Advanced Melanoma
Conditions
Keywords
Tumor-infiltrating Lymphocyte (TIL) Transfer, Nivolumab, metastatic melanoma, anti-PD-1 therapy, failed immunotherapy, personalized Investigational Medicinal Product (IMP)
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.
Interventions
DRUGCombination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2
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.
Sponsors
GMP network of Basel
University Hospital, Basel, Switzerland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | First 3 months during treatment | Number of Adverse Events to analyze safety of the combination of TIL transfer with IL-2 therapy |
| Change in body temperature (Degree Celsius) | 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 Vital signs ( body temperature) to analyze the safety of the combination of TIL transfer with IL-2 therapy |
| Change in blood pressure (mmHg) | 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 Vital signs ( blood pressure) to analyze the safety of the combination of TIL transfer with IL-2 therapy |
| Change in heart beat (beats/minute) | 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 Vital signs (heart beat) to analyze the safety of the combination of TIL transfer with IL-2 therapy |
| Change in respiratory frequency (inspiration/minute) | 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 Vital signs (respiratory frequency) to analyze the safety of the combination of TIL transfer with IL-2 therapy |
| Change in full blood Counts (number of cells) | at each treatment visit (every 2 weeks) from Day 0= Baseline to week 42 | Change in Laboratory Parameter (full blood counts) to analyze haematological toxicity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic Response | during the first 3 months after TIL transfer | Response measured by 18FDG-uptake |
| Overall Response Rate (ORR) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan | First 3 months after TIL administration | Changes of Tumor volume according to RECIST 1.1 |
| Number of Serious Adverse Events according to CTCAE 4.0 | 2 years after TIL transfer | Overall Safety during whole treatment period analyzed by collection of Serious Adverse Events according to CTCAE 4.0 |
| Progression Free Survival (PFS) | between pre-treatment and 3-months post-treatment | Progression free survival, defined as the time between registration to progression or death whichever occurs first. |
| Overall Survival (OS) defined as the time between registration to death due to any cause | 2 years after TIL transfer | 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. |
| Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | between pre-treatment and 3-months post-treatment | Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria |
| Objective response rate (ORR) | 2 years after TIL transfer | 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 |
| Number of Adverse Events according to CTCAE 4.0 | 2 years after TIL transfer | Overall Safety during whole treatment period analyzed by collection of Adverse Events according to CTCAE 4.0 |
Countries
Switzerland
Outcome results
None listed