Background: Palbociclib (Palb) is an oral CDK 4/6 inhibitor that is under development in breast cancer as a single agent and in combination with endocrine therapy. Preclinical studies suggest that Palb synergizes with paclitaxel (Pac) when given on an alternating schedule. We conducted a Phase I trial investigating the combination of weekly Pac and alternating Palb to synchronize the cell cycle in the tumors of patients (pts) with metastatic breast cancer. Methods: Pts with tumors expressing Rb protein, adequate organ function, and ≤3 prior cytotoxic metastatic regimens were eligible. Prior taxane was allowed. Palb was dose-escalated in a standard 3+3 design and taken on days 2-6, 9-14, 16-20 of each 28 day cycle. Pts received Pac 80mg/m2 weekly for 3 cycles; thereafter, Pac was administered on days 1, 8 and 15. After 6 cycles of therapy, pts had the option to drop the Pac and continue on Palb alone. Toxicity was assessed weekly and response was assessed every 2 cycles using RECIST 1.0. Results: The table below shows Palb dose level, enrollment, dose limiting toxicities (DLT), number of patients with Grade 3/4 neutropenia (NTP) and response (partial response (PR), stable disease (SD) or progressive disease (PD)). 8 patients had previously received a taxane. The only DLT was grade 3 AST and ALT (LFT). Among 11 pts with PR or SD, 8 pts continued on therapy >6 months and 4 >12 months. 11 pts are off study; 10 for PD, and one for toxicity (NTP in cycle 17) and 3 remain on study. Median time on treatment is 8 cycles. Conclusions: Combination Pac and Palb is safe and well tolerated. Prolonged tumor responses were seen. However, because uncomplicated grade 3/4 NTP was common and frequently led to dose reduction or dose interruption with 5-day Palb dosing, an additional Phase 1 expansion to examine Palb 100mg on a 3-day schedule (days 2-4, 9-11 and 16-18) is underway. Clinical trial information: NCT01320592.