Phase II Trial of Stereotactic Body Radiotherapy Followed by Ipilimumab in Treating Patients With Stage IV Melanoma

Study Overview
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Brief Summary
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This phase II trial studies how well stereotactic body radiotherapy and ipilimumab work in treating patients with stage IV melanoma. Stereotactic body radiotherapy (SBRT) may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Monoclonal antibodies, such as ipilimumab, target certain cells to interfere with the ability of tumor cells to grow and spread. Giving SBRT with ipilimumab may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine feasibility and immune-related clinical responses associated with SBRT when given in conjunction with ipilimumab. SECONDARY OBJECTIVES: I. To determine late toxicity and immune pharmacodynamic changes after SBRT followed by ipilimumab. OUTLINE: Patients undergo a total of 3 fractions of stereotactic body radiotherapy between days 1-13. Patients then receive ipilimumab intravenously (IV) every 3 weeks. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 60 days, and then every effort will be made to obtain records of patients during this follow up, and permission will be sought for the investigators and/or study team to re-contact the patient directly with regard to health status and toxicity.

Official Title
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RADVAX: A Stratified Phase II Dose Escalation Trial of Stereotactic Body Radiotherapy Followed by Ipilimumab in Metastatic Melanoma

Conditions
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Recurrent Melanoma, Stage IV Skin Melanoma

Intervention / Treatment
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* Biological: Ipilimumab
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of melanoma Previously treated or previously untreated stage IV melanoma by American Joint Committee on Cancer (AJCC) staging criteria Presence of an index lesion between 1 and 5 cm Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Signed informed consent document Adequate renal, hepatic, and hematologic indices for ipilimumab therapy Ability to tolerate stereotactic body radiation therapy (e.g. lie flat and hold position for treatment) Exclusion Criteria: Prior systemic therapy within 14 days of study enrollment; patients must be adequately recovered from prior systemic therapy side effects as deemed by the treating investigator Clinical contraindication to stereotactic body radiotherapy (e.g. active systemic sclerosis, active inflammatory bowel disease if bowel is within target field, etc) Presence of central nervous system metastasis (including active brain metastasis); active brain metastasis would be defined as untreated brain metastases; if the brain metastases have received prior treatment (usually either with surgery or radiation), they are no longer active Long-term use of systemic corticosteroids; patients with replacement steroids and not immunosuppressive steroids may enroll in the study Prior radiation therapy (RT) that precludes the delivery of SBRT

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 (stereotactic body radiotherapy, ipilimumab)<br>Patients undergo a total of 3 fractions of stereotactic body radiotherapy between days 1-13. Patients then receive ipilimumab IV every 3 weeks. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. | Biological: Ipilimumab<br>* Given IV<br>* Other names: Yervoy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune-related Clinical Response, Defined as Proportion of Patients Treated at the Maximum-tolerated Dose (MTD) Who Achieve Either a Complete or Partial Immune-related Response | Scored on a non-index lesion using immune-related response criteria according to immune-related Response Evaluation Criteria in Solid Tumors version 1.1. The number of immune-related responses will be tabled by stratum and SBRT fraction dose level. At the MTD, the immune-related response rate and 95% exact confidence interval will be estimated separately for previously untreated and previously treated metastatic patients. | Up to 60 days after last ipilimumab injection | 
| Immune-related Progression-free Survival (irPFS) | irPFS will be estimated by the Kaplan-Meier method separately for previously untreated and previously treated metastatic patients who were treated at the MTD.. For some patients no scans were available for irRECIST reads, in which case change of management was determined to be the point of progression. | Time from first day of radiotherapy to first documented immune-related progressive disease, death due to any cause or last patient contact alive and progression-free, assessed at 6 months | 
| Late Toxicities, Graded According to the Radiation Therapy Oncology Group/European Organization for Research, the Treatment of Cancer Late Morbidity Scoring System, and the Common Terminology Criteria for Adverse Events Version 4.0 | Defined generally as an adverse event associated with the treatment which occurs beyond 30 days after last injection (i.e., adverse events which are observed months after treatment are most likely associated with SBRT). All dose-limiting toxicities and late toxicities will be graded and tabled by lesion site stratum and SBRT fraction dose level. Toxicity attribution to either SBRT or ipilimumab will be described if possible. | Up to 3 years | 
| Overall Survival | Will be estimated by the Kaplan-Meier method separately for previously untreated and previously treated metastatic patients who were treated at the MTD. | Time from first day of radiotherapy to death due to any cause or last patient contact alive, assessed at 12 months |