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

Primary Purpose

Microsatellite Instability High, Mismatch Repair Deficiency, Colorectal Cancer

Status

Withdrawn

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

RT and Anti-PD-1

Anti-PD-1

About this trial

This is an interventional treatment trial for Microsatellite Instability High focused on measuring Solid tumor, Colorectal cancer, Unresectable or metastatic

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Colorado Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

RT and Anti-PD-1

Anti-PD-1

Arm Description

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 therapy alone Pembrolizumab will be given as standard of care in both arms

Outcomes

Primary Outcome Measures

Out-of-field ORR improvement

• Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment

Secondary Outcome Measures

in-field tumor control and disease control

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.

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

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

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

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

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)

Full Information

NCT ID

NCT04001101

First Posted

June 10, 2019

Last Updated

November 17, 2021

Sponsor

University of Colorado, Denver

Collaborators

National Cancer Institute (NCI), Cancer League of Colorado

1. Study Identification

Unique Protocol Identification Number

NCT04001101

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Withdrawn

Why Stopped

PI has decided to withdraw the study

Study Start Date

October 10, 2019 (Actual)

Primary Completion Date

November 17, 2021 (Actual)

Study Completion Date

November 17, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Colorado, Denver

Collaborators

National Cancer Institute (NCI), Cancer League of Colorado

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Microsatellite Instability High, Mismatch Repair Deficiency, Colorectal Cancer

Keywords

Solid tumor, Colorectal cancer, Unresectable or metastatic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

InvestigatorOutcomes 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.

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

RT and Anti-PD-1

Arm Type

Active Comparator

Arm Description

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

Arm Title

Anti-PD-1

Arm Type

Placebo Comparator

Arm Description

anti-PD-1 therapy alone Pembrolizumab will be given as standard of care in both arms

Intervention Type

Combination Product

Intervention Name(s)

RT and Anti-PD-1

Intervention Description

limited metastatic site radiation

Intervention Type

Drug

Intervention Name(s)

Anti-PD-1

Intervention Description

anti-PD-1 therapy alone

Primary Outcome Measure Information:

Title

Out-of-field ORR improvement

Description

• Out-of-field objective response rate (ORR: CR+PR) according to RECIST 1.1 assessment

Time Frame

12 months

Secondary Outcome Measure Information:

Title

in-field tumor control and disease control

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

Time Frame

12 Months

Title

Determine the chronology and profile of the radiation-associated immune response.

Description

Time Frame

12 months

Title

Durability of disease response

Description

In patients that achieve an objective response to pembrolizumab +/- RT, durability of response will be measured from the initiation of pembrolizumab until PD.

Time Frame

12 months

Title

Progression-free Survival

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.

Time Frame

12 months

Title

Overall Survival

Description

Overall survival will be measured from the date of initiation of pembrolizumab to the time of death from any cause for one year.

Time Frame

12 Months

Title

Quality of life score

Description

Time Frame

12 Months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

100 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Facility Information:

Facility Name

University of Colorado Hospital

City

Denver

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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

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