Radiation Therapy, Plasma Exchange, and Immunotherapy (Pembrolizumab or Nivolumab) for the Treatment of Melanoma

Study Overview
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Brief Summary
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This early phase I trial investigates how well radiation therapy, plasma exchange, and pembrolizumab or nivolumab work in treating patients with melanoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Plasma exchange (also known as plasmapheresis) is a way to clean or flush out the blood. Immunotherapy with monoclonal antibodies, such as pembrolizumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Plasma exchange may help to improve the effect of standard radiation therapy and immunotherapy treatment on tumor cells of patients with melanoma.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the kinetics of soluble (s)PD-L1 removal and regeneration by plasma exchange in patients with melanoma. SECONDARY OBJECTIVES: I. To observe response at 3 months after plasma exchange plus immunotherapy. II. To observe ongoing response at approximate 3 month intervals after plasma exchange plus immunotherapy. CORRELATIVE RESEARCH OBJECTIVES: I. To determine the effects of plasma exchange on immune cell function. II. To observe the kinetics of extracellular vesicles (EVs) after plasma exchange in patients with melanoma. OUTLINE: Patients undergo radiation therapy daily on days 1-5 (weekdays). Patients then undergo therapeutic plasma exchange over 1-2 hours on days 4-6 or 5-7. Beginning on day 7, patients receive pembrolizumab intravenously (IV) or nivolumab IV. Treatment with pembrolizumab continues every 3 weeks or treatment with nivolumab continues every 2 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3 weeks and then for up to 2 years.

Official Title
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Radiation Therapy, Plasma Exchange, and Immunotherapy in Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Pembrolizumab
* Radiation: Radiation Therapy
* Biological: Therapeutic Exchange Plasma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of melanoma. Patients may have completed biopsy outside of Mayo Clinic, but there must be an internal review done to confirm diagnosis prior to confirming eligibility Measurable or non-measurable disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 3 sPD-L1 levels > 1.7 ng/ml by enzyme-linked immunosorbent assay (ELISA) Feasible vascular access as determined by study apheresis technician (either by peripheral intravenous access or by placement of a temporary central line) Negative pregnancy test done =< 7 days prior to radiation therapy, for women of childbearing potential only Provide written informed consent Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Willing to provide blood samples for correlative research purposes Exclusion Criteria: Persons taking a biotin supplement sPD-L1 level < 1.7 ng/ml by ELISA Pregnant or nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiation therapy, plasma exchange, immunotherapy)<br>Patients undergo radiation therapy daily on days 1-5 (weekdays). Patients then undergo therapeutic plasma exchange over 1-2 hours on days 4-6 or 5-7. Beginning on day 7, patients receive pembrolizumab IV or nivolumab IV. Treatment with pembrolizumab continues every 3 weeks or treatment with nivolumab continues every 2 weeks in the absence of disease progression or unacceptable toxicity. | Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Biological: Therapeutic Exchange Plasma<br>* Undergo therapeutic plasma exchange<br>* Other names: TEP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of treatment approach | Feasibility will be assessed by being able to complete the study accrual in a reasonable time period. | Up to 2 years | 
| Kinetics of soluble (s)PD-L1 removal and regeneration by plasma exchange in patients with melanoma | Graphical methods and descriptive statistics will be used to explore this endpoint. The Wilcoxon Signed-Rank test will be used to assess the change in the sPD-L1 levels over time across the different timepoints of interest. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Overall response rate is the proportion of patients with a tumor response (partial response or complete response at least 4 weeks apart). | Up to 2 years | 
| Progression-free survival (PFS) | PFS will be estimated using the method of Kaplan-Meier. | From registration to the first of either disease progression or death from any cause, assessed up to 2 years | 
| Overall survival (OS) | OS will be estimated using the method of Kaplan-Meier. | From registration to death from any cause, assessed up to 2 years | 
| Incidence of adverse events (AEs) | The descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for AE reporting. The maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine AE patterns. | Up to 2 years |