Background: LEE011, an orally bioavailable, highly specific CDK4/6 inhibitor, causes cell cycle arrest and tumor growth inhibition in multiple preclinical models with intact retinoblastoma protein (pRb+). Methods: Pts withpRb+ advanced solid tumors and lymphomas were treated with escalating doses of LEE011 on a 21-of-28-d or continuous schedule. Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Primary objective: to establish the MTD and/or RP2D of LEE011. Secondary objectives: safety, efficacy, PK, and PD. Results: As of Jan 17, 2014, 132 pts were treated; 85 during escalation (50–1200 mg/d) and 47 during RP2D expansion. The following results are from dose escalation (data cut-off: July 2, 2013). Ten DLTs were observed in 10 pts: neutropenia (3 pts); asymptomatic thrombocytopenia (2 pts); mucositis, pulmonary embolism, hyponatremia, QTcF prolongation (>500 ms), and increased creatinine (1 pt each). The MTD and RP2D were declared as 900 and 600 mg/d on 21-of-28-d schedules, respectively. The most common study drug-related AEs (all grades) were neutropenia (40%), leukopenia (36%), nausea (35%), and fatigue (27%). G3/4 AEs included neutropenia (19%), lymphopenia (14%), and leukopenia (12%). Asymptomatic QTcF prolongation (>450 ms) was seen at doses ≥600 mg/d: in 10% of pts at 600 mg/d and in 27% of pts at doses >600 mg/d. Plasma exposure increases were slightly higher than dose proportional; mean T_1/2 at RP2D was 36.2 h. Paired skin biopsies from 40 pts showed reductions of ≥50% from baseline in Ki67 and phospho-pRb in 55% and 42% of samples, respectively. Among 70 evaluable pts, 2 (2.9%; 600 mg/d) had confirmed PRs: 1 pt with PIK3CA-mut, CCND1-amp, ER+ breast cancer; 1 pt with BRAF/NRAS-WT, CCND1-amp melanoma. SD for ≥4 and ≥6 cycles was seen in 26% and 14% of pts, respectively. Conclusions: LEE011 showed an acceptable safety profile, dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. The study expansion is confirming safety and efficacy. Further studies are investigating LEE011 as a single agent (neuroblastoma and malignant rhabdoid tumors) and in combination with other agents (breast cancer and melanoma). Clinical trial information: NCT01237236.