A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas

Abstract

Purpose Ribociclib (an oral, highly-specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the maximum tolerated dose (MTD), recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas. Experimental Design Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Results Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during Cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia’s corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Conclusion Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are underway in various indications.

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

“…Among 132 evaluable patients, 3 had partial responses (one with head and neck acinar carcinoma and CDK2NA loss, one with PIK3CA-mutant, CCND1-amplified, estrogen receptor-positive breast cancer, and one with BRAF/NRAS wild-type, CCND1-amplified melanoma); 43 (32.6%) patients had SD (17). The most common study drug-related grade 3/4 adverse events in !10% of adult patients at the RP2D of 600 mg/d (3-weeks-on/1-week-off schedule) were neutropenia (28%), leukopenia (19%), and lymphopenia (18%; ref.…”

“…The most common study drug-related grade 3/4 adverse events in !10% of adult patients at the RP2D of 600 mg/d (3-weeks-on/1-week-off schedule) were neutropenia (28%), leukopenia (19%), and lymphopenia (18%; ref. 17). …”

“…Although greater efficacy might be obtained with continuous daily dosing to prevent any potential tumor regrowth during the resting period, continuous dosing of 400 and 600 mg dose levels in adult patients was deemed infeasible due to the high level of hematologic toxicities requiring dose interruptions (17). Therefore, an intermittent schedule was selected in the current study, at doses of !280 mg/m 2 (considered to be therapeutic; equivalent to adult doses of !400 mg).…”

“…An intermittent dosing schedule was chosen on the basis of the expected bone marrow suppression associated with CDK4/6 inhibition which was confirmed in the adult phase I study with ribociclib (17). Ribociclib was administered orally in a fasted state, either as whole capsules or opened and poured onto semisolid food or dissolved in water in case of swallowing difficulties.…”

“…The 350 mg/ m 2 /d dose, which is equivalent to the adult RP2D (600 mg; refs. 17,22), was selected as the RP2D based on the overall safety profile and PK characteristics (discussed below).…”