Low-dose versus High-dose Carfilzomib with Dexamethasone (S1304) in Patients with Relapsed-Refractory Multiple Myeloma.

PURPOSE: Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits. PATIENTS AND METHODS: We report the Southwest Oncology Group randomized phase II trial (S1304) comparing twice weekly low-dose (27 mg/m2; arm 1) to high-dose carfilzomib (56 mg/m2; arm 2), both with dexamethasone, administered for 12 cycles (11 months) for relapsed and/or refractory multiple myeloma with up to six prior lines of therapy (NCT01903811). The primary endpoint was progression-free survival (PFS), and patients on arm 1 could cross-over to arm 2 after progression on treatment. RESULTS: Among 143 enrolled patients, of whom 121 were eligible and analyzable, the overall response rate was 42.8%, with no significant difference between the arms (P = 0.113). Also, neither the median PFS [5 months and 8 months, respectively; HR, 1.061; 80% Wald confidence interval (CI), 0.821-1.370; P = 0.384] nor the median overall survival were significantly different (26 and 22 months, respectively; HR, 1.149, 80% Wald CI, 0.841-.571; P = 0.284). Sixteen patients crossed over to arm 2 with a median PFS benefit of 3 months. Certain adverse events (AE) were more frequent in arm 2, including fatigue, thrombocytopenia, and peripheral neuropathy, but there was no significant difference in cardiopulmonary AEs. CONCLUSIONS: This randomized trial did not support a benefit of fixed duration, twice weekly 56 mg/m2 dosing of carfilzomib over the 27 mg/m2 dose for the treatment of relapsed and/or refractory multiple myeloma. However, treatment to progression in earlier patient populations with high-dose carfilzomib using different schedules should still be considered as part of the standard of care.

Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder.

PURPOSE: This 2-arm phase II multicenter trial was designed to assess the efficacy and toxicity of neoadjuvant paclitaxel, gemcitabine and carboplatin in patients with invasive bladder cancer. MATERIALS AND METHODS: Patients in arm I had clinical stage T2 with hydronephrosis or T3 bladder cancer. They received 3 cycles of chemotherapy (200 mg/m(2) paclitaxel on day 1, AUC 5 carboplatin on day 1, and 800 mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle). Response was defined as achievement of a pathological complete response (pT0). Patients in arm II with T4 or lymph node positive disease received up to 6 cycles of paclitaxel, carboplatin and gemcitabine. Response was defined as conversion to surgical resectability. RESULTS: In arm I, 31 patients were enrolled and 22 were evaluable for response. Seven patients had pT0 disease (32% of evaluable patients, 22% by intent to treat). In arm II, 37 patients were enrolled and 29 were evaluable for response with 24 suitable for surgical resection (83% of evaluable and 65% by intent to treat). The most common toxicity was neutropenia with 39 events in arm I and 68 in arm II. There were 7 deaths on study (5 during chemotherapy and 2 after cystectomy). CONCLUSIONS: Neoadjuvant paclitaxel, carboplatin and gemcitabine resulted in a significant number of responses in both arms but greater than anticipated toxicity. The pT0 rate was modest and overall efficacy was difficult to assess due to the toxicity. More studies of novel agents and combinations are needed to improve the efficacy and reduce the toxicity of neoadjuvant therapy for bladder cancer.

Phase II evaluation of oral estramustine, oral etoposide, and intravenous paclitaxel in patients with hormone-sensitive prostate adenocarcinoma.

PURPOSE: The primary objective of this study was to assess the feasibility and efficacy of administering etoposide/estramustine/paclitaxel in hormone-sensitive metastatic prostate cancer responding to hormonal therapy. PATIENTS AND METHODS: Eligible patients had metastatic prostate cancer and had received combined androgen blockade for 6-8 months with a > or = 80% decrease in prostate-specific antigen from pretreatment. They received 4 cycles of chemotherapy consisting of estramustine 280 mg orally 3 times daily, etoposide 50 mg/m2 orally on days 1-14, and paclitaxel 135 mg/m2 intravenously for 1 hour on day 2 of each 21-day cycle and were then followed until time to treatment failure (TTF). RESULTS: Twenty-six patients were evaluable for response and toxicity. Median TTF was 21.7 months (range, 11.9-64.5 months; 95% confidence interval, 15.3-26.2 months). Median survival from time of initiation of hormone therapy was 5.1 years. Neutropenia was the most common grade 3/4 toxicity, occurring in 3 patients. Significant toxicities were limited to nausea, diarrhea, and febrile neutropenia in 3 patients, respectively. CONCLUSION: The administration of paclitaxel/estramustine/etoposide in this setting is feasible and well tolerated. Although the TTF of 21.7 months by prostate-specific antigen criteria is similar to historical controls in the emergence of clinically evident androgen-independent disease after starting hormone therapy, direct comparisons cannot be made. More trials are needed to investigate the timing of chemotherapy in patients with prostate cancer.

Dose escalation of oral vinorelbine in combination with estramustine in hormone-refractory adenocarcinoma of the prostate.

BACKGROUND: The primary objective of the current study was to identify the tolerable dose level of oral vinorelbine when given in combination with estramustine to men with hormone-refractory prostate cancer (HRPC). The secondary objectives were to describe the toxicities of the combined regimen in patients with HRPC and to estimate the efficacy of oral vinorelbine in combination with estramustine based on the prostate-specific antigen (PSA) response. METHODS: Thirty-three patients with HRPC were treated on a 28-day cycle with estramustine at a dose of 140 mg orally 3 times a day on Days 1-3 and 8-10. Vinorelbine was given orally on Days 2 and 9. The initial dose of vinorelbine was 50 mg/m2 and was escalated to 70 mg/m2 using the time-to-event continual reassessment method. RESULTS: Three of 17 patients experienced dose-limiting toxicity at the 70 mg/m2 dose level of oral vinorelbine. One patient experienced dose-limiting toxicity at a dose of 60 mg/m2 and no dose-limitig toxicities were reported at the 50 mg/m2 dose. The overall response rate by > or = 50% reduction in PSA was 17.2%, (95% confidence interval, 5.9-35.8%). CONCLUSIONS: Oral vinorelbine at doses of 70 mg/m2 may be safely combined with estramustine. The combination appears to have modest activity in men with advanced prostate cancer. The trial design employed the time-to-event continual reassessment method, which potentially allows for rapid accrual, a more complete assessment of toxicities, and a larger fraction of patients to be treated at an effective dose. More active regimens are needed to further evaluate the utility of this clinical trial design in patients with prostate cancer.

Drug insight: Use of docetaxel in prostate and urothelial cancers.

Taxanes have emerged as a potent class of chemotherapeutic agents in many malignancies, with two taxanes now in clinical use. Their mechanism of action against tumor cells is by alteration of microtubule dynamics, which causes cell-cycle arrest during mitosis. Docetaxel binds to the microtubules with a higher affinity than paclitaxel, and over a broader range of cell-cycle activities. It has also been shown to promote apoptosis via BCL2 phosphorylation. In hormone-refractory prostate cancer, docetaxel has been studied as both a single agent and in combination with estramustine, and in different treatment schedules, with demonstrated efficacy. Two phase III trials have confirmed a survival benefit, making docetaxel the first chemotherapy agent with proven efficacy against prostate cancer. In urothelial cancer, docetaxel has demonstrated activity and has been investigated as a single agent and in combination regimens. A phase III trial comparing docetaxel and cisplatin to methotrexate, vinblastine, doxorubicin, and cisplatin was inferior when evaluating response rates and overall survival. More recent phase II trials combining docetaxel with two additional agents have shown promise, but confirmatory trials are needed.