Clinical trial NCT04001101: 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
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Microsatellite Instability High
Mismatch Repair Deficiency
Colorectal Cancer
Keywords: Solid tumor
Colorectal cancer
Unresectable or metastatic
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Cancer League of Colorado
First posted: 2019-06-27
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Out-of-field ORR improvement
timeFrame: 12 months
Secondary outcomes:
measure: in-field tumor control and disease control
timeFrame: 12 Months
measure: Determine the chronology and profile of the radiation-associated immune response.
timeFrame: 12 months
measure: Durability of disease response
timeFrame: 12 months
measure: Progression-free Survival
timeFrame: 12 months
measure: Overall Survival
timeFrame: 12 Months
measure: Quality of life score
timeFrame: 12 Months
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado Hospital
state: Colorado
Study officials:
References: