Gynecologic oncology | 2019
A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer.
Abstract
OBJECTIVE\nThis phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer.\n\n\nMETHODS\nPhase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000\xa0mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300\xa0mg Q12H or placebo on Days 1-14, q28d.\n\n\nRESULTS\n118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N\xa0=\xa058; P+GC, N\xa0=\xa052). The RP2D for R+GC was 200\xa0mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3\xa0mo vs. P+GC, 7.9\xa0mo; hazard ratio [HR]\xa0=\xa00.773, P\xa0=\xa00.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2\xa0mo vs. P+GC, 25.1\xa0mo; HR\xa0=\xa00.827, P\xa0=\xa00.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P\xa0=\xa00.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm.\n\n\nCONCLUSIONS\nAddition of ralimetinib to GC resulted in a modest improvement in PFS.