Phase II/pharmacodynamic trial of PD0332991 in patients with breast, colon, germ cell, and epithelial tumors containing amplification of CCND1.

Abstract

3088 Background: The cell cycle is dysregulated in most patients with epithelial cancers, through activating mutations or overexpression of cell cycle proteins, or loss of cell cycle inhibitors such as p53, p16, etc. A proportion of tumors also have amplification of CCND1, which encodes cyclin D1. In a Phase I trial of the cdk4/6 inhibitor PD0332991 we found prolonged stable disease in patients with several types of epithelial cancer. We now report a phase II trial of PD0332991 in patients with four disease types: breast cancer, Kras-mutant colorectal cancer, resistant germ cell malignancies, and any tumor demonstrated to have amplification of cyclin D1, as assessed by FISH. Methods: Eligible pts were treated with PD0332991 125 mg daily for 21 of 28 days. The primary objective was to determine the progression-free survival in cohorts of 15 patients per tumor type. Secondary objectives include anti-tumor activity, pharmacodynamics (PD) and pharmacokinetics (PK). Results: We screened 79 patients with these characteristics for Rb positivity: 26 had positive staining and were treated. Toxicity was limited to myelosuppression, mainly neutropenia, as had been observed in the phase I study. Of nine patients with colorectal cancer, five had 18F-FLT PET/CT performed before and after about 5 weeks of therapy as a pharmacodynamic marker. Maximum SUV values were computed for tumor (up to five lesions) and lumbar vertebral bodies (sum of five) as a marker of marrow effect. Bone marrow SUV values varied by a factor of three between patients, but intrapatient variability was minimal. Following treatment, marrow SUV values declined by a mean of 21.3% (range +1.7 to -55%). A similar decrease in tumor SUV values was observed (mean 27.5% decrease, range -7.3 to -47.5%), and four of the five patients had a decrease of > 25%. Pharmacokinetic studies are in progress to relate to PD markers of toxicity and activity, and to expand a model derived from Phase I data. Conclusions: PD0332991 is a well-tolerated cell cycle inhibitor with evidence of disease control in patients with various tumor types. Preliminary data in colorectal cancer suggest that FLT PET may provide a pharmacodynamic measure of drug activity.