Abstract A276: Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas.
Authors: Infante Jeffrey R. , Shapiro Geoffrey I. , Witteveen Petronella O. , Gerecitano John F. , Ribrag Vincent , Chugh Rashmi , Chakraborty Abhijit , Matano Alessandro , Zhao Xumei , Parasuraman Sudha , Cassier Philippe A. 
Published: August 2014

Abstract
Background: LEE011 is an oral small molecule inhibitor with highly specific nanomolar inhibitory activity against CDK4/cyclinD1 and CDK6/cylinD3 complexes. Preclinical studies with LEE011 have demonstrated robust anti-tumor activity in several tumor models with functional retinoblastoma protein (pRb).
Methods: The primary objective this phase 1 dose escalation study was to determine the maximum tolerated dose (MTD) based on cycle 1 dose-limiting toxicities (DLTs) and establish the recommended dose for expansion (RDE) of LEE011 in patients (pts) with pRb-positive advanced solid tumors or lymphomas. Using a Bayesian logistic regression model with overdose control principle, escalating doses of LEE011 were administered daily for 21 days of 28-day cycles. Following MTD determination, a continuous dosing schedule was also evaluated. Evaluation of safety and pharmacokinetics (PK) from all pts contributed to defining the RDE.
Results: As of June 28, 2013, a total of 70 pts were treated in the escalation phase at doses from 50-1200 mg. DLTs are described in the table. MTD was defined at 900 mg on a 21 of 28-day dosing schedule. Additional patients were treated at 750 mg and 600 mg on the current schedule and at 600 mg on a continuous schedule to define the RDE and sustain optimal long-term dosing. Following review of PK and safety data, including AEs observed beyond cycle 1, the planned RDE is 600 mg for 21 days of a 28-day treatment cycle. Common adverse events (AEs) were gastrointestinal (nausea 40%, diarrhea 30%) and hematologic (anemia 43%, neutropenia 40%); the majority of AEs were grades 1/2 and reversible. Asymptomatic QTc prolongation was observed at the higher doses. LEE011 is absorbed orally with Tmax ≈ 4 hours and effective t1/2 ≈24 hours. Dose-dependent increases in exposure were observed. Preliminary evidence of activity was observed including stable disease for ≥ 6 cycles in 10/70 pts (14%) and 1 confirmed partial response in a pt with ER-positive breast cancer. Preliminary tumor pharmacodynamic data shows evidence of modulation at doses of 600 mg and above.
Conclusions: LEE011, a highly selective inhibitor of CDK4/6, exhibited an acceptable safety profile, dose dependent PK, and preliminary clinical activity. Enrollment will continue in the expansion phase.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A276.
Citation Format: Jeffrey R. Infante, Geoffrey I. Shapiro, Petronella O. Witteveen, John F. Gerecitano, Vincent Ribrag, Rashmi Chugh, Abhijit Chakraborty, Alessandro Matano, Xumei Zhao, Sudha Parasuraman, Philippe A. Cassier. Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A276.