Elsevier

Gynecologic Oncology

Volume 156, Issue 1, January 2020, Pages 23-31
Gynecologic Oncology

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

https://doi.org/10.1016/j.ygyno.2019.11.006Get rights and content

Highlights

  • This is the first study to combine ralimetinib with gemcitabine and carboplatin.

  • Modest improvement in PFS was seen with ralimetinib combination and maintenance therapy versus standard-of-care.

  • The safety profile of ralimetinib combination therapy was mainly consistent with safety of the chemotherapy backbone alone.

  • Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm.

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.

Introduction

Platinum-based combinations are the most effective regimens for the treatment of platinum-sensitive (platinum-free interval [PFI] of 6 months or longer), recurrent ovarian cancer [1]. With these treatments, progression-free survival (PFS) has remained fairly constant at approximately 8–9 months over the past two decades [2,3]. The majority of patients with advanced ovarian epithelial cancer will experience a recurrence or persistent disease after first-line therapy and will eventually develop resistance to chemotherapy [4,5]. The introduction of molecularly targeted agents, such as the vascular endothelial growth factor (VEGF) inhibitor bevacizumab [6,7] and the poly-ADP ribose polymerase (PARP) inhibitors olaparib [8,9], rucaparib [10], and niraparib [11] has improved PFS in patients with platinum-sensitive disease. However, duration of response remains to be improved and the search for novel candidates for combination and maintenance therapeutic approaches continues [4,12,13].

Ralimetinib (LY2228820) is a selective small-molecule inhibitor of p38α and p38β mitogen-activated protein kinases (MAPK) [14,15]. p38 MAPK regulates cytokine production in the tumor microenvironment and enables cancer cell survival despite physical or chemical challenge [16]. Preclinical studies of ralimetinib have demonstrated antineoplastic activity in xenograft models as a single agent (non-small cell lung, multiple myeloma, breast, glioblastoma, and ovary) and in combination with chemotherapeutic agents such as bortezomib (multiple myeloma), temozolomide (glioblastoma), gemcitabine plus cisplatin (ovary), rapamycin (kidney), sunitinib (kidney), and 1,3-bis(2-chloroethyl)-1-nitrosourea (glioblastoma) [14,17].

A phase 1 study of ralimetinib, either as monotherapy or in combination with tamoxifen, demonstrated an acceptable safety, tolerability, and pharmacokinetic profile in cancer patients [16]. Given the preclinical data in ovarian xenograft studies, the present study was conducted to assess whether ralimetinib could improve the efficacy of carboplatin and gemcitabine when added in combination, followed by maintenance for patients with platinum sensitive recurrent disease.

Section snippets

Study oversight

The study was conducted in compliance with the principles of good clinical practice (GCP) and in accordance with the International Conference on Harmonisation (ICH), with the ethical principles of Helsinki, and approved by the independent ethics committee or institutional review board for each study site. All patients provided written informed consent.

Patient selection and eligibility criteria

Females (≥18 years) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were eligible to enroll. Patients were

Patient demographics and characteristics

Between October 12, 2012 and May 3, 2016, 119 patients were enrolled in the study and 118 received at least one dose of study drug. Of the 118 patients in the safety population, eight patients participated in the dose escalation phase and 110 patients participated in the phase 2 part of the study (Fig. 1). All 118 patients who received at least one dose of the study drug discontinued from the treatment. The most common reason for discontinuing the treatment was progressive disease (85 patients,

Discussion

The addition of ralimetinib to gemcitabine and carboplatin resulted in modest improvement in PFS vs. chemotherapy alone in patients with recurrent, platinum-sensitive ovarian cancer in this study. Secondary endpoints of OS, ORR, and CA125 response were similar between the treatment arms. With the exception of raised ALT/AST laboratory values in the ralimetinib plus gemcitabine and carboplatin arm, most AEs were balanced across the two arms and were consistent with the safety profile of the

Conclusion

The RP2D for ralimetinib in combination with gemcitabine and carboplatin was determined as 200 mg Q12H. Ralimetinib combination treatment resulted in increased PFS which met statistical significance by the trial design but lacks sufficient clinical significance for further development of this combination in a treatment landscape that has evolved. Ralimetinib combination treatment did not significantly improve other survival outcomes over that of standard-of-care. Grade 3/4 elevated ALT was more

Author contributions

Conception and design: IV, CML, RC, DLF.

Provision of study materials or patients: IV, FH, KMN, LG, RMW.

Collection and assembly of data: All authors.

Data analysis and interpretation: IV, WZ, CP, RB, DLF, KBM.

Manuscript writing and final approval: All authors.

Declaration of competing interest

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).

IV – received consulting/advisory board fees for Advaxis, AstraZeneca, Clovis Oncology, Eisai, F. Hoffman-La Roche, Genmab, Immunogen, Millennium Pharmaceuticals, MSD, Oncoinvent, Pharmamar,

Acknowledgments

The authors would like to thank all patients and their caregivers who participated in this study, as well as co-investigators, nurses, study coordinators, and operations staff at each of the clinical sites.

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