A phase II study of imatinib with pioglitazone, etoricoxib, dexamethasone, and low-dose treosulfan: Combined anti-inflammatory, immunomodulatory, and angiostatic treatment in patients (pts) with castration-refractory prostate cancer (CRPC).

Abstract

4599 Background: Therapeutic options for pts with CRPC are still limited. Continuous production and release of pro-inflammatory cytokines may account for its resistance towards cytotoxic drugs. Therefore, a phase II study was implemented in pts with CRPC to assess tumor response to combined biomodulatory agents. Primary objective was the PSA-response rate in pts with CRPC. Methods: 69 pts with histologically confirmed CRPC (according to EAU guidelines) were enrolled in 11 German centers. In the 6 months core phase and thereafter, pts were treated continuously with daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone until PSA progression. During the study, PSA-values, ECOG performance status and QoL were continuously assessed. Pts responsive to study medication were allowed to enter the extension phase until disease progression or intolerable toxicity occurred. Results: The core phase of this study was finished in July 2009. Six pts are currently under treatment in the extension phase. At baseline the median PSA value was 45.3 (5 to 3603) ng/ml. The majority of pts had PSA doubling times of 50 to 100 days. Of the 61 evaluable pts, 23 pts (37.7%) were considered as PSA responders with a confirmed PSA decline of at least 50%. During the treatment period PSA decreased from 278.9 (± 784.1) to 8.8 (±11.6) ng/ml in the responders.. Median time to PSA response and to progression as well as overall survival was not achieved. In some pts the therapy led to complete resolution of bone lesions. Of the 38 non-responders, 14 pts showed a stable disease ≥ 6 months. The increase of imatinib doses in case of progressive disease did not result in a further PSA response of the pts. Conclusions: The study evaluated a new multi-targeted approach for pts with CRPC. Although the substances show limited efficacy in single therapeutic use, this multi-targeted approach led to an impressive response rate of 37.7%. Given the good response and the comparatively low and manageable toxicity, this combination treatment might be a good alternative to present treatment regimens.