Advanced Merkel Cell Carcinoma, Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8, Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8, Metastatic Merkel Cell Carcinoma, Pathologic Stage IIIA Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIB Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage III Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8
Conditions
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.
Interventions
BIOLOGICALPembrolizumab
Given IV
RADIATIONStereotactic Body Radiation Therapy
Undergo SBRT
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Progression-free Survival | At 6 months | The rates of success will be calculated and compared across treatment arms utilizing a chi-square test. |
| Number of Participants With Grade 3+ 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 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJason J Luke
Alliance for Clinical Trials in Oncology
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group I (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.\>
\> Pembrolizumab: Given IV | 4 |
| Group II (Pembrolizumab, SBRT) 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.\> \> Pembrolizumab: Given IV\>
\> Stereotactic Body Radiation Therapy: Undergo SBRT | 5 |
| Total | 9 |
Baseline characteristics
| Characteristic | Group II (Pembrolizumab, SBRT) | Total | Group I (Pembrolizumab) |
|---|---|---|---|
| Age, Continuous | 69.0 years STANDARD_DEVIATION 9.2 | 72.1 years STANDARD_DEVIATION 9.5 | 76.0 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 |
Outcome results
Primary
Progression-free Survival (PFS)
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
Time frame: From randomization to either disease progression or death (without progression), assessed up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I (Pembrolizumab) | Progression-free Survival (PFS) | 7.5 months |
| Group II (Pembrolizumab, SBRT) | Progression-free Survival (PFS) | 5.5 months |
Secondary
Delivered Radiation Dose Using Cone-beam Computed Tomography (CT) Images
Radiation doses will be summarized descriptively and compared to the planned dose.
Time frame: Up to 3 years
Population: Group I did not receive radiation per protocol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group II (Pembrolizumab, SBRT) | Delivered Radiation Dose Using Cone-beam Computed Tomography (CT) Images | Planned Dose Cycle 1 | 24 cGY |
| Group II (Pembrolizumab, SBRT) | Delivered Radiation Dose Using Cone-beam Computed Tomography (CT) Images | Actual Dose Cycle 1 | 24 cGY |
| Group II (Pembrolizumab, SBRT) | Delivered Radiation Dose Using Cone-beam Computed Tomography (CT) Images | Planned Dose Cycle 2 | 16 cGY |
| Group II (Pembrolizumab, SBRT) | Delivered Radiation Dose Using Cone-beam Computed Tomography (CT) Images | Actual Dose Cycle 2 | 16 cGY |
Secondary
Incidence of Adverse Events
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.
Time frame: Up to 3 months
Secondary
Overall Response Rate
Defined as partial response (PR) on 2 consecutive evaluations. Response rates will be calculated and compared across treatment arms utilizing a chi-square test.
Time frame: Up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (Pembrolizumab) | Overall Response Rate | 1 Participants |
| Group II (Pembrolizumab, SBRT) | Overall Response Rate | 2 Participants |
Secondary
PFS Among All Response Evaluation Criteria in Solid Tumors Lesions
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.
Time frame: From randomization to either evidence of disease progression or death (without evidence of progression), assessed up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I (Pembrolizumab) | PFS Among All Response Evaluation Criteria in Solid Tumors Lesions | 7.5 months |
| Group II (Pembrolizumab, SBRT) | PFS Among All Response Evaluation Criteria in Solid Tumors Lesions | NA months |
Secondary
PFS for Lesions Chosen for Radiation Prior to Randomization
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.
Time frame: Up to 3 years
Population: Group I did not receive radiation per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group II (Pembrolizumab, SBRT) | PFS for Lesions Chosen for Radiation Prior to Randomization | 0 Participants |
Secondary
Progression-free Survival
The rates of success will be calculated and compared across treatment arms utilizing a chi-square test.
Time frame: At 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group I (Pembrolizumab) | Progression-free Survival | 1 Participants |
| Group II (Pembrolizumab, SBRT) | Progression-free Survival | 2 Participants |