A RANDOMIZED PHASE II TRIAL OF THE MATRIX METALLOPROTEINASE INHIBITOR BMS-275291 IN HORMONE-REFRACTORY PROSTATE CANCER PATIENTS WITH BONE METASTASES

Authors: LARA, PRIMO - UCDMC; STADLER, WALTER - UNIV. OF CHICAGO; LONGMATE, JEFF - CITY OF HOPE MED. CNT.; QUINN, DAVID - NORRIS CANCER CNT., CALIF; WEXLER, JASON - UCDMC, CANCER CENTER; Van Loan, Marta; TWARDOWSKI, PRZEMYSLAW - CITY OF HOPE MED. CNT.; GUMERLOCK, PAUL - UCDMC, CANCER CENTER; VOGELZANG, NICHOLAS - UNIV. OF CHICAGO; VOKES, EVERETT - UNIV. OF CHICAGO; LENZ, HEINZ - NORRIS CANCER CNT., CALIF; DOROSHOW, JAMES - CITY OF HOPE MED. CNT.; GANDARA, DAVID - UCD & VETS.ADMIN. NO.CA

Submitted to: Clinical Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/29/2005
Publication Date: 3/1/2006
Citation: Lara, P.N., Stadler, W.M., Longmate, J., Quinn, D.I., Wexler, J., Van Loan, M.D., Twardowski, P., Gumerlock, P.H., Vogelzang, N.J., Vokes, E.E., Lenz, H.J., Doroshow, J.H., Gandara, D.R. 2006. A RANDOMIZED PHASE II TRIAL OF THE MATRIX METALLOPROTEINASE INHIBITOR BMS-275291 IN HORMONE-REFRACTORY PROSTATE CANCER PATIENTS WITH BONE METASTASES. Clinical Cancer Research. 12:1556-1563.

Interpretive Summary: Prostate cancer is a leading cause of cancer-related deaths in men, second only to lung cancer. It is a virulent disease that generally for which no cure exists. As the disease progress cancer cells invade bone tissue this is known as bone metastasis. Bone metastasis is very common in prostate cancer patients and frequently results in bone pain and fracture. Assessment of bone metastasis is traditionally done using imaging techniques. However, these methods are not very specific and can fail to detect areas of bone degradation. Therefore, we explored the use of biochemical markers of bone metabolism as potential prognostic or predictive variables for bone turnover in prostate cancer patients. Specific markers were n-telopeptide (N-TX), deoxypridinoline and pyridinoline, all measures of bone loss. Measures on bone formation were osteocalcin, PINP, and PIIINP. These markers of bone metabolism were measured in a group on men enrolled in a prostate cancer clinical trial all of whom had bone metastases. Data were examined to determine overall survival and progression-free survival (PFS) based on initial bone biomarkers. Patients with n-telopeptide values equal to lower than 14.4 nmol/L had a higher median survival time and a higher rate of PFS at 4 months compared to patients with levels greater than 14.4 nmol/L Similar finds were observed for the other markers of bone loss. Patients with higher levels of bone formation markers, e.g. osteocalcin had better 4-month PFS rates. In other words, lower rates of bone loss and higher rates of bone formation were indicative of longer overall survival and more months of progression-free survival. This study has demonstrated the usefulness of a 1-time assessment of biochemical markers of bone metabolism as prognostic indicator for patients with advanced prostate cancer. These markers may be useful in the stratification of patients into clinical trials with investigational new drugs.

Technical Abstract: Background: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trail of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicitites. Serial serum and urine specimens were collected to assess for markers of bone metabolism. Methods: The primary end point was 4-months progression-free survival (PFS). Eligibility criteria included documentation of androgen-independent disease (including anti-androgen withdrawal), skeletal metastasis, adequate end-organ function and performance status, and no more than one prior chemotherapy regimen. Patients were randomized to 1,200 mg orally once daily (arm A) or 1,200 mg orally twice daily (arm B). Response was assessed every 56 days. Results: Eighty patients were enrolled: 39 in arm A and 41 in arm B. There were no responders by prostate-specific antigen or measurable disease to treatment. Stable disease was noted at 8 weeks in 39% of patients in arm A and in 17% of patients in arm B. Progression of disease at 8 weeks was seen in 61% of patients in arm A versus 83% of patients in arm B. Median survival time was 21.6 months (95% confidence interval, 17.5; not reached), whereas median PFS time was 1.8 months (95% confidence interval, 1.74;2) for all patients. Patients in arm A had a median survival time that was not reached whereas patients on arm B has a median survival time of 21 months (P = 0.2). PFS at 4 months favored arm A: 22% versus 10 % (log-rank, P = 0.008). Grade 3 toxicities occurred in 5 (13%) patients in arm A and in 9 (22%) patients in arm B. Grade 4 toxicities were uncommon (only 4% of patients): one each of thrombosis, fatigue, and motor neuropathy was seen in the arm B. Bone marker studies showed that baseline serum levels of N-telopeptide, osteocalcin, procollagen I NH2-terminal propeptide, and PICP had prognostic significance for PFS and/or overall survival. Conclusions: Regardless of dose schedule, BMS-275291 was well tolerated in HRPC patients and had no dose-limiting arthritis. Toxicities differed modestly according to the dose schedule employed. As overall survival and PFS favored the once daily schedule, this dose schedule is recommended for future studies. Baseline markers of bone metabolism may have prognostic value in HRPC patients with bone metastases.