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.