title: A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA).
  
  
  METHODS
  Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle.
  
  
  RESULTS
  CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007).
  
  
  CONCLUSIONS
  CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.
authors: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine.
authors: Gregory L
authors: GL
authors: Beatty
authors: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Department of Radiology.
authors: Drew A
authors: DA
authors: Torigian
authors: University of Washington, Seattle, WA.
authors: E Gabriela
authors: EG
authors: Chiorean
authors: Department of Radiology.
authors: Babak
authors: B
authors: Saboury
authors: Department of Radiology.
authors: Alex
authors: A
authors: Brothers
authors: Department of Radiology.
authors: Abass
authors: A
authors: Alavi
authors: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Department of Biostatistics and Epidemiology.
authors: Andrea B
authors: AB
authors: Troxel
authors: University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors: Weijing
authors: W
authors: Sun
authors: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine.
authors: Ursina R
authors: UR
authors: Teitelbaum
authors: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine.|Abramson Family Cancer Research Institute.
authors: Robert H
authors: RH
authors: Vonderheide
authors: Abramson Cancer Center; University of Pennsylvania, Philadelphia, PA.|Division of Hematology-Oncology, Department of Medicine.
authors: Peter J
authors: PJ
authors: O'Dwyer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000401:mortality; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D049268:Positron-Emission Tomography; D013534:Survival; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D019013:CD40 Antigens; C518149:selicrelumab; D003841:Deoxycytidine; D000093542:Gemcitabine
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