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

Authors: Vergote I, Heitz F, Buderath P, Powell M, Sehouli J, Lee CM, Hamilton A, Fiorica J, Moore KN, Teneriello M, Golden L, Zhang W, Pitou C, Bell RL, Campbell R, Farrington DL, Bell-McGuinn K, Wenham RM
Publication: Clinical Trial Gynecol Oncol
Keywords: alanine aminotransferase, carboplatin, gemcitabine, Ralimetinib
Division: PBPK

Abstract

Objective

This 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.

Methods

Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1–10 (q21d) in combination with G (1000 mg/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 mg Q12H or placebo on Days 1–14, q28d.

Results

118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). 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.

Conclusions

Addition of ralimetinib to GC resulted in a modest improvement in PFS.

By Ignace Vergote, Florian Heitz, Paul Buderath, Matthew Powell, Jalid Sehouli, Christine M. Lee, Anne Hamilton, James Fiorica, Kathleen N. Moore, Michael Teneriello, Lisa Golden, Wei Zhang, Celine Pitou, Robert Bell, Robert Campbell, Daphne L. Farrington, Katherine Bell-McGuinn and Robert M. Wenham