Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 400 patients with melanoma. In this trial, we are determining if there is a difference in the response between patients who have received prior anti-programmed cell death-1 (PD-1) treatment to those who have not received this prior ant-PD1 treatment. Objectives: - To determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not. Eligibility: - Individuals at least 18 years and less than or equal to 70 years of age who have metastatic melanoma. Design: Work up stage: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Surgery: Surgery or biopsy will be performed to obtain tumor from which to grow white blood cells. White blood cells will be grown from the tumor in the laboratory. Leukapheresis: Participants will have leukapheresis to collect additional white blood cells. (Leukapheresis is a common procedure which removes only the white blood cells from the patient.) Treatment: Participants will receive standard dose chemotherapy to prepare their immune system to accept the white blood cells. Participants will receive an infusion of their own white blood cells grown from tumor. They will also receive aldesleukin for up to five days to boost the immune system s response to the white blood cells. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed Description
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Background: Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine. In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gray (Gy) or 12 Gy total body irradiation (TBI) objective response rates using Response Evaluation Criteria In Solid Tumors (RECIST) criteria were 49%, 52%, and 72%, respectively. Of the 20 complete regressions seen in this trial, 19 are on-going at 70 to 114 months. The chemotherapy alone preparative regimen required in-patient treatment and was associated with significant neutropenia and thrombocytopenia requiring multiple transfusions and treatment for febrile neutropenia. Objectives: With amendment D, to determine if there is a difference in the rate of response between patients who have received prior anti-PD1 and those who have not; both groups will receive non-myeloablative lymphoid depleting preparative regimen followed by autologous young tumor infiltrating lymphocytes (TIL) and administration of high dose aldesleukin. To determine the toxicity of the treatment. Eligibility: Age greater than or equal to 18 and less than or equal to 70 years Evaluable metastatic melanoma Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL No contraindications to high-dose aldesleukin administration No concurrent major medical illnesses or any form of immunodeficiency Design: Patients with metastatic melanoma will have lesions resected and after TIL growth is established, patients will receive ACT with TIL plus aldesleukin following high dose chemotherapy preparative regimen. Up to 64 patients may be enrolled over 4-5 years.

Official Title
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A Phase II Study for Metastatic Melanoma Using High-Dose Chemotherapy Preparative Regimen Followed by Cell Transfer Therapy Using Tumor-Infiltrating Lymphocytes Plus IL-2 With the Administration of Pembrolizumab in the Retreatment Arm

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Drug: Aldesleukin
* Drug: Fludarabine
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Cyclophosphamide
* Drug: Cyclophosphamide
* Biological: Young TIL
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation and at least one other lesion that can be measured by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of National Cancer Institute (NCI). Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Greater than or equal to 18 years of age and less than or equal to 70 years of age. Ability of subject to understand and the willingness to sign the Informed Consent Document Willing to sign a durable power of attorney. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment. Serology: Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.) Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Hematology: Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim White blood cell (WBC) greater than or equal to 3000/mm(3) Platelet count greater than or equal to 100,000/mm(3) Hemoglobin > 8.0 g/dl Chemistry: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 2.5 times the upper limit of normal Serum Creatinine less than or equal to 1.6 mg/dl Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Patients must have progressive disease after prior treatment. Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less. Subjects must be co-enrolled in 03-C-0277 EXCLUSION CRITERIA: Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Active systemic infections, (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses. Concurrent systemic steroid therapy. History of severe immediate hypersensitivity reaction to any of the agents used in this study. History of coronary revascularization or ischemic symptoms. Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45% Documented LVEF of less than or equal to 45%, note: testing is required in patients with: Age greater than or equal to 65 years old Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or history of ischemic heart disease or chest pain. Patients who are receiving other investigational agents Documented forced expiratory volume (FEV1) less than or equal to 60% predicted tested in patients with: A prolonged history of cigarette smoking (20 pack (pk)/year of smoking within the past 2 years). Symptoms of respiratory dysfunction

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1N -Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin<br>Standard Chemo Prep Regimen. Young Tumor Infiltrating Lymphocytes (TIL) Plus High Dose Interleukin-2, Standard Chemo Preparative Regimen in participants without prior treatment pembrolizumab or nivolumab Standard preparative regimen + Young Tumor Infiltrating Lymphocytes (TIL) Cells Aldesleukin: 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days Cyclophosphamide: 60 mg/kg/day X 2 days intravenous (IV) Young TIL: Day 0: Cells will be infused intravenously (IV) | Drug: Aldesleukin<br>* 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).<br>* Other names: Proleukin;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 60 mg/kg/day X 2 days intravenous (IV)<br>* Other names: Cytoxan;Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV)<br>* Other names: Young Tumor Infiltrating Lymphocytes;|
| Experimental: Arm 1P - Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin<br>Standard Chemo Prep Regimen Young Tumor Infiltrating Lymphocytes (TIL) Plus High Dose Interleukin-2, Standard Chemo Preparative Regimen in participants previously treated with pembrolizumab or nivolumab. Standard preparative regimen + Young Tumor Infiltrating Lymphocytes (TIL) Cells Aldesleukin: 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days Cyclophosphamide: 60 mg/kg/day X 2 days intravenous (IV) Young TIL: Day 0: Cells will be infused intravenously (IV) | Drug: Aldesleukin<br>* 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).<br>* Other names: Proleukin;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 60 mg/kg/day X 2 days intravenous (IV)<br>* Other names: Cytoxan;Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV)<br>* Other names: Young Tumor Infiltrating Lymphocytes;|
| Experimental: Arm 2/Foll By Arm 1P-Low dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin<br>Decreased Chemo Prep Regimen+Retreat. Young TIL+High Dose Interleukin-2, Decreased Chemo Preparative Regimen. Young TIL+High Dose Interleukin-2, Standard Chemo (Retreat). Lower dose preparative regimen + Young TIL Cells. Aldesleukin: 720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 30 mg/kg/day intravenous piggy-back (IVPB) daily for 3 days. Cyclophosphamide: Days -5 to -3 (low-dose arm): Cyclophosphamide 300 mg/m^2 IV over 60 minutes. Young TIL: Day 0: Cells will be infused IV. Retreatment: Standard Chemo Prep Regimen. Aldesleukin: 720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days. Cyclophosphamide: 60 mg/kg/day X 2 days IV. Young TIL: Day 0: Cells will be infused IV. | Drug: Aldesleukin<br>* 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).<br>* Other names: Proleukin;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days<br>* Other names: Fludara;Drug: Fludarabine<br>* 30 mg/kg/day intravenous piggy-back (IVPB) daily for 3 days.<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 60 mg/kg/day X 2 days intravenous (IV)<br>* Other names: Cytoxan;Drug: Cyclophosphamide<br>* Days -5 to -3 (low-dose arm): 300 mg/m^2 IV over 60 minutes.<br>* Other names: Cytoxan;Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV)<br>* Other names: Young Tumor Infiltrating Lymphocytes;|
| Experimental: Arm 2- Low Dose Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin<br>Decreased Chemo Prep Regimen. Young Tumor Infiltrating Lymphocytes (TIL) Plus High Dose Interleukin-2 Lower Dose preparative regimen + Young Tumor Infiltrating Lymphocytes (TIL) Cells Aldesleukin: 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine: 30 mg/kg/day intravenous piggy-back (IVPB) daily for 3 days Cyclophosphamide: Days -5 to -3 (low-dose arm): Cyclophosphamide 30 mg/kg IV over 60 minutes for 2 days. Young TIL: Day 0: Cells will be infused intravenously (IV) | Drug: Aldesleukin<br>* 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).<br>* Other names: Proleukin;Drug: Fludarabine<br>* 30 mg/kg/day intravenous piggy-back (IVPB) daily for 3 days.<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Days -5 to -3 (low-dose arm):30 mg/kg IV over 60 minutes for 2 days<br>* Other names: Cytoxan;Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV)<br>* Other names: Young Tumor Infiltrating Lymphocytes;|
| Experimental: Arm 1P/Foll By Arm-1P/R-Standard Chemotherapy Preparative Regimen + TIL + 720,000 IU/kg Aldesleukin<br>Standard Chemo Prep Regimen(SCPR)+Retreat. Young TIL+High Dose(HD) Interleukin-2, SCPR. Young TIL+HD Interleukin-2, SC(Retreat). SCPR+Young TIL Cells retreatment with SCPR+Young TIL Cells+pembrolizumab. Aldesleukin:720,000 IU/kgIV every eight hours (+/-1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine:25 mg/m^2/day intravenous piggy-back(IVPB) daily for 5 days. Cyclophosphamide:60 mg/kg/day X 2 days IV. Young TIL:Day 0: Cells will be infused IV. Retreatment with standard preparative regimen+Young TIL Cells+pembrolizumab. Aldesleukin:720,000 IU/kg IV every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses). Fludarabine:25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days. Cyclophosphamide:60 mg/kg/day X 2 days IV. Young TIL: Day 0:Cells will be infused IV. Pembrolizumab:2 mg/kg IV on Days -2, 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days). | Drug: Aldesleukin<br>* 720,000 IU/kg intravenous (IV) every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).<br>* Other names: Proleukin;Drug: Fludarabine<br>* 25 mg/m^2/day intravenous piggy-back (IVPB) daily for 5 days<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 60 mg/kg/day X 2 days intravenous (IV)<br>* Other names: Cytoxan;Biological: Young TIL<br>* Day 0: Cells will be infused intravenously (IV)<br>* Other names: Young Tumor Infiltrating Lymphocytes;Drug: Pembrolizumab<br>* 2 mg/kg intravenous (IV) on Days -2, 21 (+/- 2 days), 42 (+/- 2 days), and 63 (+/- 2 days).<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Grade 3-5 Adverse Events in Arm 1N and Arm 1P | Number of participants with Grades 3-5 treatment-related adverse events were compared in Arm 1N and Arm 1P; and adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe. Grade 4 is life-threatening, and Grade 5 is death related to adverse event. | 30 days after end of treatment | 
| Number of Participants Who Have a Clinical Response to Treatment (Objective Tumor Regression) | Clinical response to treatment was assessed by the Response Evaluation Criteria In Solid Tumors (RECIST v1.0). Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive Disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD. | 4 weeks after cell infusion, then every 3 months x 3 and then every 6 months for 5 years, then per Principal Investigator (PI) discretion up to 5 years or disease progression | 
| Overall Response Rate (ORR) | Overall response is the best response recorded from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.0). Progression is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Date of cells until time of disease progression, up to approximately 67.2 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-related Adverse Events for Participants Who Received Pembrolizumab | Number of treatment-related adverse events for participants who received pembrolizumab. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. | Date treatment consent signed until approximately 4 weeks following last dose of Pembrolizumab, up to 4 weeks | 
| Progression-free Survival (PFS) | PFS is defined as the time to disease progression following the start of treatment, and time to death following the start of treatment. Progression was assessed by the Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 and is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Date of cells until time of disease progression up to approximately 67.2 months. | 
| Overall Survival | Overall survival is defined as the time from treatment start date until date of death, or date last known alive. | Date of cells until time to death, up until 90.1 months. | 
| Overall Survival | Overall survival is defined as the time from treatment start date until date of death, or date last known alive. | An average of 25.6 months. | 
| Overall Progression Free Survival (PFS) | PFS is defined as the time to disease progression following the start of treatment, and time to death following the start of treatment. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 and is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Time to progression and time to death, approximately up to 67.2 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Adoptive Cell Therapy