- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04001101
Anti-PD-1 +/- RT for MSI-H Solid Tumors
November 17, 2021 updated by: University of Colorado, Denver
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
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.
Study Overview
Status
Withdrawn
Intervention / Treatment
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
Interventional
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Colorado
-
Denver, Colorado, United States, 80045
- University of Colorado Hospital
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 100 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Provision to sign and date the consent form.
- Stated willingness to comply with all study procedures and be available for the duration of the study.
- Adult patients, 18-100 years of age.
- ECOG 0 or 1.
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
- Confirmation from medical or gynecologic oncology that the patient is eligible to receive pembrolizumab per FDA-approved indication for patients not currently receiving pembrolizumab .
- 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.
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:
- Pregnant women. Pregnancy testing is required for all female subjects of childbearing potential.
- 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.
- History of immunodeficiency, hypersensitivity to pembrolizumab, or other medical contraindication to receipt of pembrolizumab.
- Active infection.
- Active CNS metastases. Patients with treated CNS metastases are eligible.
- Patients with a separate non-cutaneous cancer diagnosis for which the patient has not been without evidence of disease for at least 5 years.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / 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 |
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
|
anti-PD-1 therapy alone
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Out-of-field ORR improvement
Time Frame: 12 months
|
• Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment
|
12 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
12 Months
|
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.
|
12 months
|
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.
|
12 months
|
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.
|
12 months
|
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.
|
12 Months
|
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)
|
12 Months
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
October 10, 2019
Primary Completion (Actual)
November 17, 2021
Study Completion (Actual)
November 17, 2021
Study Registration Dates
First Submitted
June 10, 2019
First Submitted That Met QC Criteria
June 26, 2019
First Posted (Actual)
June 27, 2019
Study Record Updates
Last Update Posted (Actual)
November 30, 2021
Last Update Submitted That Met QC Criteria
November 17, 2021
Last Verified
November 1, 2021
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 19-0556.cc
- P30CA046934 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
Drug and device information, study documents
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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