Testing the Addition of Radiation Therapy to Immunotherapy for Merkel Cell Carcinoma

Phase 2

Active, not recruiting

Conditions: Advanced Merkel Cell Carcinoma
Pathologic Stage III Cutaneous Merkel Cell Carcinoma AJCC v8
Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8
Pathologic Stage IIIA Cutaneous Merkel Cell Carcinoma AJCC v8
Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8
Metastatic Merkel Cell Carcinoma
Pathologic Stage IIIB Cutaneous Merkel Cell Carcinoma AJCC v8
Pathologic Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8

Interventions: Biological: Pembrolizumab
Radiation: Stereotactic Body Radiation Therapy

Registration Number: NCT03304639

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial studies how well pembrolizumab with or without stereotactic body radiation therapy works in treating patients with Merkel cell cancer that has spread to other places in the body (advanced). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pembrolizumab with stereotactic body radiation therapy may work better in treating patients with Merkel cell cancer.

Detailed Description: PRIMARY OBJECTIVE:

I. To describe the progression-free survival (PFS) of stereotactic body radiation therapy (SBRT) + pembrolizumab (MK-3475) compared to pembrolizumab (MK-3475) alone in advanced/metastatic Merkel cell carcinoma (MCC) patients.

SECONDARY OBJECTIVES:

I. To describe the PFS of SBRT + MK-3475 compared to pembrolizumab (MK-3475) alone across Response Evaluation Criteria in Solid Tumors (RECIST) measurable (including both radiated and non-radiated) cancer deposits.

II. To describe the overall response rate of SBRT + pembrolizumab (MK-3475) compared to pembrolizumab(MK-3475) alone in both radiated and in non-radiated deposit(s).

III. To determine the PFS at 6 months of SBRT + pembrolizumab (MK-3475) compared to pembrolizumab (MK-3475) alone across all cancerous deposits by RECIST.

IV. To determine the rate of grade \> 3-4 adverse events, by organ system, by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

V. To determine the local control of SBRT treated tumors. VI. To calculate delivered radiation dose using cone-beam computed tomography (CT) images collected on the radiation treatment table in the final treatment position.

CORRELATIVE SCIENCE OBJECTIVES:

I. To test the utility of CT-based radiomics to predict radiation-induced pneumonitis and true delivered dose of SBRT based on cone beam collected imaging and diagnostic scans.

II. Biobanking for future correlative science projects.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo SBRT for 3 doses during cycle 1.

After completion of study treatment, patients are followed up every 6 months for up to 5 years.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 9

Inclusion Criteria

Patients must have pathologically (histologically or cytologically) proven diagnosis of MCC by local pathology review
Have measurable disease based on RECIST 1.1 including at least two cancerous deposits; at least one deposit must be RECIST measurable while at least one deposit must meet criteria for SBRT; non-radiated tumor will be identified prior to randomization on the protocol
Patients must have advanced or metastatic MCC defined as evidence of distant metastasis(es) on imaging
- Patients with locoregionally confined disease are not eligible
No prior immunotherapy for advanced/metastatic MCC
Patients with known or suspected central nervous system (CNS) metastases, untreated CNS metastases, or with the CNS as the only site of disease are excluded; however, subjects with controlled brain metastases will be allowed to enroll; controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment (or 4 weeks of observation if no intervention is clinically indicated), and off of steroids for at least 2 weeks, and no new or progressive neurological signs and symptoms
Patients having received palliative radiotherapy for extracranial metastasis(es) are eligible as long as there are 2 cancerous deposits that have not received prior radiation therapy (RT) and they meet the following criteria
- No prior radiation therapy (> 5 Gy) to the metastasis intended to be treated with SBRT
No history of the following:
- Autoimmunity requiring systemic immunosuppression within 2 years
- Patients known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following:
  - CD4 counts >= 350 mm^3
  - Serum HIV viral load of < 25,000 IU/ml
No other active malignancy that the investigator determines would interfere with the treatment and safety analysis
Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown; therefore, for women of childbearing potential only, a negative (if your test schedule specifically indicates a urine or serum pregnancy test, add that information at this point) pregnancy test done =< 28 days prior to registration is required
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 9.0 g/dl
Total bilirubin =< 2.0 mg/dl
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)
Systolic blood pressure (BP) =< 150 mg HG
Diastolic BP =< 90 mg HG
Albumin > 3 mg/dl
Blood urea nitrogen (BUN) =< 30 mg/dl
Creatinine =< 1.7 mg/dl
The following imaging workup to document metastases within 45 days prior to study registration are required: CT scans of the chest, abdomen and pelvis with radionuclide bone scan OR whole body (at least skull base to midthigh) positron emission tomography (PET)/CT

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I (pembrolizumab)	Pembrolizumab	Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Group II (pembrolizumab, SBRT)	Pembrolizumab	Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo SBRT for 3 doses during cycle 1.
Group II (pembrolizumab, SBRT)	Stereotactic Body Radiation Therapy	Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo SBRT for 3 doses during cycle 1.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	From randomization to either disease progression or death (without progression), assessed up to 3 years	Will compare PFS in non-radiated lesion(s) of patients receiving either (a) stereotactic body radiation therapy (SBRT) + pembrolizumab compared to (b) pembrolizumab alone in patients with advanced Merkel cell carcinoma. Kaplan- Meier curves will be constructed and median PFS times will be calculated for each arm. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	At 6 months	The rates of success will be calculated and compared across treatment arms utilizing a chi-square test.
Incidence of Adverse Events	Up to 3 months	Graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0. Maximum grade adverse events will be summarized by treatment arm in a tabular setting.
PFS Among All Response Evaluation Criteria in Solid Tumors Lesions	From randomization to either evidence of disease progression or death (without evidence of progression), assessed up to 3 years	Same as the primary endpoint, but includes both irradiated and non-radiated lesions. It is a time to event endpoint and will be evaluated using the Kaplan- Meier method. Median PFS times will be calculated for each arm and a cox proportional hazards model will be constructed to determine if there is a PFS benefit for patients receiving SBRT + pembrolizumab compared to pembrolizumab alone.
PFS for Lesions Chosen for Radiation Prior to Randomization	Up to 3 years	The protocol irradiated tumors are considered to be controlled if they have no evidence of progression. No evidence of progression is defined as complete response, PR, or stable disease. Local control of the protocol-irradiated tumor will be described using the Kaplan-Meier technique.
Overall Response Rate	Up to 3 years	Defined as partial response (PR) on 2 consecutive evaluations. Response rates will be calculated and compared across treatment arms utilizing a chi-square test.
Delivered Radiation Dose Using Cone-beam Computed Tomography (CT) Images	Up to 3 years	Radiation doses will be summarized descriptively and compared to the planned dose.

Trial Locations

Locations (255): Rush MD Anderson Cancer Center
🇺🇸
Chicago, Illinois, United States
Oncology Las Vegas - Henderson
🇺🇸
Henderson, Nevada, United States
Anchorage Associates in Radiation Medicine
🇺🇸
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
🇺🇸
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
🇺🇸
Anchorage, Alaska, United States
Alaska Women's Cancer Care
🇺🇸
Anchorage, Alaska, United States
Anchorage Oncology Centre
🇺🇸
Anchorage, Alaska, United States
Katmai Oncology Group
🇺🇸
Anchorage, Alaska, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
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Rush MD Anderson Cancer Center
🇺🇸Chicago, Illinois, United States