Affiliation:
1. Daniel D. Von Hoff, Ramesh K. Ramanathan, TGen/Virginia G. Piper Cancer Center; Mitesh J. Borad, Mayo Clinic; Ronald L. Korn, Scottsdale Medical Imaging, Scottsdale, AZ; Daniel A. Laheru, N.V. Rajeshkumar, and Anirban Maitra, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD; Lon S. Smith, South Texas Oncology/Hematology, San Antonio, TX; Tina E. Wood, University of Alabama at Birmingham, Birmingham, AL; Neil Desai, Vuong Trieu, Jose L. Iglesias, Hui Zhang, and...
Abstract
PurposeThe trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake.Patients and MethodsPatients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m2nab-paclitaxel followed by gemcitabine 1,000 mg/m2on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents.ResultsA total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m2, respectively. The MTD was 1,000 mg/m2of gemcitabine plus 125 mg/m2of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [18F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone.ConclusionThe regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
Publisher
American Society of Clinical Oncology (ASCO)
Cited by
900 articles.
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