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 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.

Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696-705. ©2016 AACR.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest: P.O.Witteveen declares no additional competing interests outside the submitted work.

©2016 American Association for Cancer Research.

Figures

Figure 1. Ribociclib pharmacokinetic profile

(A, B) Mean plasma concentration–time profiles at (A) Cycle 1 Day 1 and (B) Cycle 1 Day 18 for the 128 patients who received ribociclib, and were evaluable for pharmacokinetic analysis. Data cut-off: March 28, 2014. (C) Cmax and AUC0–24 of ribociclib after multiple daily oral doses on Cycle 1 Day 18 or 21 across the dose range (50–1,200 mg). Data cut-off: April 24, 2014. The model ln(Cmax or AUC0–24) = α + β ln(dose) was used to assess the dose proportionality of ribociclib. The solid blue line represents the model estimated regression line; black open circles represent individual values; red filled triangles represent the least square mean; and vertical lines represent the 90% confidence interval of least square mean. The time points for collection of blood samples for PK analysis on Cycle 1 Day 1 and Day 18/21 were: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 h post-dose. Abbreviations: AUC0–24, area under the curve from time zero to 24 hours; Cmax, maximal plasma concentration; SD, standard deviation.

Figure 2. Ribociclib pharmacodynamics

(A, B) Mean percentage inhibition of Ki67 in (A) skin and (B) tumor vs. ribociclib dose. Tables provide the minimum and maximum percent change in Ki67 from baseline for each dose group, plus the SD for the mean percent change in Ki67 from baseline. (C) ANC over time (two cycles of ribociclib treatment) in the 600 mg/day ribociclib 3-weeks-on/1-week-off dose group (restricted to patients with a Cycle 1 duration of 28 days or less; n = 31). (D) Absolute neutrophil count by exposure (Ctrough Day 21). (E) Platelet count by exposure (Ctrough Day 21). The relation between the Ctrough and changes in (D) absolute neutrophil count and (E) platelet count were described by the equation: Emax·CtroughCtrough+EC50 Data cut-off: April 24, 2014. Abbreviations: 28d, 28-day continuous dosing schedule; ANC, absolute neutrophil count; C, cycle; Ctrough, trough plasma concentration; D, day; NA, not applicable; SD, standard deviation. a3-weeks-on/1-week-off schedule. bContinuous dosing schedule. cPost-baseline tumor samples collected at Cycle 2 Day 15. dPost-baseline tumor samples collected at Cycle 1 Day 15.

Figure 3. Duration of exposure vs. observed somatic CDKN2A/B and CCND1 alterations

Data cut-off: April 24, 2014. Abbreviations: 28d cont., 28-day continuous dosing schedule; AMP, amplification; CNV, copy number variation; DEL, deletion; HNSCC, head and neck squamous cell carcinoma; INS, insertion; MUT, mutation; NSCLC, non-small cell lung cancer; REA, rearrangement; SEQ, sequence; TRUN, truncation.