Phase I trial of ribociclib (LEE-011) with platinum-based chemotherapy in recurrent platinum sensitive ovarian cancer

Objectives: Platinum-based chemotherapies have been and remain the core of ovarian cancer treatment. Preventing platinum resistance and extending the progression-free interval after platinum therapy is a major challenge in the treatment of ovarian cancer. Preclinical studies with ribociclib, a CDK4/6 cell cycle checkpoint inhibitor, demonstrated that ribociclib synergizes with platinum chemotherapy to increase cancer cell death and could be used as maintenance therapy to increase duration of response. Here we tested the safety and efficacy of ribociclib in patients with platinum-sensitive ovarian cancer. The primary endpoint was to determine the maximum tolerated dose (MTD) of ribociclib (LEE-011) when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS). Download : Download high-res image (83KB) Download : Download full-size image Methods: This study was a phase 1, open-label, single institution dose-escalation trial of ribociclib with platinum-based chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients must have had at least 1 prior platinum-based chemotherapy regimen. Ribociclib was given on days 1-4, 8-11, and 15-18. Ribociclib dosing levels were (1) 200mg, (2) 400mg, and (3) 600mg, and dose levels were assigned based on a time-to-event continual reassessment method (TITE-CRM) starting at dose level 1. Weekly carboplatin (AUC2) and paclitaxel (60 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle for a planned 6 total cycles. Patients with at least a partial response to therapy received maintenance ribociclib 600mg daily until time of progression. Results: A total of 35 patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% had received prior maintenance therapy (11 PARPi (31%), 12 bevacizumab (34.3%), and 5 both (14.3%)). The MTD was 400mg. No patients in the 200mg group and 11 patients (33.3%) in the 400mg group experienced DLTs. Grade 3/4 adverse events (AEs) were more common during concurrent therapy (n=35 events) than during maintenance (n=9 events). The most common AEs included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), nausea (77.1%), hypertension (62.9%), and thrombocytopenia (40.0%). Overall RR was 79.3% (n=23) and PFS was 11.4 months. RR was similar among patients with and without prior maintenance therapy (82% PARPi vs 78% without, 83% bevacizumab vs 78% without), and among patients with 1 prior line of chemotherapy vs > 1 prior line (83% vs 76%). On exploratory analysis, PFS was not significantly different between patients with and without prior maintenance therapy (10.1 vs 14.4 months, p=0.07). Conclusions: This trial demonstrated safe use of ribociclib (LEE-011), both concurrently with platinum and taxane chemotherapy and as maintenance therapy. Ribociclib 400mg concurrent with chemotherapy was the MTD. RR (79.3%) and PFS (11.4 months) were encouraging, particularly given the high rates of prior maintenance therapy. These results support further investigation of the role of ribociclib in ovarian cancer treatment.