Ipilimumab With Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Melanoma Mets Pts

Not Applicable

Active, not recruiting

Conditions: Metastatic Melanoma

Interventions: Drug: Ipilimumab
Procedure: Tumor Infiltrating Lymphocytes (TIL)
Drug: Administration of Lymphodepletion
Drug: Cyclophosphamide as Part of Lymphodepletion
Drug: Fludarabine as Part of Lymphodepletion
Drug: High Dose IL-2
Biological: Adoptive Cell Therapy with TIL

Registration Number: NCT01701674

Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Brief Summary: Purpose of this Pilot Study: The investigators want to study the safety, side effects, and benefits of tumor infiltrating lymphocytes (TILs), when they are given with the drug ipilimumab. Ipilimumab is a type of immunotherapy - a drug that is used to boost the ability of the immune system to fight cancer, infection, and other diseases.

Detailed Description: The primary endpoints of this pilot trial will be the safety and feasibility of administering ipilimumab with Adoptive Cell Therapy (ACT) using TIL. The data analysis will mainly be descriptive. All study results will be preliminary and of exploratory in nature due to the pilot status and small sample size of the trial. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL. All participants will be evaluable for toxicity from the time of their first protocol treatment. Toxicity will be reported by type and severity according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 4.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 13

Inclusion Criteria

Participants must have unresectable metastatic stage IV melanoma or stage III intransit or regional nodal disease, and in the opinion of the institutional PI is an acceptable candidate for ACT with high dose IL-2
Residual measurable disease after resection of target lesion(s) for TIL growth
Tumor may have a B-RAF V600 mutation or be BRAF wild type, and patients must not have been previously treated with ipilimumab
Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1. ECOG performance status of 0-1 will be inferred if the patient's level of energy is ≥ 50% of baseline.
May have been previously treated for metastatic disease, or may have not had prior systemic treatment. Patients with a V600 BRAF mutated tumor may have previously received a prior BRAF inhibitor.
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of screening.
Adequate renal, hepatic and hematologic function, including creatinine of less than or equal to 1.7 gm/dL, total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL, aspartate aminotransferase (AST) and alanine transaminase (ALT) of less than 3 X institutional upper limit of normal, hemoglobin of 8 gm/dL or more, white blood count (WBC) of 3000 per mcL and total granulocytes of 1000 per mcL or more, and platelets of 100,000 per mcL or more.
Must have a positive screening Epstein-Barr virus (EBV) antibody titre on screening test
Potential participants with antibiotic allergies per se are not excluded; although the production of TIL for adoptive transfer includes antibiotics, extensive washing after harvest will minimize systemic exposure to antibiotics.
At screening, patients with ≤ 3 untreated CNS metastases may be included provided none of the untreated lesions are > 1 cm in greatest dimension, and there is no peri-tumoral edema present on brain imaging (MRI or CT if MRI is contraindicated).
At screening, patients with central nervous system (CNS) metastases treated with either surgical resection and/or radiation therapy may be included. Patients may be included if the largest lesion is ≤ 1 cm, and there is no evidence of progressive CNS disease on brain imaging at least 28 days after treatment.
At screening, patients may be included if the largest lesion is > 1 cm or > 3 in number, and there is no evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy.
No evidence of ongoing cardiac dysrhythmia ≥ grade 2 (NCI Common Terminology Criteria for Adverse Events [CTCAE], v4.0)
All laboratory and imaging studies must be completed and satisfactory within 30 days of signing the consent document, with the exceptions of: negative serum pregnancy test for women of child-bearing potential which must be negative within 7 days of screening, human leukocyte antigen (HLA) typing which will not be repeated if performed previously, and pulmonary function tests (PFTs)/cardiac stress tests whose results are valid for 6 months if performed previously.

Exclusion Criteria

Active systemic infections requiring intravenous antibiotics, coagulation disorders or other major medical illness of the cardiovascular, respiratory or immune system, which in the opinion of the principal investigator (PI) or treating coinvestigator is not acceptable risk for ACT, are excluded.
Testing positive for HIV titre, Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody, Human T-Lymphotropic Virus (HTLV) I or II antibody, or both Rapid. Plasma Reagin (RPR) and fluorescent treponemal antibodies (FTA) positive are excluded.
Pregnant or nursing
Patients needing chronic, immunosuppressive systemic steroids are excluded
History of autoimmune disease that require immunosuppressive medications at the time of screening
Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated
Patients with > 3 untreated CNS metastases or evidence of peri-tumoral edema
Patients with ≤ 3 untreated CNS metastases but with at least one lesion >1 cm or peri-tumoral edema
Patients with invasive malignancy other than melanoma at the time of enrollment and within 2 years prior to the first TIL administration are excluded, except for adequately treated (with curative intent) basal or squamous cell carcinoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years.
Patients with treated CNS metastases > 1 cm or > 3 in number will be excluded if there is evidence of progressive CNS disease on brain imaging at least 90 days after treatment with surgery and/or radiation therapy.
Unable to comprehend and give informed consent
Male patients with WOCBP partners who do not agree to use two FDA-accepted forms of contraception during sexual intercourse with women of child-bearing potential from the start of ipilimumab and up to at least 6 months after ACT
WOCBP who do not agree to use 2 FDA forms of contraception during sexual intercourse from the start of ipilimumab and up to at least 6 months after ACT
Patients who have received ipilimumab in the past

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Combination Therapy	Tumor Infiltrating Lymphocytes (TIL)	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Combination Therapy	Administration of Lymphodepletion	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Combination Therapy	Cyclophosphamide as Part of Lymphodepletion	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Combination Therapy	Fludarabine as Part of Lymphodepletion	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Combination Therapy	Adoptive Cell Therapy with TIL	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Combination Therapy	High Dose IL-2	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
Combination Therapy	Ipilimumab	The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.

Primary Outcome Measures

Name	Time	Method
Occurrence of Dose Limiting Toxicity (DLT) Events	3 months	Occurrence of adverse events with dose limiting toxicity, per adverse event category.
Rate of Meeting Feasibility Requirements	3 months	Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	12 weeks	Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..
Progression Free Survival (PFS)	42 months	Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.