TY - JOUR
T1 - 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
AU - Vergote, Ignace
AU - Heitz, Florian
AU - Buderath, Paul
AU - Powell, Matthew
AU - Sehouli, Jalid
AU - Lee, Christine M.
AU - Hamilton, Anne
AU - Fiorica, James
AU - Moore, Kathleen N.
AU - Teneriello, Michael
AU - Golden, Lisa
AU - Zhang, Wei
AU - Pitou, Celine
AU - Bell, Robert
AU - Campbell, Robert
AU - Farrington, Daphne L.
AU - Bell-McGuinn, Katherine
AU - Wenham, Robert M.
N1 - Funding Information:
This study was sponsored by Eli Lilly and Company . Medical writing assistance was provided by Samantha Forster of ProScribe, part of the Envision Pharma Group, and was funded by Eli Lilly and Company . Envision Pharma’s services complied with international guidelines for Good Publication Practice (GPP3).
Funding Information:
KNM – reports research grants from Eli Lilly and Company, PTC Therapeutics, and Merck, personal fees from advisory boards and/or nonpromotional speaking for Aravive, AstraZeneca, Clovis, Eisai, Genentech/Roche, Immunogen, Merck, OncoMed, Samumed, and Tesaro.
Funding Information:
This study was sponsored by Eli Lilly and Company. Medical writing assistance was provided by Samantha Forster of ProScribe, part of the Envision Pharma Group, and was funded by Eli Lilly and Company. Envision Pharma's services complied with international guidelines for Good Publication Practice (GPP3).JS – received honoraria from AstraZeneca, Clovis Oncology, Eisai, Johnson & Johnson, MSD Oncology, Olympus, Pfizer, Pharmamar, Tesaro, and Teva, consultancy/advisory fees from AstraZeneca, Clovis Oncology, Eli Lilly and Company, MSD Oncology, Pfizer, Pharmamar, Roche, and Tesaro, travel/accommodation expenses from AstraZeneca, Clovis Oncology, MSD Oncology, Pfizer, Pharmamar, Roche, and Tesaro, and research funding via his institution from AstraZeneca, Bayer, Clovis Oncology, Merck, MSD Oncology, Pfizer, Pharmamar, and Tesaro.AH – received research funding via her institution from Abbvie, Amgen, Eli Lilly and Company, GlaxoSmithKline, and Janssen.RMW – owns stock in Ovation Diagnostics, has received honoraria from Tesaro, consulting/advisory fees from Clovis Oncology, Genentech, Merck, Mersana, and Tesaro, is on the speakers bureau of Clovis Oncology, Genentech, and Tesaro, has received travel/accommodation expenses from TapImmune, and has received research funding via his institution from Merck and Prescient Therapeutics.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
KW - Clinical trial
KW - Ovarian cancer
KW - Small-molecule inhibitor
KW - p38 mitogen-activated protein kinase
UR - http://www.scopus.com/inward/record.url?scp=85077850781&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2019.11.006
DO - 10.1016/j.ygyno.2019.11.006
M3 - Article
C2 - 31791552
AN - SCOPUS:85077850781
VL - 156
SP - 23
EP - 31
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 1
ER -