Platinum-based chemotherapy is active in several solid tumors including lung, head and neck, colon, bladder, ovarian, and testicular cancers. The traditional platinum agents, cisplatin, carboplatin, and oxaliplatin are all administered intravenously and are associated in varying degrees with neurotoxicity, nephrotoxicity, myelosuppression, and ototoxicity. Satraplatin, an oral platinum, has convenient dosing and in phase 1 testing was not associated with neurotoxicity, nephrotoxicity, or ototoxicity [6
]. For these reasons it is an attractive candidate for clinical applications.
In phase 1 testing, linear pharmacokinetics were noticed with a daily 5-day dosing schedule, repeating every 3–4 weeks [7
]. The primary dose limiting was myelosuppression, although this recovered by day 28. Another phase 1 study used satraplatin in combination with paclitaxel in patients with advanced malignancies [20
]. In that study, satraplatin for 5 days and paclitaxel on day 1 repeated every 21 days was used and, in general, the combination was tolerable with neutropenia being the most frequent side effect. They reported an overall response rate of 21%, stable disease in 24%, and progression disease in 42%.
In the phase III trial, satraplatin and prednisone against refractory cancer (SPARC) trial, men with metastatic castrate resistant prostate cancer who were previously treated with at least 1 chemotherapy regimen, were randomized to either satraplatin 80 mg/m2
days 1–5 of a 35-day cycle plus prednisone vs. prednisone plus placebo [21
]. The primary end points were progression-free survival and overall survival. The trial did not demonstrate a survival benefit for the population receiving satraplatin compared with placebo (median overall survival 61.3 weeks for satraplatin vs. 61.4 weeks for placebo, HR = 0.98). As a result, satraplatin was not approved for second-line use in metastatic CRPC.
However, the SPARC trial did demonstrate an improvement in a composite progression-free survival end point (11.1 weeks for satraplatin vs. 9.7 weeks for placebo, P < 0.001), an increased time to progression, a reduction in pain response, and an improvement in PSA response. Since the trial was initiated in 2003 before docetaxel became the standard first line option for metastatic CRPC, only half (51%) of the patients received prior docetaxel therapy. A prespecified analysis of docetaxel-pretreated patients demonstrated improved median overall survival with satraplatin compared with placebo (66.1 weeks vs. 62.9 weeks, P = 0.039).
The current trial builds on this experience by combining satraplatin with docetaxel in patients with advanced malignancies with an expansion cohort of chemotherapy naïve metastatic castrate resistant prostate cancer patients. After completion of the phase 1 portion, we then proceeded to define the recommended phase 2 dose in combination with prednisone in patients with metastatic CRPC.
Overall, the combination of satraplatin and docetaxel was well tolerated. Ten (35%) of the patients required dosage modifications due to toxicity; 24% of cycles were delayed, but the most common reason was scheduling related (43%). Similar to other trials using satraplatin, the most common toxicity was hematologic; 86% of the patients experienced grade 1–4 neutropenia and leukopenia, while 52% experienced grade 1–4 anemia. For the phase 1 portion of the trial, 4 disease-limiting toxicities were noted and all them were related to grade 3/4 neutropenia. The most common non-hematologic toxicities were nausea, vomiting, fatigue, and alopecia. There were no reported grade 4 non-hematologic toxicities in any of the cycles, and grade 3 non-hematologic toxicity was uncommon. The recommended phase 2 dose was docetaxel 60 mg/m2 i.v. day 1 with satraplatin 40 mg/m2 PO days 1–5, without G-CSF support, repeated in 3-week cycles. With G-CSF support, the recommended phase II dose was docetaxel 70 mg/m2 i.v. day 1 with satraplatin 50 mg/m2 PO days 1–5 repeated in 3-week cycles. For patients with metastatic CRPC, the recommended phase 2 dose of docetaxel 75mg/m2 i.v. day 1 with satraplatin 50 mg/m2/day PO days 1–5, with G-CSF and prednisone 10 mg daily, repeated in 3-week cycles appeared safe with no DLTs noted.
The overall response rate (complete response and partial response) for this study was 16% (95% CI: 6%–35%). Fifty-two percent of the patients achieved stable disease. The PSA response in the phase 1b, as defined by ≥50% decline in PSA, was 50%.
While satraplatin alone failed to extend the median overall survival in the SPARC trial, the results of this study establish that the combination of satraplatin and docetaxel was well tolerated and safe. Based on this preliminary data, the combination appeared active and, therefore, may warrant further evaluation in selected patient populations. If future studies utilize this combination, we recommend the routine use of GCSF to minimize hematologic toxicity.