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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; Macarulla, Teresa.
Afiliação
  • Hidalgo M; Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York.
  • Garcia-Carbonero R; Oncology Department, Hospital Universitario 12 de Octubre, Imas12, UCM, CNIO, CIBERONC, Madrid, Spain.
  • Lim KH; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
  • Messersmith WA; School of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
  • Garrido-Laguna I; Department of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
  • Borazanci E; HonorHealth/TGen, Scottsdale, Arizona.
  • Lowy AM; Department of Surgery, UC San Diego Moores Cancer Center, San Diego, California.
  • Medina Rodriguez L; Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain.
  • Laheru D; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Salvador-Barbero B; School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom.
  • Malumbres M; Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • Shields DJ; Centers for Therapeutic Innovation, Pfizer Inc, New York, New York.
  • Grossman JE; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • Huang X; Pfizer Oncology, San Diego, California.
  • Tammaro M; Pfizer Oncology, San Diego, California.
  • Martini JF; Pfizer Oncology, San Diego, California.
  • Yu Y; Pfizer Oncology, San Diego, California.
  • Kern K; Pfizer Oncology, San Diego, California.
  • Macarulla T; Gastrointestinal Cancer Unit, Vall d´Hebrón University Hospital and Vall d´Hebrón Institute of Oncology (VHIO), IOB Quirón, Barcelona, Spain.
Cancer Res Commun ; 2(11): 1326-1333, 2022 11.
Article em En | MEDLINE | ID: mdl-36970055
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. Trial Registration Pfizer Inc (NCT02501902).

Significance:

In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Neutropenia Limite: Humans Idioma: En Revista: Cancer Res Commun Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Neutropenia Limite: Humans Idioma: En Revista: Cancer Res Commun Ano de publicação: 2022 Tipo de documento: Article