Dose escalation and pharmacokinetics study of enzastaurin and sunitinib versus placebo and sunitinib in patients with metastatic renal cell carcinoma.

OBJECTIVE: To assess antiangiogenic effects of enzastaurin in combination with sunitinib in patients with renal cell carcinoma (RCC). METHODS: This was a multicenter, phase 2 study of enzastaurin and sunitinib versus placebo and sunitinib for adult patients with metastatic clear cell RCC. Part 1 was a 6-week, open-label, safety lead-in phase with 2 cohorts (sunitinib, both cohorts: 50 mg/d for 4 weeks; enzastaurin, cohort 1: a loading dose of 500 mg, followed by 250 mg daily; cohort 2: a loading dose of 1125 mg, followed by 500 mg daily). Part 2 was to be a randomized, double-blinded phase, with efficacy as the primary objective. Secondary objectives included the assessment of treatment-emergent adverse events (TEAEs) and pharmacokinetics. RESULTS: Seventeen patients received ≥1 dose of study medication. Six patients (54.5%) in cohort 1 and 2 patients (33.3%) in cohort 2 received ≥6 cycles of treatment. All patients experienced ≥1 TEAE possibly related to study drug. Dose reductions were required as follows: cohort 1--enzastaurin, n=4 (36.4%), sunitinib, n=6 (54.5%); cohort 2--enzastaurin, n=3 (50.0%), sunitinib, n=2 (33.3%). CONCLUSIONS: Whereas the hypothesis that combining sunitinib and enzastaurin may result in greater antiangiogenic effects in RCC is based on solid scientific evidence, part 2 of the study was not activated due to the high number of TEAE-related dose reductions at the expected efficacious dose and overall decision by the sponsor not to pursue further development of enzastaurin for solid tumors.