Clinical trial NCT04165967: Adoptive Tumor-infiltrating Lymphocyte Transfer With Nivolumab for Melanoma
Official title: A Phase I Study of Adoptive Tumor-infiltrating Lymphocyte Transfer in Combination With Nivolumab in Patients With Advanced Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Melanoma
Keywords: Tumor-infiltrating Lymphocyte (TIL) Transfer
Nivolumab
metastatic melanoma
anti-PD-1 therapy
failed immunotherapy
personalized Investigational Medicinal Product (IMP)
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: GMP network of Basel
First posted: 2019-11-18
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Adverse Events
timeFrame: First 3 months during treatment
measure: Change in body temperature (Degree Celsius)
timeFrame: 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)
measure: Change in blood pressure (mmHg)
timeFrame: 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)
measure: Change in heart beat (beats/minute)
timeFrame: 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)
measure: Change in respiratory frequency (inspiration/minute)
timeFrame: 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)
measure: Change in full blood Counts (number of cells)
timeFrame: at each treatment visit (every 2 weeks) from Day 0= Baseline to week 42
Secondary outcomes:
measure: Overall Response Rate (ORR) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan
timeFrame: First 3 months after TIL administration
measure: Progression Free Survival (PFS)
timeFrame: between pre-treatment and 3-months post-treatment
measure: Overall Survival (OS) defined as the time between registration to death due to any cause
timeFrame: 2 years after TIL transfer
measure: Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
timeFrame: between pre-treatment and 3-months post-treatment
measure: Objective response rate (ORR)
timeFrame: 2 years after TIL transfer
measure: Number of Adverse Events according to CTCAE 4.0
timeFrame: 2 years after TIL transfer
measure: Metabolic Response
timeFrame: during the first 3 months after TIL transfer
measure: Number of Serious Adverse Events according to CTCAE 4.0
timeFrame: 2 years after TIL transfer
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: Division of Medical Oncology and Cancer Immunology, University Hospital Basel
Study officials:
affiliation: Division of Medical Oncology and Cancer Immunology, University Hospital Basel
name: Heinz Läubli, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Medical Oncology and Cancer Immunology, University Hospital Basel
name: Alfred Zippelius, Prof.
role: STUDY_CHAIR
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