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出境医 / 临床实验 / Anti-PD-1 +/- RT for MSI-H Solid Tumors

Anti-PD-1 +/- RT for MSI-H Solid Tumors

Study Description
Brief Summary:
To determine if the out-of-field ORR is improved with the addition of radiation therapy to anti-PD-1 for patients with MSI-H/dMMR metastatic solid tumors. Determine the rates of in-field tumor control, disease control (stable disease, partial response, complete response), durability of disease response, progression-free survival, overall survival, and to assess quality of life and toxicity. Determine the chronology and profile of the radiation-associated immune response.

Condition or disease Intervention/treatment Phase
Microsatellite Instability High Mismatch Repair Deficiency Colorectal Cancer Combination Product: RT and Anti-PD-1 Drug: Anti-PD-1 Phase 2

Detailed Description:
This is a randomized phase II study with a primary objective to compare the objective response rate (ORR) for anti-PD-1 therapy alone versus anti-PD-1 therapy and limited metastatic site radiation, in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic solid tumors. The anti-PD-1 agent, pembrolizumab, received recent FDA accelerated approval for the use in patients with metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment or without satisfactory alternative treatment options. FDA approval for pembrolizumab was based on the results of five multi-cohort, multi-center, single-arm trials, which together showed an ORR of 39.6% among 149 patients with MSI-H/dMMR cancers. Importantly, there is mounting preclinical and clinic evidence supporting the safety and efficacy of combining radiation therapy with systemic immunotherapy, although no prospective comparative data, to the best of our knowledge. In this study, the investigators will focus on patients with MSI-H/dMMR tumors, given their baseline responsiveness to immune checkpoint inhibition, and test the hypothesis that ORR will be improved with radiation and anti-PD-1 therapy compared to anti-PD-1 therapy alone, through a randomized phase II trial design.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking Description: In an effort to minimize bias, the study will utilize a randomization. The randomization list will be generated by the study biostatistician and provided only to the study personnel who will be responsible for assigning each subject to a cohort of the study.
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Anti-PD-1 and Limited Metastatic Site Radiation Therapy Versus Anti-PD-1 Alone for Patients With Microsatellite Instability-high (MSI-H) and Mismatch Repair Deficient (dMMR) Metastatic Solid Tumors
Actual Study Start Date : October 10, 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : July 2021
Arms and Interventions
Arm Intervention/treatment
Active Comparator: RT and Anti-PD-1

In the pembrolizumab + RT arm, pembrolizumab will be started on study within 7 days (+/- 7 days) of start of RT.

Pembrolizumab will be given as standard of care in both arms

 Combination Product: RT and Anti-PD-1
limited metastatic site radiation
Placebo Comparator: Anti-PD-1
anti-PD-1 therapy alone Pembrolizumab will be given as standard of care in both arms
 Drug: Anti-PD-1
anti-PD-1 therapy alone
Outcome Measures
Primary Outcome Measures :
  1. Out-of-field ORR improvement [ Time Frame: 12 months ]
    • Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment


Secondary Outcome Measures :
  1. in-field tumor control and disease control [ Time Frame: 12 Months ]
    In-field tumor control and disease control will be defined as SD, PR, or CR, of the target lesion, by RECIST 1.1 criteria

  2. Determine the chronology and profile of the radiation-associated immune response. [ Time Frame: 12 months ]
    The University of Colorado School of Medicine Human Immune Monitoring Shared Resource (HIMSR) will quantify peripheral CD8, CD4, and regulatory T cell populations and characterize the relative functional state of these cells using activation markers (CD45RO, ICOS, and CD25) and inhibitory markers (TIM-3, CTLA-4, LAG-3, and PD-1). The HIMSR will also characterize peripheral dendritic cells (pDCs, CD1c+, and CD141+ subsets), monocytes (classical and non-classical subsets), myeloid-derived suppressor cells (MDSCs, granulocytic and monocytic subsets), and expression of activation (CD80 and HLA-DR) and inhibitory molecules (PDL1) on these cells. Further, cytokine production by NK cells, B cells, T cells, and monocytes will be measured by flow cytometry after brief ex-vivo stimulation. The HIMSR will also perform a protein multiplex array of 40 potential biomarkers in plasma.

  3. Durability of disease response [ Time Frame: 12 months ]
    In patients that achieve an objective response to pembrolizumab +/- RT, durability of response will be measured from the initiation of pembrolizumab until PD.

  4. Progression-free Survival [ Time Frame: 12 months ]
    Progression-free survival will be measured from the date of initiation of pembrolizumab to the time of tumor progression or death from any cause for one year.

  5. Overall Survival [ Time Frame: 12 Months ]
    Overall survival will be measured from the date of initiation of pembrolizumab to the time of death from any cause for one year.

  6. Quality of life score [ Time Frame: 12 Months ]
    Quality of life questionnaire, 28 questions rating experience from 1 to 4 (4 being "very much", 1 being "not at all") and two questions rating overall health and quality of life on a scale from 1 to 7 (7 being excellent)


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision to sign and date the consent form.
  2. Stated willingness to comply with all study procedures and be available for the duration of the study.
  3. Adult patients, 18-100 years of age.
  4. ECOG 0 or 1.

  5. Unresectable or metastatic MSI-H/dMMR tumors eligible to receive pembrolizumab according to FDA-approved indications:

    • Solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR
    • Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan11
  6. Confirmation from medical or gynecologic oncology that the patient is eligible to receive pembrolizumab per FDA-approved indication for patients not currently receiving pembrolizumab .
  7. At least one site of disease amenable to radiation therapy per the acceptable dosing regimens outlined in section 6.2, and at least one additional site of measurable disease suitable for out-of-field response assessment.

  8. Adequate baseline labs for initiation of trial treatment:

    • absolute neutrophil count (ANC) >1,000/µL
    • platelets >75,000/µL
    • hemoglobin >8 g/dL
    • serum creatinine < 1.5 x ULN
    • serum total bilirubin < 1.5 x ULN
    • AST and ALT < 2.5 x ULN, or < 5 x ULN if liver metastasis are present

Exclusion Criteria:

  1. Pregnant women. Pregnancy testing is required for all female subjects of childbearing potential.
  2. Patients with active collagen vascular disease (CVD), specifically systemic lupus erythematosus or scleroderma. Patients with a history of CVD without evidence of active disease are eligible for enrollment at the discretion of the study PI.
  3. History of immunodeficiency, hypersensitivity to pembrolizumab, or other medical contraindication to receipt of pembrolizumab.
  4. Active infection.
  5. Active CNS metastases. Patients with treated CNS metastases are eligible.
  6. Patients with a separate non-cutaneous cancer diagnosis for which the patient has not been without evidence of disease for at least 5 years.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Robyn Swing 720-848-0607 robyn.swing@ucdenver.edu
Contact: Christine Fisher, MD christine.fisher@ucdenver.edu

Locations
Layout table for location information
United States, Colorado
University of Colorado Hospital Recruiting
Denver, Colorado, United States, 80045
Contact: Suzanne Withrow    720-848-0593    suzanne.withrow@cuanschutz.edu   
Principal Investigator: Christine Fisher, MD         
Sponsors and Collaborators
University of Colorado, Denver
National Cancer Institute (NCI)
Cancer League of Colorado, Inc
Tracking Information
First Submitted Date  ICMJE June 10, 2019
First Posted Date  ICMJE June 27, 2019
Last Update Posted Date November 6, 2020
Actual Study Start Date  ICMJE October 10, 2019
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2019) 		Out-of-field ORR improvement [ Time Frame: 12 months ]
• Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2019)
  • in-field tumor control and disease control [ Time Frame: 12 Months ]
    In-field tumor control and disease control will be defined as SD, PR, or CR, of the target lesion, by RECIST 1.1 criteria
  • Determine the chronology and profile of the radiation-associated immune response. [ Time Frame: 12 months ]
    The University of Colorado School of Medicine Human Immune Monitoring Shared Resource (HIMSR) will quantify peripheral CD8, CD4, and regulatory T cell populations and characterize the relative functional state of these cells using activation markers (CD45RO, ICOS, and CD25) and inhibitory markers (TIM-3, CTLA-4, LAG-3, and PD-1). The HIMSR will also characterize peripheral dendritic cells (pDCs, CD1c+, and CD141+ subsets), monocytes (classical and non-classical subsets), myeloid-derived suppressor cells (MDSCs, granulocytic and monocytic subsets), and expression of activation (CD80 and HLA-DR) and inhibitory molecules (PDL1) on these cells. Further, cytokine production by NK cells, B cells, T cells, and monocytes will be measured by flow cytometry after brief ex-vivo stimulation. The HIMSR will also perform a protein multiplex array of 40 potential biomarkers in plasma.
  • Durability of disease response [ Time Frame: 12 months ]
    In patients that achieve an objective response to pembrolizumab +/- RT, durability of response will be measured from the initiation of pembrolizumab until PD.
  • Progression-free Survival [ Time Frame: 12 months ]
    Progression-free survival will be measured from the date of initiation of pembrolizumab to the time of tumor progression or death from any cause for one year.
  • Overall Survival [ Time Frame: 12 Months ]
    Overall survival will be measured from the date of initiation of pembrolizumab to the time of death from any cause for one year.
  • Quality of life score [ Time Frame: 12 Months ]
    Quality of life questionnaire, 28 questions rating experience from 1 to 4 (4 being "very much", 1 being "not at all") and two questions rating overall health and quality of life on a scale from 1 to 7 (7 being excellent)
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • in-field tumor control and disease control [ Time Frame: 12 Months ]
    In-field tumor control and disease control will be defined as SD, PR, or CR, of the target lesion, by RECIST 1.1 criteria
  • Determine the chronology and profile of the radiation-associated immune response. [ Time Frame: 12 months ]
    The University of Colorado School of Medicine Human Immune Monitoring Shared Resource (HIMSR) will quantify peripheral CD8, CD4, and regulatory T cell populations and characterize the relative functional state of these cells using activation markers (CD45RO, ICOS, and CD25) and inhibitory markers (TIM-3, CTLA-4, LAG-3, and PD-1). The HIMSR will also characterize peripheral dendritic cells (pDCs, CD1c+, and CD141+ subsets), monocytes (classical and non-classical subsets), myeloid-derived suppressor cells (MDSCs, granulocytic and monocytic subsets), and expression of activation (CD80 and HLA-DR) and inhibitory molecules (PDL1) on these cells. Further, cytokine production by NK cells, B cells, T cells, and monocytes will be measured by flow cytometry after brief ex-vivo stimulation. The HIMSR will also perform a protein multiplex array of 40 potential biomarkers in plasma.
  • Durability of disease response [ Time Frame: 12 months ]
    In patients that achieve an objective response to pembrolizumab +/- RT, durability of response will be measured from the initiation of pembrolizumab until PD.
  • Progression-free Survival [ Time Frame: 12 months ]
    Progression-free survival will be measured from the date of initiation of pembrolizumab to the time of tumor progression or death from any cause for one year.
  • Overall Survival [ Time Frame: 12 Months ]
    Overall survival will be measured from the date of initiation of pembrolizumab to the time of death from any cause for one year.
  • Quality of life [ Time Frame: 12 Months ]
    Descriptive statistics will be used to summarize the quality of life questionnaire
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anti-PD-1 +/- RT for MSI-H Solid Tumors
Official Title  ICMJE A Randomized Phase II Study of Anti-PD-1 and Limited Metastatic Site Radiation Therapy Versus Anti-PD-1 Alone for Patients With Microsatellite Instability-high (MSI-H) and Mismatch Repair Deficient (dMMR) Metastatic Solid Tumors
Brief Summary To determine if the out-of-field ORR is improved with the addition of radiation therapy to anti-PD-1 for patients with MSI-H/dMMR metastatic solid tumors. Determine the rates of in-field tumor control, disease control (stable disease, partial response, complete response), durability of disease response, progression-free survival, overall survival, and to assess quality of life and toxicity. Determine the chronology and profile of the radiation-associated immune response.
Detailed Description This is a randomized phase II study with a primary objective to compare the objective response rate (ORR) for anti-PD-1 therapy alone versus anti-PD-1 therapy and limited metastatic site radiation, in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic solid tumors. The anti-PD-1 agent, pembrolizumab, received recent FDA accelerated approval for the use in patients with metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment or without satisfactory alternative treatment options. FDA approval for pembrolizumab was based on the results of five multi-cohort, multi-center, single-arm trials, which together showed an ORR of 39.6% among 149 patients with MSI-H/dMMR cancers. Importantly, there is mounting preclinical and clinic evidence supporting the safety and efficacy of combining radiation therapy with systemic immunotherapy, although no prospective comparative data, to the best of our knowledge. In this study, the investigators will focus on patients with MSI-H/dMMR tumors, given their baseline responsiveness to immune checkpoint inhibition, and test the hypothesis that ORR will be improved with radiation and anti-PD-1 therapy compared to anti-PD-1 therapy alone, through a randomized phase II trial design.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking Description:
In an effort to minimize bias, the study will utilize a randomization. The randomization list will be generated by the study biostatistician and provided only to the study personnel who will be responsible for assigning each subject to a cohort of the study.
Primary Purpose: Treatment
Condition  ICMJE
  • Microsatellite Instability High
  • Mismatch Repair Deficiency
  • Colorectal Cancer
Intervention  ICMJE
  • Combination Product: RT and Anti-PD-1
    limited metastatic site radiation
  • Drug: Anti-PD-1
    anti-PD-1 therapy alone
Study Arms  ICMJE
  • Active Comparator: RT and Anti-PD-1

    In the pembrolizumab + RT arm, pembrolizumab will be started on study within 7 days (+/- 7 days) of start of RT.

    Pembrolizumab will be given as standard of care in both arms

    Intervention: Combination Product: RT and Anti-PD-1
  • Placebo Comparator: Anti-PD-1
    anti-PD-1 therapy alone Pembrolizumab will be given as standard of care in both arms
    Intervention: Drug: Anti-PD-1
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 26, 2019) 		140
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Provision to sign and date the consent form.
  2. Stated willingness to comply with all study procedures and be available for the duration of the study.
  3. Adult patients, 18-100 years of age.
  4. ECOG 0 or 1.

  5. Unresectable or metastatic MSI-H/dMMR tumors eligible to receive pembrolizumab according to FDA-approved indications:

    • Solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR
    • Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan11
  6. Confirmation from medical or gynecologic oncology that the patient is eligible to receive pembrolizumab per FDA-approved indication for patients not currently receiving pembrolizumab .
  7. At least one site of disease amenable to radiation therapy per the acceptable dosing regimens outlined in section 6.2, and at least one additional site of measurable disease suitable for out-of-field response assessment.

  8. Adequate baseline labs for initiation of trial treatment:

    • absolute neutrophil count (ANC) >1,000/µL
    • platelets >75,000/µL
    • hemoglobin >8 g/dL
    • serum creatinine < 1.5 x ULN
    • serum total bilirubin < 1.5 x ULN
    • AST and ALT < 2.5 x ULN, or < 5 x ULN if liver metastasis are present

Exclusion Criteria:

  1. Pregnant women. Pregnancy testing is required for all female subjects of childbearing potential.
  2. Patients with active collagen vascular disease (CVD), specifically systemic lupus erythematosus or scleroderma. Patients with a history of CVD without evidence of active disease are eligible for enrollment at the discretion of the study PI.
  3. History of immunodeficiency, hypersensitivity to pembrolizumab, or other medical contraindication to receipt of pembrolizumab.
  4. Active infection.
  5. Active CNS metastases. Patients with treated CNS metastases are eligible.
  6. Patients with a separate non-cutaneous cancer diagnosis for which the patient has not been without evidence of disease for at least 5 years.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Robyn Swing 720-848-0607 robyn.swing@ucdenver.edu
Contact: Christine Fisher, MD christine.fisher@ucdenver.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04001101
Other Study ID Numbers  ICMJE 19-0556.cc
P30CA046934 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Cancer League of Colorado, Inc
Investigators  ICMJE Not Provided
PRS Account University of Colorado, Denver
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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