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Cancer Therapy: Clinical

A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

Gregory L. Beatty, Drew A. Torigian, E. Gabriela Chiorean, Babak Saboury, Alex Brothers, Abass Alavi, Andrea B. Troxel, Weijing Sun, Ursina R. Teitelbaum, Robert H. Vonderheide and Peter J. O'Dwyer
Gregory L. Beatty
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Drew A. Torigian
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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E. Gabriela Chiorean
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Babak Saboury
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Alex Brothers
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Abass Alavi
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Andrea B. Troxel
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Weijing Sun
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Ursina R. Teitelbaum
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Robert H. Vonderheide
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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Peter J. O'Dwyer
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
1Abramson Cancer Center; 2Division of Hematology-Oncology, Department of Medicine, 3Departments of Radiology, and 4Biostatistics and Epidemiology; University of Pennsylvania, Philadelphia; 5Abramson Family Cancer Research Institute; 6University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and 7University of Washington, Seattle, Washington
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DOI: 10.1158/1078-0432.CCR-13-1320 Published November 2013
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Abstract

Purpose: 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).

Experimental Design: Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m2 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-[18F]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. Clin Cancer Res; 19(22); 6286–95. ©2013 AACR.

See related article by Le and Jaffee, p. 6061

This article is featured in Highlights of This Issue, p. 6059

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Prior presentation: Preliminary findings have been reported in Science 2011;331:1612–6 and at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4–8, 2010, Chicago, IL.

  • This article presents original results of a phase I study of CP-870,893 with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma.

  • Received May 13, 2013.
  • Revision received July 30, 2013.
  • Accepted August 17, 2013.
  • ©2013 American Association for Cancer Research.
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Clinical Cancer Research: 19 (22)
November 2013
Volume 19, Issue 22
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A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma
Gregory L. Beatty, Drew A. Torigian, E. Gabriela Chiorean, Babak Saboury, Alex Brothers, Abass Alavi, Andrea B. Troxel, Weijing Sun, Ursina R. Teitelbaum, Robert H. Vonderheide and Peter J. O'Dwyer
Clin Cancer Res November 15 2013 (19) (22) 6286-6295; DOI: 10.1158/1078-0432.CCR-13-1320

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A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma
Gregory L. Beatty, Drew A. Torigian, E. Gabriela Chiorean, Babak Saboury, Alex Brothers, Abass Alavi, Andrea B. Troxel, Weijing Sun, Ursina R. Teitelbaum, Robert H. Vonderheide and Peter J. O'Dwyer
Clin Cancer Res November 15 2013 (19) (22) 6286-6295; DOI: 10.1158/1078-0432.CCR-13-1320
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