A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is deregulated in castration-resistant prostate cancer (CRPC). We investigated the efficacy and toxicity of temsirolimus, an mTOR inhibitor, in chemotherapy-naïve CRPC. METHODS: In this phase II open label study, eligible patients received IV temsirolimus at 25 mg weekly until objective disease progression, unacceptable toxicity or investigator's discretion. Toxicity was assessed every 4 weeks and responses every 8 weeks. Primary end point was calculating the overall response (OR) rate as well as measuring stable disease (SD) to assess the overall clinical benefit calculated as OR+SD. Secondary end points included prostatic-specific antigen (PSA) changes and time to progression biochemically and radiographically. Correlative studies included prospective assessment of quality of life (QoL) using two previously validated scales. RESULTS: Although the sponsor halted the study early, 21 patients were enrolled of which, 15 were evaluable for efficacy and OR. Median age was 74 (range: 57-89), median PSA was 237.5 ng ml(-1) (range: 8.2-2360), visceral disease present in 11 patients (52%), and 17 patients (81%) patients had Gleason score (7-10). Two patients had a partial response (PR) and eight had SD. The OR was 13% (2/15) and the overall clinical benefit (OR+SD) was 67% (10/15). Median time to radiographic disease progression was 2 months (range 2-10 months). Biochemical response assessment was available for 14/15 patients. Any PSA decline was observed in four patients (28.5%; 4/14) with one patient (7%) having >50% PSA decline. Median time to progression by PSA was 2 months (range 1-10 months). With a median follow-up of 32 months, median overall survival (OS) was 13 months (range: 2-37) and three patients remain alive at the data cutoff (5/2013) for an OS of 14% at 4 years on an intent-to-treat analysis. Major non-haematologic toxicities included fatigue (19%) and pneumonia (14%). Main laboratory toxicities included hyperglycaemia (24%) and hypophosphatemia (14%). Also, 52% of enrolled patients had serious adverse events. Other toxicities were consistent with previously reported adverse events with temsirolimus. Despite these observed adverse events, temsirolimus did not adversely impact QoL. CONCLUSION: Temsirolimus monotherapy has minimal activity in chemotherapy-naïve CRPC.

Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer.

BACKGROUND: Determining the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of sorafenib (S) plus imatinib (IM) in castration-resistant prostate cancer (CRPC) patients. METHODS: Refractory CRPC patients were enrolled onto this 3+3 dose escalation designed study. Imatinib pharmacokinetics (PK) were determined on day 15, 4 h post dose with a validated LC-MS assay. RESULTS: Seventeen patients were enrolled; 10 evaluable (6 at 400 mg S qd with 300 mg IM qd (DL0) and 4 at 400 mg S bid with 300 mg IM qd (DL1)); inevaluable patients received <1 cycle. The median age was 73 (57-89); median prostatic serum antigen was 284 ng ml(-1) (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12). Dose-limiting toxicities were diarrhoea and hand-foot syndrome. Maximum tolerated dose was 400 mg S and 300 mg IM both daily. No biochemical responses were observed. Two patients had stable disease by RECIST. Median time to progression was 2 months (1-5). Median OS was 6 months (1-30+) with 3/17 patients (17%) alive at 21 months median follow-up. Ten patients had PK data suggesting that S reduced IM clearance by 55%, resulting in 77% increased exposure (P=0.005; compared with historical data). CONCLUSION: This is the first report showing that S+IM can be administered in CRPC at a dose of 400 mg S and 300 mg IM, daily.

Docetaxel and oxaliplatin as first-line therapy for advanced non-small cell lung cancer: a phase II trial.

We sought to evaluate the safety and efficacy of docetaxel and oxaliplatin combination as first-line therapy for patients with stage IV or wet III(B )non small cell lung cancer. Patients received oxaliplatin at 85 mg/m(2) intravenously over 2 hours on days 1 and 15 along with docetaxel at 30 mg/m(2) intravenously on days 1 and 8; both given every 28 days. Cycles were repeated every 4 weeks for a maximum of 6. Fifteen patients were enrolled for an overall response rate of 50% (95% CI 21-74%). Median progression-free survival was 2.4 months with a 1-year progression free survival of 10%. Median overall survival was 7.9 months with 49% of patients alive at 1 year. Most common toxicities were nausea, vomiting, and dehydration. This combination has notable activity in advanced non-small cell lung cancer with a favorable toxicity profile.