Gemcitabine Plus<i>nab</i>-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial

Daniel D. Von Hoff , Ramesh K. Ramanathan , Mitesh J. Borad , Daniel D. Von Hoff , Ramesh K. Ramanathan , Mitesh J. Borad , Daniel A. Laheru , Lon Smith , Tina E. Wood , Ronald L. Korn , Neil Desai , Vuong Trieu , J. L. Mesías Iglesias , Hui Zhang , Patrick Soon‐Shiong , Tao Shi , N.V. Rajeshkumar , Anirban Maitra , Manuel Hidalgo
2011 Journal of Clinical Oncology 1,034 citations

Abstract

Purpose The 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 Methods Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2 , respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of 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 [ 18 F]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. Conclusion The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

Keywords

MedicineGemcitabinePancreatic cancerNeutropeniaRegimenPaclitaxelInternal medicineOncologyResponse Evaluation Criteria in Solid TumorsGastroenterologyFOLFIRINOXPhases of clinical researchUrologyChemotherapyCancerIrinotecan

MeSH Terms

AdenocarcinomaAdultAgedAged80 and overAlbuminsAnimalsAntineoplastic Combined Chemotherapy ProtocolsDeoxycytidineDisease-Free SurvivalDrug Administration ScheduleDrug EvaluationPreclinicalFemaleHumansMaleMaximum Tolerated DoseMiceMiddle AgedNeoplasm MetastasisPaclitaxelPancreatic NeoplasmsPositron-Emission TomographyRetreatmentTreatment OutcomeGemcitabine

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Publication Info

Year
2011
Type
article
Volume
29
Issue
34
Pages
4548-4554
Citations
1034
Access
Closed

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Cite This

Daniel D. Von Hoff, Ramesh K. Ramanathan, Mitesh J. Borad et al. (2011). Gemcitabine Plus<i>nab</i>-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial. Journal of Clinical Oncology , 29 (34) , 4548-4554. https://doi.org/10.1200/jco.2011.36.5742

Identifiers

DOI
10.1200/jco.2011.36.5742
PMID
21969517
PMCID
PMC3565012

Data Quality

Data completeness: 86%