Description:
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.
Title
- Brief Title: Anti-PD-1 +/- RT for MSI-H Solid Tumors
- 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
Clinical Trial IDs
- ORG STUDY ID:
19-0556.cc
- SECONDARY ID:
P30CA046934
- NCT ID:
NCT04001101
Conditions
- Microsatellite Instability High
- Mismatch Repair Deficiency
- Colorectal Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| Anti-PD-1 | | Anti-PD-1 |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| RT and Anti-PD-1 | Active Comparator | 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 | |
| Anti-PD-1 | Placebo Comparator | anti-PD-1 therapy alone Pembrolizumab will be given as standard of care in both arms | |
Eligibility 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.
| Maximum Eligible Age: | 100 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Out-of-field ORR improvement |
| Time Frame: | 12 months |
| Safety Issue: | |
| Description: | • Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment |
Secondary Outcome Measures
| Measure: | in-field tumor control and disease control |
| Time Frame: | 12 Months |
| Safety Issue: | |
| Description: | In-field tumor control and disease control will be defined as SD, PR, or CR, of the target lesion, by RECIST 1.1 criteria |
| Measure: | Determine the chronology and profile of the radiation-associated immune response. |
| Time Frame: | 12 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Durability of disease response |
| Time Frame: | 12 months |
| Safety Issue: | |
| Description: | In patients that achieve an objective response to pembrolizumab +/- RT, durability of response will be measured from the initiation of pembrolizumab until PD. |
| Measure: | Progression-free Survival |
| Time Frame: | 12 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Survival |
| Time Frame: | 12 Months |
| Safety Issue: | |
| Description: | Overall survival will be measured from the date of initiation of pembrolizumab to the time of death from any cause for one year. |
| Measure: | Quality of life score |
| Time Frame: | 12 Months |
| Safety Issue: | |
| Description: | 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) |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | University of Colorado, Denver |
Trial Keywords
- Solid tumor
- Colorectal cancer
- Unresectable or metastatic
Last Updated
July 2, 2021
