title: Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
authors.affiliation: TGen/Virginia G Piper Cancer Ctr, 445 N Fifth St, Suite 600, Phoenix, AZ 85004, USA. dvh@tgen.org
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Laheru
authors.forename: Lon S
authors.initials: LS
authors.lastname: Smith
authors.forename: Tina E
authors.initials: TE
authors.lastname: Wood
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Korn
authors.forename: Neil
authors.initials: N
authors.lastname: Desai
authors.forename: Vuong
authors.initials: V
authors.lastname: Trieu
authors.forename: Jose L
authors.initials: JL
authors.lastname: Iglesias
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Patrick
authors.initials: P
authors.lastname: Soon-Shiong
authors.forename: Tao
authors.initials: T
authors.lastname: Shi
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049268:Positron-Emission Tomography; D019233:Retreatment; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine