Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.