A preclinical and phase Ib study of palbociclib plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas

Hidalgo, Manuel, Garcia-Carbonero, Rocio, Lim, Kian-Huat, Messersmith, Wells A., Garrido-Laguna, Ignacio, Borazanci, Erkut, Lowy, Andrew M., Medina Rodriguez, Laura, Laheru, Daniel, Salvador-Barbero, Beatriz, Malumbres, Marcos, Shields, David J., Grossman, Joseph E., Huang, Xin, Tammaro, Meggan, Martini, Jean-François, Yu, Yanke, Kern, Kenneth and Macarulla, Teresa 2022. A preclinical and phase Ib study of palbociclib plus nab-paclitaxel in patients with metastatic adenocarcinoma of the pancreas. Cancer Research Communications 2 (11) , 1326–1333. 10.1158/2767-9764.CRC-22-0072

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Abstract

Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and 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 I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/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 three of four 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 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/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% confidence interval, 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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	American Association for Cancer Research
ISSN:	2767-9764
Date of First Compliant Deposit:	30 May 2023
Date of Acceptance:	14 September 2022
Last Modified:	29 Jun 2023 10:26
URI:	https://orca.cardiff.ac.uk/id/eprint/160024

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