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Adoptive Tumor-infiltrating Lymphocyte Transfer With Nivolumab for Melanoma (BaseTIL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04165967
Recruitment Status : Not yet recruiting
First Posted : November 18, 2019
Last Update Posted : February 19, 2020
Sponsor:
Collaborator:
GMP network of Basel
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

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.


Condition or disease Intervention/treatment Phase
Advanced Melanoma Drug: Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Intervention Model: Single Group Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Adoptive Tumor-infiltrating Lymphocyte Transfer in Combination With Nivolumab in Patients With Advanced Melanoma
Estimated Study Start Date : July 2020
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : August 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma
Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Tumor-infiltrating lymphocyte product (TIL) transfer
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

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.

Other Names:
  • TIL Transfer
  • anti-PD-1 Therapy Nivolumab
  • low dose IL-2




Primary Outcome Measures :
  1. Number of Adverse Events [ Time Frame: First 3 months during treatment ]
    Number of Adverse Events to analyze safety of the combination of TIL transfer with IL-2 therapy

  2. Change in body temperature (Degree Celsius) [ Time Frame: 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

  3. Change in blood pressure (mmHg) [ Time Frame: 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

  4. Change in heart beat (beats/minute) [ Time Frame: 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

  5. Change in respiratory frequency (inspiration/minute) [ Time Frame: 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

  6. Change in full blood Counts (number of cells) [ Time Frame: 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 Outcome Measures :
  1. Overall Response Rate (ORR) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan [ Time Frame: First 3 months after TIL administration ]
    Changes of Tumor volume according to RECIST 1.1

  2. Progression Free Survival (PFS) [ Time Frame: between pre-treatment and 3-months post-treatment ]
    Progression free survival, defined as the time between registration to progression or death whichever occurs first.

  3. Overall Survival (OS) defined as the time between registration to death due to any cause [ Time Frame: 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.

  4. Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [ Time Frame: between pre-treatment and 3-months post-treatment ]
    Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

  5. Objective response rate (ORR) [ Time Frame: 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

  6. Number of Adverse Events according to CTCAE 4.0 [ Time Frame: 2 years after TIL transfer ]
    Overall Safety during whole treatment period analyzed by collection of Adverse Events according to CTCAE 4.0

  7. Metabolic Response [ Time Frame: during the first 3 months after TIL transfer ]
    Response measured by 18FDG-uptake

  8. Number of Serious Adverse Events according to CTCAE 4.0 [ Time Frame: 2 years after TIL transfer ]
    Overall Safety during whole treatment period analyzed by collection of Serious Adverse Events according to CTCAE 4.0



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04165967


Contacts
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Contact: Heinz Läubli, MD PhD +41612655074 heinz.laeubli@usb.ch
Contact: Frank Stenner, Prof. +41612655074 frank.stenner@usb.ch

Locations
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Switzerland
Division of Medical Oncology and Cancer Immunology, University Hospital Basel
Basel, Switzerland, 4031
Contact: Heinz Läubli, MD PhD    +41 61 265 5074    heinz.laeubli@usb.ch   
Contact: Frank Stenner, Prof.    +41 61 265 5074    frank.stenner@usb.ch   
Sponsors and Collaborators
University Hospital, Basel, Switzerland
GMP network of Basel
Investigators
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Principal Investigator: Heinz Läubli, MD PhD Division of Medical Oncology and Cancer Immunology, University Hospital Basel
Study Chair: Alfred Zippelius, Prof. Division of Medical Oncology and Cancer Immunology, University Hospital Basel

Publications:

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Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT04165967    
Other Study ID Numbers: 2019-01908; me18Laeubli
First Posted: November 18, 2019    Key Record Dates
Last Update Posted: February 19, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Basel, Switzerland:
Tumor-infiltrating Lymphocyte (TIL) Transfer
Nivolumab
metastatic melanoma
anti-PD-1 therapy
failed immunotherapy
personalized Investigational Medicinal Product (IMP)
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Melanoma
Nevi and Melanomas
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents