Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and maximum tolerated dose (MTD) of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase 1 clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range 50‒125mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28 day cycle at 100‒125mg/m2. The modified dose–regimen cohorts received palbociclib 75mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD. Results: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in 3 of 4 PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed (mucositis [n=1], neutropenia [n=2], febrile neutropenia [n=1]). The MTD was palbociclib 100mg for 21 of every 28 days and nab-paclitaxel 125mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n=27), the 12-month survival probability was 50% (95% CI, 29.9%–67.2%). Conclusions: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.

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