criteria for rising PSA required a minimum of 3 measurements obtained more than 1 week apart, with the last value >5 ng/mL (5
The pre-study evaluation included a history and physical examination, complete blood and platelet count, chemistry panel, PSA level, and electrocardiogram (ECG). Imaging for metastatic disease included a radionuclide bone scan and either computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, chest, abdomen, and pelvis. Patients with a history of significant cardiac disease or a seizure disorder were excluded.
BMS-641988 was administered orally under fasting conditions. The starting dose in the US study was 5 mg per day, and subsequent dosages were 10, 20, 40, 60, 100, and 150 mg per day. In the companion Japanese study, the starting dose was 20 mg. Beginning with the 40 mg cohort, the first two patients of each group in the US were randomized in a 1:1 ratio and in a double-blinded fashion to receive a single dose of BMS-641988 or placebo on Cycle 1, Day 1 (Cycles defined as 28 days), to evaluate single-dose PK and the QTc interval. Assuming acceptable safety results, both patients subsequently received BMS-641988 continuously on a daily schedule starting on Cycle 1, Day 8, and four additional patients were enrolled at the same dosage. These additional patients were not randomized but had single-dose PK sampling and a 7-day washout before continuous daily dosing. All patients were observed for 28 days to insure safety before the next higher dose level was opened for enrollment. At least 3 to 6 patients were treated at each dose level, provided no DLTs occurred; and for the purposes of acquiring additional safety and efficacy data, an additional number of participants could have been enrolled at any dose level that had no DLT.
Patients were examined and assessed for adverse events at a minimum of monthly intervals, and toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 3.0). Routine clinical and laboratory assessments were conducted weekly during the first 8 weeks of treatment and every 2 weeks in subsequent cycles. Twelve-lead ECGs were obtained in triplicate on Day 1 of each cycle and more frequently in patients who were randomized to receive a single Day 1 dose followed by continuous dosing 7 days later. The ECGs were analyzed by a central laboratory and evaluated for changes in QTcF and QTcB from baseline. PSA measurements were performed every cycle or more frequently if indicated. Bone scans and CT and/or MRI were repeated at 3-month intervals.
Due to the preclinical toxicity studies, all investigators and research participants were counseled about the potential risk of seizures, and neurological monitoring with examinations and active precautions, including driving restrictions, were implemented prophylactically.
Blood samples starting from Cycle 1, Day 1 were collected over a 144-hour period for PK assessment. Blood samples for PK evaluation were also collected over 24 hours on Cycle 1, Day 15 and Cycle 2, Day 8. Trough plasma drug concentrations were measured before dosing on Day 1 of every cycle beginning with Cycle 3. Plasma samples from all patients were assayed for BMS-641988, BMS-501949, and BMS-570511 concentrations using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay.
The plasma concentration-time data for BMS-641988, BMS-501949, and BMS-570511 were analyzed by the non-compartmental method using Kinetica Version 4.4.1 (Thermo Electron Corporation, Philadelphia, Pennsylvania, USA). The PK parameters assessed included maximum observed concentration (Cmax), time of maximum observed concentration (Tmax), area under the plasma concentration-time curve during a dosing interval (AUCTAU), and terminal phase half-life (T1/2).
The Cmax and Tmax were obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration time curve was identified by least-square linear regression of at least three data points that yielded a maximum G-criterion, which is also referred to as adjusted R2. The T1/2 was calculated as Ln 2/Kel, where Kel was the absolute value of the slope of the terminal log-linear phase. The AUCTAU was calculated using the mixed log-linear trapezoidal algorithm in Kinetica.
Since BMS-570511 is rapidly converted to BMS-501949 in all animal species tested, no preclinical assessment of its toxicity could be made before using in humans. As a result, 1/10 of the No Observable Adverse Effect Level (NOAEL) for BMS-501949 corresponding to an AUC0–24 of 101.0 µM*hr was used as a threshold guide for dose escalations, along with projected exposures of parent and all active metabolites before the decision to escalate to the next dose level.
Anti-tumor effects were assessed using the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (6
). Specifically, PSA changes were reported using waterfall plots, and osseous disease on radionuclide bone scan was recorded as improved, progressed, or no change. Soft-tissue disease was evaluated based on CT imaging by modified Response Evaluation Criteria in Solid Tumors (RECIST) (7
). Every effort was made to keep patients on BMS-641988 therapy until the time of radiological progression.