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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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  • Figure 1.
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    Figure 1.

    Treatment schema. Gemcitabine (1,000 mg/m2) was infused on days 1, 8, and 15 of each 28-day cycle, with CP-870,893 administered once during each treatment cycle on day 3.

  • Figure 2.
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    Figure 2.

    FDG-PET/CT imaging of (A and B) primary pancreatic tumors and (C and D) metastatic hepatic lesions. A and C, change relative to baseline in MVPmean as a measure of metabolic activity. B and D, CT, FDG-PET, and fused PET/CT images (baseline vs. end of cycle 4) showing (B), a responding primary pancreatic lesion (green arrow) and (D) a mixed response in liver with representative new or progressive lesions (red arrowheads), stable lesions (yellow arrowheads), and responding lesions (green arrows). Normal FDG excretion in kidneys and ureters is also seen.

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    Figure 3.

    The response of individual lesions measured by changes in lesional MVPmean from baseline to end of cycle 2, shown for: A, each patient, and B, for each metastatic site (all patient lesions pooled) including liver, lung, lymph node (LN), and peritoneal cavity. Changes in MVPmean were classified as CMR indicating disappearance of lesion; PMR indicating ≥25% reduction in MVPmean; progressive metabolic disease (PMD) indicating >25% increase in MVPmean or new lesion; and stable metabolic disease (SMD) indicating insufficient decrease to qualify for PMR and insufficient increase to qualify for PMD.

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    Figure 4.

    Biologic correlatives for OS after treatment with CP-870,893 in combination with gemcitabine. A, median OS and PFS for patients (n = 21) receiving at least one dose of CP-870,893. Relationship between (B) percentage change in CA19-9 at end of one cycle of therapy compared with baseline (R = −0.579; P = 0.049), (C) OS and tumor response determined by RECIST 1.0 at completion of two cycles of therapy (R = −0.652; P = 0.002), and (D) percentage change in total MVPmean for all lesions, primary pancreatic lesion, and all hepatic lesions after 2 weeks of therapy compared with baseline (R = −0.929; P = 0.007). Best overall tumor response measured by RECIST 1.0 is indicated in (B), (C), and (D) using open circles (PR), gray circles (stable disease), and black circles (progressive disease).

Tables

  • Figures
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  • Table 1.

    Baseline patient demographics and clinical characteristics

    CP-870,893 Dose cohort
    0.1 mg/kg (n = 3)0.2 mg/kg (n = 6)MTD expansion 0.2 mg/kg (n = 13)
    Characteristicn (%)n (%)n (%)
    Age, y
     Median5959
     Range57–7240–81
    Sex
     Male2 (67)3 (50)9 (69)
     Female1 (33)3 (50)4 (31)
    Race/ethnicity
     White0 (0)5 (83)11 (84)
     Black3 (100)1 (17)1 (8)
     Asian0 (0)0 (0)1 (8)
    ECOG PS
     02 (67)5 (83)2 (15)
     11 (33)1 (17)11 (85)
    Extent of disease
     Locally advanced0 (0)0 (0)2 (15)
     Metastatic3 (100)6 (100)11 (85)
    Location of primary
     Head2 (67)2 (33)4 (31)
     Body or tail1 (33)2 (33)9 (69)
     Not reported0 (0)2 (33)0 (0)
    Site of metastases
     Liver3 (100)5 (83)10 (77)
     Lung0 (0)2 (33)0 (0)
     Peritoneal0 (0)0 (0)3 (23)
     Skeleton0 (0)2 (33)0 (0)
     Other0 (0)0 (0)1 (8)
    Prior radiotherapies
     No3 (100)6 (100)11 (84)
     Yes0 (0)0 (0)1 (8)
     Not reported0 (0)0 (0)1 (8)
  • Table 2.

    Summary of the most commonly reported adverse events by grade

    CP-870,893 dose cohort
    0.1 mg/kg (n = 3)0.2 mg/kg (n = 6)MTD expansion 0.2 mg/kg (n = 13)
    Grade 1 or 2Grade 3 or 4Grade 1 or 2Grade 3 or 4Grade 1 or 2Grade 3 or 4
    Adverse eventsn (%)n (%)n (%)n (%)n (%)n (%)
    Clinical events
     CRS2 (67)1 (33)6 (100)0 (0)11 (85)0 (0)
     Fatigue3 (100)0 (0)5 (83)0 (0)11 (85)0 (0)
     Nausea3 (100)0 (0)5 (83)0 (0)10 (77)0 (0)
     Vomiting1 (33)0 (0)3 (50)0 (0)6 (46)0 (0)
     Pyrexia1 (33)0 (0)1 (17)0 (0)6 (46)0 (0)
     Peripheral edema3 (100)0 (0)2 (33)0 (0)3 (23)0 (0)
     Constipation1 (33)0 (0)3 (50)0 (0)6 (46)0 (0)
     Cerebrovascular accident0 (0)0 (0)0 (0)0 (0)0 (0)1 (8)
    Hematologic events
     Anemia3 (100)0 (0)4 (67)1 (17)10 (77)2 (15)
     Lymphopenia1 (33)1 (33)4 (67)0 (0)7 (54)4 (31)
     Neutropenia2 (67)0 (0)1 (17)3 (50)3 (23)2 (15)
     Thrombocytopenia2 (67)0 (0)3 (50)0 (0)3 (23)0 (0)
    Nonhematologic events
     ALT2 (67)0 (0)4 (67)0 (0)8 (62)0 (0)
     AST2 (67)0 (0)3 (50)0 (0)11 (85)0 (0)
     Alkaline Phosphatase2 (67)0 (0)5 (83)1 (17)8 (62)2 (15)
     Total bilirubin2 (67)1 (33)2 (33)1 (17)5 (38)1 (8)
     Hyperglycemia2 (67)1 (33)2 (33)4 (67)11 (85)1 (8)
     Hypocalcemia2 (67)0 (0)1 (17)0 (0)10 (77)0 (0)
    Hyponatremia2 (67)0 (0)3 (50)0 (0)2 (15)2 (15)

Additional Files

  • Figures
  • Tables
  • Supplementary Data

    Files in this Data Supplement:

    • Supplementary Figure Legends - Supplementary Figure Legends - PDF file 64K, Supplementary Figure Legends
    • Supplementary Figure 1 - Supplementary Figure 1 - PDF file 99K, Pharmacodynamic effects of gemcitabine and CP-870,893
    • Supplementary Figure 2 - Supplementary Figure 2 - PDF file 71K, Analysis of cytokines as correlatives of overall survival
    • Supplementary Table 1 - Supplementary Table 1 - PDF file 56K, Spearman Rank Correlation Analysis of Biomarkers for Overall Survival
  • CCR Translation for This Article

    The following CCR Translation is available for this article:
    Harnessing Immune Responses in the Tumor Microenvironment: All Signals Needed
    Dung T. Le and Elizabeth M. Jaffee

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    Clinical Cancer Research: 19 (22)
    November 2013
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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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