title: A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.
abstract: BACKGROUND
  Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer.
  
  
  METHODS
  Gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab.
  
  
  RESULTS
  From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%).
  
  
  CONCLUSIONS
  Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.
  
  
  BACKGROUND
  NCT00556023.
authors.affiliation: Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin. Electronic address: massimo.aglietta@ircc.it.
authors.forename: M
authors.initials: M
authors.lastname: Aglietta
authors.affiliation: Department of Medical Oncology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Barone
authors.affiliation: Department of Oncology, University of Alberta, Edmonton.
authors.forename: M B
authors.initials: MB
authors.lastname: Sawyer
authors.affiliation: Division of Medical Oncology, Princess Margaret Hospital and University of Toronto, Toronto.
authors.forename: M J
authors.initials: MJ
authors.lastname: Moore
authors.affiliation: Department of Oncology, McGill University, Montreal, Canada.
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: Department of Medical Oncology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bagalà
authors.affiliation: Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin.
authors.forename: F
authors.initials: F
authors.lastname: Colombi
authors.affiliation: Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin.
authors.forename: C
authors.initials: C
authors.lastname: Cagnazzo
authors.affiliation: Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin.
authors.forename: L
authors.initials: L
authors.lastname: Gioeni
authors.affiliation: Pfizer Oncology Global Research and Development, Groton, USA.
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.affiliation: Pfizer Oncology Global Research and Development, Groton, USA.
authors.forename: B
authors.initials: B
authors.lastname: Huang
authors.affiliation: Pfizer Oncology Global Research and Development, Groton, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Fly
authors.affiliation: Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin.
authors.forename: F
authors.initials: F
authors.lastname: Leone
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003841:Deoxycytidine; C520704:tremelimumab; D000093542:Gemcitabine
keywords: gemcitabine chemotherapy; immunotherapy; metastatic pancreatic cancer; tremelimumab