A Study of Immunotherapy With TIL (Tumor Infiltrating Lymphocytes) in Combination With Intra-tumoral Injections of Interferon Gamma-adenovirus (Ad-IFNg) in Patients With Stage IIIc or Stage IV Metastatic Melanoma (AJCC)(Protocol TIL-Ad-INFg)

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the clinical and biologic toxicity of cell therapy by adoptive transfer of TIL in combination with intra-tumoral injections of Ad-INFg.

Official Title
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A Phase I/II Study of Immunotherapy With TIL (Tumor Infiltrating Lymphocytes) in Combination With Intra-tumoral Injections of Interferon Gamma-adenovirus (Ad-IFNg) in Patients With Stage IIIc or Stage IV Metastatic Melanoma (AJCC)

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Other: TIL-Ad-INFg


Participation Criteria
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Eligibility Criteria
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Pre-Inclusion Criteria: Male or female patients ≥ 18 and ≤ 75 years of age Patients must have signed informed consent A negative pregnancy test for women with childbearing potential Patients with stage IIIc/IV metastatic melanoma (AJCC 6th edition) with nodal relapse, in transit metastasis, unresectable cutaneous metastases, visceral metastases except bone and brain metastases Presence of at least one lesion accessible for intra-tumoral injections of Ad-IFNg A negative brain scan, eliminating any brain metastases ECOG performance status of 0-2 Adequate bone-marrow reserve, renal function and hepatic function as assessed by standard laboratory criteria Subjects affiliated to an appropriate social security system Inclusion Criteria: Negative viral serology (HIV ½, p24 Ag, HTLV 1 / 2, B and C hepatitis) Exclusion Criteria: For female : the patient is pregnant or lactating or not using contraception and proved by a negative pregnancy test Positive viral serology for HIV ½, p24 Ag, HTLV 1 / 2 or B and C hepatitis History or current manifestations of severe progressive heart disease (congestive heart failure, coronary artery disease, uncontrolled arterial hypertension, serious rhythm disorders or ECG signs of previous myocardial infarction) Any serious illness, acute or chronic, e.g. active infection requiring antibiotics, bleeding disorders or any other condition that requires concomitant medications not allowed during this study Presence of a second active cancer except in situ cervical cancer or skin carcinoma Intercurrent disease requiring a corticosteroid treatment or a treatment with interferon-α Any autoimmune disease including active diabetes mellitus or immunodeficiency. Vitiligo in not an exclusion criteria Uncontrolled thyroid dysfunction Concurrently participation in a biomedical research (drug or radiotherapy) within the month preceding inclusion Metastatic lymph node stage alone with an indication of lymphadenectomy Brain or bone metastases discovered by radiological examination during the inclusion assessment Surgically resectable metastases Ocular melanoma More than one line of chemotherapy for treatment of melanoma Chemotherapy, immunotherapy or radiotherapy within 4 weeks before baseline (6 weeks for nitroso-ureas and mitomycin C) Contraindication for the use of vasopressor agents Treatment with molecules in pre-marketing development or whose development is finished less than 4 weeks

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TIL-Ad-INFg<br> | Other: TIL-Ad-INFg<br>* After verification of inclusion and non-inclusion criteria and after obtaining informed consent from the patients, a tumor sample will be taken for sterile production of TIL. Patients will receive intra-tumoral injections of Ad-INFg every 15 days from J-15 to M2, then every month from M3 to M11 or until disease progression. The Ad-INFg will be administered by intra-tumoral injection at a dose of 5x1010 vp (viral particles) per lesion. A maximum of 6 lesions will be treated simultaneously. They will also receive two infusion of TIL at M0 (Cycle 1) and M1 (Cycle 2) by intravenous infusion lasting 30 to 65 minutes followed by subcutaneous injections of IL2 from J1 to J5 and from J8 to J12 of each cycle.An evaluation of injected and not injected tumoral lesions including photographs will be realised at the pre-inclusion visit, J-15, M0 and every month until M12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical and biological toxicity of combined treatment TIL, IL2 et Ad-INFg | The evaluation of clinical and biological toxicity of combined treatment including infusion of TIL associated with subcutaneous injections of low-doses of IL-2 and intra-tumoral injections of Ad-IFNg will be performed according to clinical and biological criteria defined by NCI (Common Toxicity Criteria - version 3.0, August 2006). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | The evaluation of the objective response rate | 12 months | 
| Tumoral response | The evaluation of the tumoral response of injected lesions every month | 12 months | 
| Progression-free survival | The evaluation of the progression-free survival, | 12 months | 
| Overall survival | The evaluation of the overall survival | 12 months | 
| Immunological response | The evaluation of the immunological response | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy TIL (Tumor Infiltrating Lymphocytes), Intra-tumoral injection, Interferon gamma-adenovirus(Ad-IFNg), Metastatic melanoma, A stage IIIc/IV metastatic melanoma with nodal relapse, in transit metastasis, cutaneous unresectable metastases, visceral metastases