Comparison of High-dose IL-2 and High-dose IL-2 With Radiation Therapy in Patients With Metastatic Melanoma.

Study Overview
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Brief Summary
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The purpose of this study is compare the response rates in patients with metastatic melanoma treated with high-dose IL-2 to patients treated with high-dose IL-2 along with radiation therapy.

Detailed Description
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All patients will receive high-dose IL-2. Half the patients enrolled will be randomly selected to receive radiation therapy to up to three tumors prior to receiving high-dose IL-2. Among the first 20 patients enrolled, those assigned to receive radiation will receive a single dose of radiation and for patients 21-44, those assigned to receive radiation will receive 2 doses of radiation.

Official Title
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Phase II Randomized Study of High Dose Interleukin-2 Versus Stereotactic Body Radiation (SBRT) and High Dose Interleukin-2 (IL-2) in Patients With Metastatic Melanoma

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Other: Radiation therapy and high-dose IL-2
* Drug: High-dose IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of melanoma will be required by previous biopsy or cytology. Patients must be ≥ 18 years of age. Patients must have tumors amenable to SBRT in lungs, mediastinum, chest wall, bones (other than long bones), or liver (inclusive of immediately adjacent masses), 1 - 3 foci; no minimum size, but none greater than 7 cm. Patients may have other metastases but only a maximum of 3 will be treated. ECOG performance status of 0-1. Women of childbearing potential must have a serum or urine pregnancy test performed within 72 hours prior to the start of protocol treatment. The results of this test must be negative in order for the patient to be eligible. In addition, women of childbearing potential as well as male patients must agree to take appropriate precautions to avoid pregnancy. Patients must sign a study-specific consent form. Exclusion Criteria: No metastatic site amenable to SBRT. Patients with brain metastases not candidates for radiosurgery. Previous radiation to sites proposed for radiation as part of this study. Patients with active systemic, pulmonary, or pericardial infection. Pregnant or lactating women. Evidence of ischemia on exercise tolerance test, stress thallium study, or baseline EKG. DLCO, FEV1 or FEV1/FVC less than 70% of predicted due to clinically significant underlying pulmonary disease. For any pulmonary function test values less than predicted values, the PI will review, and document the patient's suitability for high dose IL-2 therapy. WBC < 3.0 x 109/L Hgb < 9.0 g/dL AST/ALT > 3 times the upper limit of the normal range total bilirubin > 1.9 g/dL creatinine > 1.9 g/dL Patient requires chronic steroids.

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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: IL-2 Monotherapy<br>Patients receive standard high-dose IL-2 therapy, with an opportunity to crossover to the experimental arm if there is disease progression noted after two cycles of high-dose IL-2. Crossover patients will be included in Arm A. | Drug: High-dose IL-2<br>* IL-2 will be given on a Monday at a dose of 600,000 IU per kilogram IV every 8 hours for up to 14 doses each cycle. The second cycle is planned 16 days after cycle 1 but may be delayed up to one week to allow toxicity to resolve. The maximum number of doses that can be given during two cycles will be 28 doses. Patients who respond after two cycles can receive 4 more cycles of IL-2. Patients with disease progression after 2 cycles may elect to receive radiation before a 3rd cycle of IL-2. If patients crossover, IL-2 will be given on the Monday following the last dose of radiation, at a dose of 600,000 IU per kilogram IV every 8 hours for a maximum of 14 doses each cycle. Another cycle is planned 16 days after cycle 3 but may be delayed up to one week to allow toxicity to resolve.<br>* Other names: Stereotactic Body Radiation Therapy (SBRT).;|
| Experimental: Arm B: SBRT + IL-2<br>Patients will receive two doses of radiation before receiving high-dose IL-2. | Other: Radiation therapy and high-dose IL-2<br>* Patients 1 - 20 will receive a single fraction of radiation. Patients 21 through the completion of the study will receive two fractions. The dose for all patients will be 20 Gy per fraction to the prescription line at the edge of the planning treatment volume (PTV) with the last dose delivered on a Friday before IL-2 administration. For patients receiving two radiation doses, the doses can be administered on the Wednesday and Friday before IL-2 starts. Patients who are assigned to IL-2 monotherapy and have progressive disease after two IL-2 cycles are then eligible to receive SBRT before cycle 3 of IL-2 commences, single fraction for patients 1-20 and two fractions for patients 21- end of study.<br>* Other names: Stereotactic Body Radiation Therapy (SBRT);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Tumor Response of High Dose IL-2 vs. SBRT + High Dose IL-2 | Determine the best overall tumor response rate of high dose IL-2 versus SBRT + high-dose IL-2 using RECIST v1.1 assessed by CT/MRI, criteria applied to all target and non-target lesions with the exclusion of sites treated with SBRT. For patients who have SBRT after progression on IL-2 monotherapy, the response rate will be recorded, but not counted as a response for the primary objective. Overall response rate (ORR) includes all measurable and non-measurable target lesions except the lesions treated by SBRT, which were assessed separately. Both CT and positron emission tomography imaging were employed to assess response. Complete Response: disappearance of all target/non-target lesions and no abnormalities on PET; Partial Response: ≥30% decrease in sum of longest diameter (LD) of target lesions; Progressive Disease: ≥20% increase in sum of LD recorded since tx start or appearance of ≥1 new lesions; Stable Disease: Neither qualifying for PR nor PD since tx started. | At the end of Cycle 2 (Week 14). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate in Crossover Patients | Measure the response rate of patients who have disease progression after the first IL-2 cycles (using RECIST criteria) who received SBRT prior to cycle 3 of IL-2. | 7 weeks following Cycle 2 (Week 21). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic melanoma, IL-2, Interleukin 2, Radiation, Stereotactic Body Radiation Treatment, SBRT, Immunotherapy