BACKGROUND New therapeutic combinations to improve outcomes of patients with ovarian cancer are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer.METHODS This phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib, followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS).RESULTS Thirty-five patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab. The MTD was 400 mg. The most common adverse events included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). The overall RR was 79.3%, with a stable disease rate of 18%, resulting in a clinical benefit rate of 96.6%. Median PFS was 11.4 months. RR and PFS did not differ based on the number of lines of prior chemotherapy or prior maintenance therapy.CONCLUSION This work demonstrates that the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease.TRIAL REGISTRATION ClinicalTrials.gov NCT03056833.FUNDING This investigator-initiated trial was supported by Novartis, which provided drugs and funds for trial execution.
Lan G. Coffman, Taylor J. Orellana, Tianshi Liu, Leonard G. Frisbie, Daniel Normolle, Kent Griffith, Shitanshu Uppal, Karen McLean, Jessica Berger, Michelle Boisen, Madeleine Courtney-Brooks, Robert P. Edwards, Jamie Lesnock, Haider Mahdi, Alexander Olawaiye, Paniti Sukumvanich, Sarah E. Taylor, Ronald Buckanovich
Time-to-event continual reassessment method study schema.