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TIL-ACT After NMA Chemo With IL-2 and Nivo Rescue in Metastatic Melanoma (mMEL)

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ClinicalTrials.gov Identifier: NCT03475134
Recruitment Status : Recruiting
First Posted : March 23, 2018
Last Update Posted : March 26, 2018
Sponsor:
Information provided by (Responsible Party):
George Coukos, MD, PhD, Centre Hospitalier Universitaire Vaudois

Tracking Information
First Submitted Date  ICMJE February 16, 2018
First Posted Date  ICMJE March 23, 2018
Last Update Posted Date March 26, 2018
Actual Study Start Date  ICMJE February 21, 2018
Estimated Primary Completion Date June 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 23, 2018)
  • Feasibility of TIL-ACT - successful Rapid Expansion Protocol (REP) [ Time Frame: Evaluated for each patient at day 0 (5-10 days after chemotherapy start). After day 0 of the last patient, the number of patients with successful REP/ start of TIL-ACT infusion will be calculated. ]
    Number of patients for whom TIL cultures after REP achieve the required cell number and release criteria to start TIL-ACT infusion
  • Feasibility of TIL-ACT - successful infusion [ Time Frame: Evaluated for each patient at day 0 (5-10 days after chemotherapy start), up to 60 mins after start of TIL-ACT infusion. At day 0 of the last patient, the number of patients with successful TIL-ACT infusion will be calculated. ]
    Number of patients receiving a complete TIL-ACT infusion (full NMA chemo and at least partial TIL infusion; no minimum IL-2 required)
  • Toxicity of TIL-ACT [ Time Frame: 37 days after chemotherapy start (TLT period) ]
    Number of patients with adverse events as assessed by CTCAE version 4.03
Original Primary Outcome Measures  ICMJE
 (submitted: March 16, 2018)
  • Feasibility of TIL-ACT - successful REP [ Time Frame: Evaluated for each patient at day 0 (5-10 days after chemotherapy start). After day 0 of the last patient, the number of patients with successful REP/ start of TIL-ACT infusion will be calculated. ]
    Number of patients for whom TIL cultures after REP achieve the required cell number and release criteria to start TIL-ACT infusion
  • Feasibility of TIL-ACT - successful infusion [ Time Frame: Evaluated for each patient at day 0 (5-10 days after chemotherapy start), up to 60 mins after start of TIL-ACT infusion. At day 0 of the last patient, the number of patients with successful TIL-ACT infusion will be calculated. ]
    Number of patients receiving a complete TIL-ACT infusion (full NMA chemo and at least partial TIL infusion; no minimum IL-2 required)
  • Toxicity of TIL-ACT [ Time Frame: 37 days after chemotherapy start (TLT period) ]
    Number of patients with adverse events as assessed by CTCAE version 4.03
Change History Complete list of historical versions of study NCT03475134 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2018)
  • Feasibility of nivolumab rescue following TIL-ACT [ Time Frame: 6 months from nivolumab start/ 100 days after end of nivolumab treatment ]
    Number of patients included in the 'nivolumab rescue' population
  • Toxicity of nivolumab rescue [ Time Frame: 6 months from nivolumab start/ 100 days after end of nivolumab treatment ]
    Number of patients receiving nivolumab with adverse events as assessed by CTCAE version 4.03
  • Objective response rate (ORR) [ Time Frame: 6, 12, 24, 36, 48 and 60 months ]
    Best overall response
  • Progression free survival (PFS) for TIL-ACT [ Time Frame: 5 years ]
    Time from start of NMA chemotherapy until objective tumor progression (using RECIST criteria and iRECIST) or death if not documented progression.
  • Progression free survival (PFS) in the nivolumab rescue phase [ Time Frame: 5 years ]
    Time from start of nivolumab treatment until objective tumor progression (using RECIST criteria and iRECIST) or death if not documented progression.
  • Overall survival (OS) [ Time Frame: 5 years ]
    Time from start of NMA chemotherapy until death
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 23, 2018)
  • Exploratory endpoints: immune monitoring [ Time Frame: 5 years ]
    Immune monitoring of the peripheral and tumor immune by Human Leukocyte Antigen (HLA) determination, immunohistochemistry, T-cell Receptor (TCR) sequencing, RNA expression and single-cell analyses, in order to correlate immune parameters in the tumor microenvironment with clinical response
  • Exploratory endpoints: tumor neoangiogenesis [ Time Frame: 5 years ]
    Tumor neoangiogenesis using 68Ga-NODAGA-RGD PET-CT to explore correlation with clinical response
  • Exploratory endpoints: tumor metabolism [ Time Frame: 5 years ]
    Tumor metabolism using 18FDG PET-CT to explore correlation with response to TIL-ACT
Original Other Pre-specified Outcome Measures
 (submitted: March 16, 2018)
  • Exploratory endpoints: immune monitoring [ Time Frame: 5 years ]
    Immune monitoring of the peripheral and tumor immune by HLA determination, immunohistochemistry, TCR sequencing, RNA expression and single-cell analyses, in order to correlate immune parameters in the tumor microenvironment with clinical response
  • Exploratory endpoints: tumor neoangiogenesis [ Time Frame: 5 years ]
    Tumor neoangiogenesis using 68Ga-NODAGA-RGD PET-CT to explore correlation with clinical response
  • Exploratory endpoints: tumor metabolism [ Time Frame: 5 years ]
    Tumor metabolism using 18FDG PET-CT to explore correlation with response to TIL-ACT
 
Descriptive Information
Brief Title  ICMJE TIL-ACT After NMA Chemo With IL-2 and Nivo Rescue in Metastatic Melanoma (mMEL)
Official Title  ICMJE Phase I Study to Assess Feasibility and Safety of Adoptive Transfer of Autologous Tumor-Infiltrating Lymphocytes in Combination With Interleukin-2 Followed by Nivolumab Rescue for Advanced Metastatic Melanoma
Brief Summary This is a single center, single arm phase I trial to test the feasibility and safety of Tumor- Infiltrating Lymphocyte-Adoptive Cell Therapy (TIL-ACT) followed by nivolumab rescue in advanced metastatic melanoma patients. The trial is based on lymphodepleting chemotherapy followed by ACT, utilizing ex vivo expanded TILs in combination with high dose interleukin-2 (IL-2) (optional, depending on patient's tolerance), followed by nivolumab rescue (if indicated) for a maximum duration of 2 years.
Detailed Description

The objective of the trial is to define the feasibility and safety of TIL-ACT in metastatic melanoma patients. In addition, the feasibility and safety of nivolumab rescue in patients with advanced metastatic disease is examined.

Study treatment will begin with intravenous non-myeloablative (NMA) lymphodepleting chemotherapy composed by fludarabine and cyclophosphamide. Both treatments will be started on the same day. Fludarabine will be administered for five days, and cyclophosphamide for two days. TILs will be infused intravenously over a period of 20-30 minutes. Two to three hours after the infusion of TILs, optional IL-2 will be started as a bolus administration every eight hours, for a maximum of eight doses. In order to avoid profound and long-lasting neutropenia, pegfilgrastim will be given subcutaneously. Supportive care will be given during the recovery phase from immune depletion and IL-2 therapy.

Nivolumab rescue will be initiated for eligible patients. For all patients, the first on-treatment radiological assessment will be performed 30 days after the TIL infusion, and then at month 3, and then every 12 weeks for the first 3 years of follow-up and every 4-6 months for the next 2 years, until progression.

Two Positron Emission Tomography-Computed Tomography (PET-CT) (18FDG (Fludeoxyglucose (F18)) and 68Ga-NODAGA-RGD ((68)Ga-labelled NOTA-conjugated RGD peptide) will be performed at baseline, following chemotherapy, and between 22-30 days after the TIL infusion.

The safety assessment for TIL-ACT (TLT (treatment-limiting toxicity) period) will extend from day -7 (when NMA chemo starts) till 30 days after TIL infusion.

The first three evaluable patients will be enroled no less than 2 weeks apart from each other. An interim analysis of safety at our center will be performed at the completion of the TLT period of the third evaluable patient.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Melanoma
Intervention  ICMJE
  • Other: TIL
    Adoptive transfer of Autologous Tumor-Infiltrating Lymphocytes
  • Drug: Cyclophosphamide
    Cyclophosphamide will be administered as an intravenous (IV) infusion for two days.
  • Drug: Fludarabine
    Fludarabine will be administered as an intravenous (IV) infusion for five days.
  • Drug: Interleukin-2
    After TIL infusion, IL-2 (optional) will be started as a bolus administration every eight hours, for a maximum of eight doses.
  • Drug: Nivolumab
    Nivolumab (3mg/kg) will be administered every two weeks for maximum 24 months.
Study Arms  ICMJE Experimental: TIL-ACT +/- Nivolumab rescue
Non-myeloablative lymphodepleting chemotherapy (cyclophosphamide and fludarabine), Tumor Infiltrating Lymphocyte (TIL)-Adoptive Cell Therapy (ACT), Interleukin-2 (IL-2), Nivolumab rescue
Interventions:
  • Other: TIL
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Drug: Interleukin-2
  • Drug: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 16, 2018)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2024
Estimated Primary Completion Date June 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Patient has provided informed consent to receive TIL-ACT treatment prior to initiation of any study-specific activities/procedures.
  2. Histologically confirmed diagnosis of melanoma.
  3. Patients with stage IV melanoma who have progressed on at least 1 standard first line therapy, including but not limited to chemotherapy, B-Raf proto-oncogene, serine/threonine kinase (BRAF) and Mitogen-Activated Protein Kinase/Extracellular signal-Regulated Kinase (MEK) inhibitors, anti-Cytotoxic T-lymphocyte Associated 4 (CTLA4), anti-Programmed Cell Death-1 (PD-1), anti-Programmed Cell Death Ligand-1 (PD-L1) or anti-Lymphocyte-activation gene 3 (LAG3) antibodies and/or the combination.
  4. Patients who have previously undergone tumor resection or biopsy and for whom pre-REP TILs are already available and adequate for further REP expansion. The following conditions have to be met:

    • Pre-REP TIL cultures obtained are required to have 5-50 x10^6 cells, ≥70% viable (if cryopreserved, this viability criterion applies to pre-thawing sample).
    • In cases where more than one collected material is available for a given patient, the "Center of Experimental Therapeutics" (CTE) "Good Manufacturing Practices (GMP) Manufacturing facility (in agreement with the sponsor) will decide which material will be used for further expansion.
    • Pre-REP TIL (only for cryopreserved material) must meet quality control (QC) release criteria as specified in the Investigator's Brochure (IB).
  5. Male or female age ≥ 18 to ≤ 70 years at the time of informed consent.
  6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) of 0, 1 or 2
  7. Life expectancy of greater than 12 weeks.
  8. Radiologically measurable and clinically evaluable disease (as per RECIST v1.1).
  9. At least one biopsiable metastatic lesion
  10. In case of brain metastasis, patients must have three or fewer residual brain metastases that are less than 1 cm in diameter and asymptomatic, provided that all lesions have been adequately treated with stereotactic radiation therapy or gamma knife therapy. Lesions should be stable for 1 month, as determined by CT or MRI evaluation, after treatment and should not require steroids. Patients with surgically resected brain metastasis are eligible independently of the size of the metastasis.
  11. Serology:

    • Seronegative for HIV infection (anti-HIV-1/-2)
    • Seronegative for hepatitis B infection (HBs Ag, total anti-hemoglobin C (HBc), anti-HBs). Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen HBsAg test and a positive anti-HBc antibody test) are eligible, if hepatitis B virus (HBV) DNA test is negative.
    • Seronegative for hepatitis C infection (anti-HCV): if a patient has positive anti-HCV antibody, a negative hepatitis C virus (HCV) RNA need to be obtain to register the patient.
  12. Hematology

    • Absolute neutrophil count ≥ 1 x 10^9 cell/L without the support of granulocyte colony stimulating factor (G-CSF).
    • Platelet count ≥ 100 x 10^9 cell/L
    • Hemoglobin ≥ 80 g/L. Subjects may be transfused to reach this cut-off.
  13. Coagulation

    • International normalization ratio (INR) or prothrombin time (PT) ≤1.5 times the upper limit of normal (x ULN) unless the subject is receiving anticoagulant therapy as long as PT and partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.
    • PTT or activated PTT (aPTT) ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy as long as PT and PTT/aPTT is within therapeutic range of intended use of anticoagulants.
  14. Chemistry:

    • Serum alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) ≤ to 3 x ULN (even in case of liver metastasis).
    • Total bilirubin ≤1.5 x ULN, except in patients with Gilbert's Syndrome who must have a total bilirubin ≤2.5 x ULN
    • Serum creatinine ≤1.5 x ULN or creatinine clearance by Cockcroft-Gault formula ≥ 50 ml/min.
  15. Adequate cardiovascular function, with documented left ventricular ejection fraction (LVEF) ≥ 45%
  16. Adequate respiratory function with forced expiratory volume in 1 second (FEV1) ≥ 65% predicted, forced vital capacity (FVC) ≥ than 65% predicted and diffusing capacity of the lung for carbon monoxide (CO) (DLCO) ≥ than 50% predicted corrected.
  17. At the time the patient receives the preparative regimen (NMA chemotherapy), ≥21 days must have elapsed from the time of any antibody therapy that could affect an anti-cancer immune response, including but not limited to anti-CTLA4, anti-PD-1, PD-L1 or anti-LAG3 antibody therapy or their combination.
  18. Patients' toxicities from previous treatments must have recovered to a grade 1 or less according to NCI CTCAE 4.03, except for immune mediated-toxicities described below, as long as they do not put at risk the patient's condition and do not require systemic immunosuppressive steroids at any dose, including but not limited to:

    • Alopecia
    • Skin disorders
    • Stable neuropathy
    • Endocrinopathies requiring replacement treatment

    Note: For other medical conditions, prior discussion and agreement with the Principal Investigator is mandatory.

    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.

  19. For women of childbearing potential (WOCBP: sexually mature women who have not undergone a hysterectomy, have not been naturally post‑menopausal for at least 24 consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 mIU/ml (milli international units/ml)):

    • Agreement to use 2 acceptable methods of contraception from screening until month number 6 of the study, in case of women not receiving nivolumab; for women receiving nivolumab, they are required to use two forms of acceptable contraception, during participation in the trial and for the 5 months after last nivolumab infusion.
    • Negative pregnancy test (urine or serum) during screening.
  20. For men participating in the trial and their female partners: agreement to use 2 acceptable methods of effective contraception from screening until month number 6 of the study in case of patients not receiving nivolumab; when patients are receiving nivolumab, they are required to use two forms of acceptable contraception, during participation in the trial and for the 7 months after last nivolumab infusion.

Exclusion criteria:

  1. Primary uveal melanoma.
  2. Patients with an active second malignancy. Patients who have a history of malignancy are not considered to have an active malignancy if they have completed therapy and are considered by their treating investigator to be at ≤ 30% risk for relapse in 5 years following diagnosis.
  3. Active systemic infections or severe infections within four weeks prior to beginning of NMA chemotherapy.
  4. History of myocardial infarction or unstable angina within six months of enrolment
  5. Patient requiring regular systemic immunosuppressive therapy (for example for organ transplantation, chronic rheumatologic disease); all immunosuppressive medications including but not limited to steroids, mycophenolate mofetil, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor a (TNFa) agents must have been discontinued within the last two weeks prior to starting NMA chemotherapy.

    Note: Use of inhaled or topical steroids or corticosteroid use for radiographic procedures is permitted.

    Note: The use of physiologic corticosteroid replacement therapy is permitted.

  6. History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin)
  7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  8. History of immediate hypersensitivity reaction to aminoglycosides (e.g. gentamicin or streptomycin).
  9. Participation in a research project using radiation sources exceeding an effective dose of 5mSv (milli Sievert) with no direct benefit within the 12 last months.
  10. Women who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  11. Subjects for whom there are concerns that they will not reliably comply with the requirements for contraception should not be enrolled into the study.
  12. Any serious underlying medical condition that could interfere with study medication.
  13. Any mental or other impairment that may compromise compliance with the requirements of the study.
  14. Patient participation in any other study currently receiving treatment. If the patient is in the follow-up period, he/she may be enrolled, as far as no less than 21 days have elapsed since the last previous treatment administration and the preparative regimen (NMA chemotherapy).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lana Kandalaft, PharmD, PhD +41213147823 lana.kandalaft@chuv.ch
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03475134
Other Study ID Numbers  ICMJE CHUV-DO-ATATIL-2016
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party George Coukos, MD, PhD, Centre Hospitalier Universitaire Vaudois
Study Sponsor  ICMJE Centre Hospitalier Universitaire Vaudois
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: George Coukos, MD, PhD Department director
PRS Account Centre Hospitalier Universitaire Vaudois
Verification Date March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP