Phase II, double-blind, randomized trial of capecitabine plus enzastaurin versus capecitabine plus placebo in patients with metastatic or recurrent breast cancer after prior anthracycline and taxane therapy.

Capecitabine is frequently used in the treatment of recurrent/progressive metastatic breast cancer (MBC) after prior anthracycline and taxane therapy. With the intention of improving the efficacy of single agent capecitabine, we initiated a randomized, double-blind, placebo-controlled Phase II study of the novel serine/threonine kinase inhibitor enzastaurin in combination with capecitabine in a heavily pretreated patient population. Patients received capecitabine 1,250 mg/m(2) twice daily plus enzastaurin 500 mg/day, or capecitabine plus placebo. The capecitabine was administered for the first 14 days of each 21 day cycle. The primary outcome was progression-free survival (PFS) using the log-rank test (1-sided significance level of 0.20). Of 109 patients assessed for eligibility, 85 were enrolled, randomized, and treated (42 and 43 patients in each respective treatment group). The study was terminated early following a preplanned futility analysis. Median PFS (95% CI) was 2.8 (2.1-4.6) months with capecitabine plus enzastaurin versus 4.3 (2.9-6.2) months with capecitabine plus placebo (adjusted hazard ratio: 1.728 [1.00-2.97]; P = 0.048). Median overall survival (95% CI) was lower with capecitabine plus enzastaurin than with capecitabine plus placebo (9.9 [7.0-16.6] months vs 14.9 [9.9-19.3] months, P = 0.181). Grade 3/4 adverse events were more frequent with capecitabine plus enzastaurin (42.9% vs 32.6%). Given the lack of PFS benefit, capecitabine plus enzastaurin is unsuitable as therapy for patients with recurrent/progressive MBC after prior anthracycline and taxane therapy. This trial is registered on www.clinicaltrials.gov (identifier: NCT00437294).

Ipilimumab in Pretreated Patients With Advanced Malignant Melanoma: Results of the South African Expanded-Access Program.

PURPOSE: The primary objective of this study was to evaluate 1- and 2-year survival rates and durable remissions in pretreated patients with advanced (unresectable or metastatic) malignant melanoma treated with ipilimumab in a South African expanded-access program (SA-EAP). PATIENTS AND METHODS: This multicenter, retrospective study obtained data from pretreated patients with advanced malignant melanoma who were eligible for the ipilimumab SA-EAP. Ipilimumab was administered at a dose of 3 mg/kg intravenously every 3 weeks for four cycles to adults with advanced melanoma for whom at least one line of treatment for metastatic disease had failed. Data from the medical records of 108 patients treated within the SA-EAP were collected and statistically analyzed to determine overall (OS) and progression-free survival (PFS) at 1 and 2 years. RESULTS: In the population of 108 patients, a median OS of 8.98 months (95% CI, 7.47 to 10.79 months) was observed. One-year OS was 36% (95% CI, 26% to 45%), and 2-year survival was observed as 20% (95% CI, 12% to 27%). The median survival without progression (ie, PFS) was 3.44 months (95% CI, 2.98 to 4.16 months), and 1- and 2-year PFS were 22% (95% CI, 14% to 29%) and 14% (95% CI, 8% to 21%), respectively. The longest recorded survival was 3.4 years. No independent prognostic variables were identified to predict for OS by multivariate Cox proportional hazards model. CONCLUSION: In this multicenter South African setting, ipilimumab at a dose of 3 mg/kg was an effective treatment with long-term OS in a subset of patients with pretreated advanced malignant melanoma.