Adoptive Tumor-infiltrating Lymphocyte Transfer With Nivolumab for Melanoma

Study Overview
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Brief Summary
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This study is to investigate safety and feasibility of a combination therapy of a tumor infiltrating lymphocytes (TIL) transfer with anti-programmed cell death protein (PD)-1 therapy in patients with metastatic melanoma that failed immunotherapy.Tumor-infiltrating lymphocytes will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose Interleukin (IL)-2 and nivolumab anti-PD-1 treatment. The study uses a personalized Investigational Medicinal Product (IMP), i.e. TIL product and in combination with IL-2 treatment and nivolumab.

Detailed Description
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Adoptive cell therapy has been previously shown to be an effective treatment option for patients with melanoma. Due to an immunosuppressive microenvironment, not all patients respond to this therapy. In this trial, the immune suppressive microenvironment will be targeted by adding a PD-1 blocking antibody in combination with a TIL Transfer. Tumor-infiltrating lymphocytes will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment. The study uses a personalized IMP, i.e. TIL product and in combination with IL-2 treatment and nivolumab.

Official Title
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A Phase I Study of Adoptive Tumor-infiltrating Lymphocyte Transfer in Combination With Nivolumab in Patients With Advanced Melanoma

Conditions
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Advanced Melanoma

Intervention / Treatment
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* Drug: Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed unresectable or metastatic melanoma At least 1 PD-1 targeted immunotherapy and BRAF inhibition in case of BRAF mutated melanoma Resectable tumor mass and measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion) World Health Organization (WHO) clinical performance Status (ECOG) 0-1 Adequate organ function Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for five months after receiving the last dose of nivolumab for women and seven months for men Patients must be able to understand and sign the Informed consent document Hematology: Absolute neutrophil count greater than 1.5 x 109/L without support of filgrastim. Platelet count greater than 100 x 109/L. Hemoglobin greater than 5 mmol/L, or 80 g/L. Chemistry: Serum alanine aminotransferase (ALAT)/ aspartate transaminase (ASAT) less than 3 times the upper limit of normal, unless patients have liver metastases (< 5 times ULN). Serum creatinine clearance 50 ml/min or higher. Total Bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 50 micromol/L. Lactate dehydrogenase (LDH) ≤ 2x ULN Serology: Seronegative for HIV antibody. Seronegative for hepatitis B antigen, and hepatitis C antibody. Seronegative for syphilis. Exclusion Criteria: Life expectancy of less than three months Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma. 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 Uncontrolled central nervous system (CNS) metastases. Controlled CNS metastases must be for at least 4 weeks stable. Documented Forced expiratory volume at one second (FEV1) less than or equal to 50% predicted for patients with: A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years) Symptoms of respiratory distress 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. Contraindication for IL-2 or nivolumab (allergies etc.). Any autoimmune disease: patients with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, autoimmune thyroiditis (e.g. Hashimoto's disease), autoimmune hepatitis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (e.g., Wegener's Granulomatosis). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré Syndrome) are excluded from this study. Patients with vitiligo are eligible to enter the study

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
Interventional Model Description: Tumor-infiltrating infiltrate will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tumor-infiltrating lymphocyte product (TIL) transfer<br>The TIL product will be produced from excised tumor lesions from the patient. Expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment. The transplant product will be produced in the Good Manufacturing Practice (GMP) facility of the University Hospital in Basel. TIL transfer to Patient at Day 0. | Drug: Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2<br>* The study uses a personalized IMP, i.e. TIL product and in combination with IL-2 treatment and nivolumab. Day 0: Autologous TIL: (minimum 5 x 109 and up to a maximum of 2 x 1011 lymphocytes) administered intravenously over 20 to 30 minutes. Day 0: Interleukin-2 (Proleukin): 125.000 IU/kg/day s.c. for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing). Actual body weight will be used in calculating the dose of interleukin-2. Starting Day 14: Nivolumab application 240 mg i.v. over 30 minutes ever 2 weeks with a maximum to 2 years, or until disease progression or inacceptable toxicity.<br>* Other names: low dose IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | Number of Adverse Events to analyze safety of the combination of TIL transfer with IL-2 therapy | First 3 months during treatment | 
| Change in body temperature (Degree Celsius) | Change in Vital signs ( body temperature) to analyze the safety of the combination of TIL transfer with IL-2 therapy | at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing) | 
| Change in blood pressure (mmHg) | Change in Vital signs ( blood pressure) to analyze the safety of the combination of TIL transfer with IL-2 therapy | at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing) | 
| Change in heart beat (beats/minute) | Change in Vital signs (heart beat) to analyze the safety of the combination of TIL transfer with IL-2 therapy | at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing) | 
| Change in respiratory frequency (inspiration/minute) | Change in Vital signs (respiratory frequency) to analyze the safety of the combination of TIL transfer with IL-2 therapy | at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing) | 
| Change in full blood Counts (number of cells) | Change in Laboratory Parameter (full blood counts) to analyze haematological toxicity | at each treatment visit (every 2 weeks) from Day 0= Baseline to week 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan | Changes of Tumor volume according to RECIST 1.1 | First 3 months after TIL administration | 
| Progression Free Survival (PFS) | Progression free survival, defined as the time between registration to progression or death whichever occurs first. | between pre-treatment and 3-months post-treatment | 
| Overall Survival (OS) defined as the time between registration to death due to any cause | Overall survival will be measured from the beginning of the treatment to the death of the patient or to survival status analysis acquired during the last follow up. | 2 years after TIL transfer | 
| Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | between pre-treatment and 3-months post-treatment | 
| Objective response rate (ORR) | In order to assess the objective response rate CT scans and FDG-PET/CT scans will be performed. Response will be measured by best reduction of tumor volume according to RECIST 1.1 | 2 years after TIL transfer | 
| Number of Adverse Events according to CTCAE 4.0 | Overall Safety during whole treatment period analyzed by collection of Adverse Events according to CTCAE 4.0 | 2 years after TIL transfer | 
| Metabolic Response | Response measured by 18FDG-uptake | during the first 3 months after TIL transfer | 
| Number of Serious Adverse Events according to CTCAE 4.0 | Overall Safety during whole treatment period analyzed by collection of Serious Adverse Events according to CTCAE 4.0 | 2 years after TIL transfer | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor-infiltrating Lymphocyte (TIL) Transfer, Nivolumab, metastatic melanoma, anti-PD-1 therapy, failed immunotherapy, personalized Investigational Medicinal Product (IMP)