Study Comparing TIL to Standard Ipilimumab in Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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In this randomized controlled phase III study the investigators will evaluate whether TIL infusion preceded by non-myeloablative chemotherapy and followed by high dose bolus interleukin-2 can result in an improved progression free survival when randomly compared to ipilimumab in 168 stage IV melanoma patients. A health technology assessment (HTA) will be performed to evaluate the impact of the TIL treatment on patients and organizational processes and cost-effectivity.

Detailed Description
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In this randomized controlled phase III study the investigators will evaluate whether TIL infusion preceded by non-myeloablative chemotherapy and followed by high dose bolus interleukin-2 can result in an improved progression free survival when randomly compared to ipilimumab in 168 stage IV melanoma patients. A health technology assessment (HTA) will be performed to evaluate the impact of the TIL treatment on patients and organizational processes and cost-effectivity. This will be done via questionnaires at baseline, just after treatment and during follow-up. Also healthcare providers will be interviewed after 6 months after starting the trial.

Official Title
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Randomized Phase III Study Comparing a Non-myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Tumor Infiltrating Lymphocytes and Interleukin-2 to Standard Ipilimumab Treatment in Metastatic Melanoma

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Procedure: Translational research
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Interleukin-2
* Drug: Ipilimumab infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed unresectable AJCC stage III or stage IV melanoma Patients must have metastatic melanoma with a resectable metastatic lesion(s) of sufficient size (≥ 2-3 cm in total) and must be willing to undergo such a resection for experimental purposes. Patients should have received maximum one line of systemic therapy (except for ipilimumab) for unresectable or metastatic melanoma.[ Patients must be ≥ 18 years and ≤ 75 years of age and must have measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion). Patients must have a clinical performance status of ECOG 0 or 1. Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen. Patients must be able to understand and sign the Informed Consent document. Exclusion Criteria: Life expectancy of less than three months. Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma. Adjuvant treatment with ipilimumab within 6 months prior to randomization. Requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within the last 3 weeks prior to randomization. Patients who have a more than two CNS metastases. Patients who have any CNS lesion that is symptomatic, greater than 1 cm in diameter or show significant surrounding edema on MRI scan will not be eligible until they have been treated and demonstrated no clinical or radiologic CNS progression for at least 2 months. All patients' toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less. Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Any active systemic infections, coagulation disorders or other active major medical illnesses. Any autoimmune disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ipilimumab<br>4 cycles of ipilimumab treatment, the standard treatment | Procedure: Translational research<br>* Before during and at progression/regression biopsies and blood will be taken for translational research<br>* Other names: blood;Drug: Ipilimumab infusion<br>* In arm A patients will be treated with 4 infusion of ipilimumab<br>* Other names: standard treatment;|
| Experimental: TIL treatment<br>non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of tumor infiltrating lymphocytes and interleukin-2 | Procedure: Translational research<br>* Before during and at progression/regression biopsies and blood will be taken for translational research<br>* Other names: blood;Drug: Cyclophosphamide<br>* The patient receives 2 days cyclophosphamide via IV to deplete T-cells.<br>* Other names: chemotherapy;Drug: Fludarabine<br>* The patient receives 5 days fludarabine via IV to deplete T-cells.<br>* Other names: chemotherapy;Drug: Interleukin-2<br>* After infusion of the TIL, the patient receives IL-2 to keep the TIL active.<br>* Other names: Proleukin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival according to RECIST 1.1 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune related progression free survival |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melanoma, TIL treatment, tumor infiltrating lymphocytes, ipilimumab, interleukin 2, non-myeloablative, randomization