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Cancer Therapy: Clinical

Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma

Edward J. Kim, Vaibhav Sahai, Ethan V. Abel, Kent A. Griffith, Joel K. Greenson, Naoko Takebe, Gazala N. Khan, John L. Blau, Ronald Craig, Ulysses G. Balis, Mark M. Zalupski and Diane M. Simeone
Edward J. Kim
1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Vaibhav Sahai
1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
2Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
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Ethan V. Abel
2Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
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Kent A. Griffith
3Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
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Joel K. Greenson
4Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Naoko Takebe
5Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
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Gazala N. Khan
1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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John L. Blau
4Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Ronald Craig
4Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Ulysses G. Balis
4Department of Pathology, University of Michigan, Ann Arbor, Michigan.
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Mark M. Zalupski
1Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Diane M. Simeone
2Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.
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  • For correspondence: simeone@med.umich.edu
DOI: 10.1158/1078-0432.CCR-14-1269 Published December 2014
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  • Figure 1.
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    Figure 1.

    Median PFS (A) and OS (B) in patients with metastatic pancreatic adenocarcinoma receiving 150 mg of GDC-0449 daily for 4 weeks followed by 150 mg GDC-0449 daily and 1,000 mg/m2 of gemcitabine on days 1, 8, and 15 every 28 days.

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    Figure 2.

    A, immunostaining for SHH shows high (>200) and low (≤200) SHH score in patients with pancreatic adenocarcinoma. B, trichrome staining shows decrease in fibrosis on repeat biopsy after 3 weeks of GDC-0449 monotherapy compared with baseline. C, pancreatic adenocarcinoma tissue from same patient immunostained for Ki-67 shows decrease in expression on repeat biopsy after 3 weeks of GDC-0449 monotherapy compared with baseline. The tissue was also stained with H&E to assess for morphology.

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  • Table 1.

    Demographics and baseline characteristics

    Total patients enrolled (N = 25)
    VariablePatients, n%
    Age, y
     Median65
     Range46–80
    Sex
     Male1560
     Female1040
    ECOG performance status
     01664
     1936
    Race
     Caucasian2496
     African American14
    Histology
     Adenocarcinoma2496
     Acinar14
    Location of biopsy
     Liver metastasis1768
     Primary pancreatic mass416
     Omental metastasis28
     Other (perihepatic mass, neck lymph node)28
    Serum CA 19-9
     Median, U/mL3211
     Range, U/mL4–429,939
     >150 U/mL1872
    Biopsy
     Baseline25100
     At 3 wks2392
  • Table 2.

    Summary of efficacy

    VariableNo. of Patients%
    Number of evaluable patients25
    PFS
     At 3 mo1040
     Median, mo2.8
     95% CI, mo1.4–4.7
    OS
     Median, mo5.3
     Range, mo3.6–8.4
    Evaluable patients, n23
    Radiologic response, after 4 wks on GDC-0449 alone
     Complete response00
     Partial response00
     Stable disease1460.9
     Progressive disease939.1
     Objective response rate00
    Radiologic response, best overall
     Complete response00
     Partial response521.7
     Stable disease1043.5
     Progressive disease834.8
     Objective response rate521.7
    CA 19-9 response, after 4 wks on GDC-0449 alone
     Evaluable patientsa,n2087
     >20% decrease00
     ≤20% decrease15
     Primary increase1995
    CA 19-9 response, best overall
     Evaluable patientsa, n1982.6
     >50% decrease631.6
     ≤50% decrease210.5
     Primary increase1157.9
    • ↵aNumber of patients is less than the 23 (= overall evaluable patients) due to normal values throughout course of therapy (n = 3) and missing values at follow-up (n = 1).

  • Table 3.

    Impact of clinical and correlative variables on overall survival

    Evaluable patients (N = 23)
    VariableNo. of patientsaHR95% CIP
    Age
     >65 y92.720.98–7.580.05
     ≤65 y14
    Gender
     Male140.630.25–1.600.33
     Female9
    Baseline CA 19-9
     >1,000 U/mL152.150.82–5.630.12
     ≤1,000 U/mL8
    Baseline SHH
     >200120.760.29–1.990.76
     ≤2008
    Baseline Ki-67
     >30%130.680.26–1.790.43
     ≤30%7
    Baseline GLI1
     >0.591.010.42–2.460.98
     ≤0.514
    Baseline PTCH1
     >2.0110.790.33–1.890.60
     ≤2.012
    Baseline fibrosis
     >50%140.440.18–1.100.08
     ≤50%9
    Baseline CSCs
     >5%90.750.30–1.860.54
     ≤5%13
    Change in Ki-67, after 3 wks
     Decrease90.870.32–2.350.79
     Increase8
    Change in GLI1, after 3 wks
     >75% decrease150.850.32–2.260.74
     ≤75% decrease, or increase6
    Change in PTCH1, after 3 wks
     Decrease190.790.26–2.390.68
     Increase4
    Change in fibrosis, after 3 wks
     Decrease101.070.44–2.610.89
     Increase12
    Change in CSCs, after 3 wks
     Decrease110.620.24–1.600.32
     Increase10
    CA 19-9 response, best overall
     >50% decrease60.130.03–0.600.01
     ≤50% decrease, or increase13
    • ↵aNumber of patients may be less if both pretreatment and posttreatment samples were not available.

  • Table 4.

    Summary of correlative studies

    Evaluable patients (N = 23)
    Relative change in variable between baseline and repeat biopsy after 3 weeks on GDC-0449Patients, n%
    Ki-67 index, IHC
     Evaluable patients, n1768
     >20% decrease317.65
     ≤20% decrease635.29
     Increase847.06
     Median−1.07
    CSCs,% FACS
     Evaluable patients, n2184
     >20% decrease1047.62
     ≤20% decrease14.76
     Increase1047.62
     Median−16.08
    Fibrosis, trichrome
     Evaluable patients, n2288
     >50% decrease313.64
     0–50% decrease731.82
     Increase1254.54
     Median0
    GLI1, qRT-PCR
     Evaluable patients, n23100
     >50% decrease1982.61
     0–50% decrease313.04
     Increase14.35
     Median−93
    PTCH1, qRT-PCR
     Evaluable patients, n23100
     >50% decrease939.13
     ≤50% decrease1043.48
     Increase417.39
     Median−38

Additional Files

  • Figures
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  • Supplementary Data

    Files in this Data Supplement:

    • Supplementary Figure 1 Legend - Supplementary Figure 1 Legend. Median overall survival correlated with change in CA 19-9 (>50% decrease, versus {less than or equal to}50% decrease, or primary increase)
    • Supplementary Figure 1 - Supplementary Figure 1. Median overall survival correlated with change in CA 19-9 (>50% decrease, versus {less than or equal to}50% decrease, or primary increase) compared to baseline.
    • Supplementary Table 1 - Supplementary Table 1. Summary of Treatment-Related Adverse Events
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Clinical Cancer Research: 20 (23)
December 2014
Volume 20, Issue 23
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Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma
Edward J. Kim, Vaibhav Sahai, Ethan V. Abel, Kent A. Griffith, Joel K. Greenson, Naoko Takebe, Gazala N. Khan, John L. Blau, Ronald Craig, Ulysses G. Balis, Mark M. Zalupski and Diane M. Simeone
Clin Cancer Res December 1 2014 (20) (23) 5937-5945; DOI: 10.1158/1078-0432.CCR-14-1269

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Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma
Edward J. Kim, Vaibhav Sahai, Ethan V. Abel, Kent A. Griffith, Joel K. Greenson, Naoko Takebe, Gazala N. Khan, John L. Blau, Ronald Craig, Ulysses G. Balis, Mark M. Zalupski and Diane M. Simeone
Clin Cancer Res December 1 2014 (20) (23) 5937-5945; DOI: 10.1158/1078-0432.CCR-14-1269
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