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

NCT03475134 | Completed Phase 1 DMC

• 1 other identifier: CHUV-DO-ATATIL-2016
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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 unresectable locally advanced or 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.

Conditions

Metastatic Melanoma

Outcome Measures

Primary Outcomes (3)

• Feasibility of TIL-ACT - successful Rapid Expansion Protocol (REP)

  Number of patients for whom TIL cultures after REP achieve the required cell number and release criteria to start TIL-ACT infusion

  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.

• Feasibility of TIL-ACT - successful infusion

  Number of patients receiving a complete TIL-ACT infusion (full NMA chemo and at least partial TIL infusion; no minimum IL-2 required)

  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.

• Toxicity of TIL-ACT

  Number of patients with adverse events as assessed by CTCAE version 5

  37 days after chemotherapy start (TLT period)

Secondary Outcomes (6)

• Feasibility of nivolumab rescue following TIL-ACT

  6 months from nivolumab start/ 100 days after end of nivolumab treatment

• Toxicity of nivolumab rescue

  6 months from nivolumab start/ 100 days after end of nivolumab treatment

• Objective response rate (ORR)

  6, 12, 24, 36, 48 and 60 months

• Progression free survival (PFS) for TIL-ACT

  5 years

• Progression free survival (PFS) in the nivolumab rescue phase

  5 years

Other Outcomes (3)

• Exploratory endpoints: immune monitoring

  5 years

• Exploratory endpoints: tumor neoangiogenesis

  5 years

• Exploratory endpoints: tumor metabolism

  5 years

Study Arms (1)

TIL-ACT +/- Nivolumab rescue

EXPERIMENTAL

Non-myeloablative lymphodepleting chemotherapy (cyclophosphamide and fludarabine), Tumor Infiltrating Lymphocyte (TIL)-Adoptive Cell Therapy (ACT), Interleukin-2 (IL-2), Nivolumab rescue

Other: TIL; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Interleukin-2; Drug: Nivolumab

Interventions

TIL OTHER

Adoptive transfer of Autologous Tumor-Infiltrating Lymphocytes

TIL-ACT +/- Nivolumab rescue

Cyclophosphamide DRUG

Cyclophosphamide will be administered as an intravenous (IV) infusion for two days.

TIL-ACT +/- Nivolumab rescue

Fludarabine DRUG

Fludarabine will be administered as an intravenous (IV) infusion for five days.

TIL-ACT +/- Nivolumab rescue

Interleukin-2 DRUG

After TIL infusion, IL-2 (optional) will be started as a bolus administration every eight hours, for a maximum of eight doses.

TIL-ACT +/- Nivolumab rescue

Nivolumab DRUG

Nivolumab will be administered for maximum 24 months as follows: first year: 240 mg every 2 weeks; second year: 480 mg every 4 weeks.

TIL-ACT +/- Nivolumab rescue

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has provided informed consent to receive TIL-ACT treatment prior to initiation of any study-specific activities/procedures.
• Histologically confirmed diagnosis of melanoma.
• Patients with unresectable locally advanced (stage IIIc) or metastatic (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.
• 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:
• The CTE GMP Manufacturing facility / sponsor representative confirms that adequate pre-REP material (in quantity and quality) is available to move to REP. In cases where more than one collected material is available for a given patient, the CTE GMP Manufacturing facility (in agreement with the sponsor) will decide which material will be used for further expansion.
• Male or female age ≥ 18 to ≤ 70 years at the time of informed consent. Patients aged \>70 will be evaluated by the investigator, and decision will be made according to patient's status, upon agreement with the PI.
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) of 0, 1 or 2
• Life expectancy of greater than 12 weeks.
• Radiologically measurable and clinically evaluable disease (as per RECIST v1.1).
• At least one biopsiable metastatic lesion
• 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.
• 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.

You may not qualify if:

• Primary uveal melanoma.
• Patients with symptomatic and/or untreated brain metastases. Patients with definitively-treated brain metastases will be considered for enrollment after agreement with PI, as long as lesions are stable for ≥ 14 days prior to beginning the chemotherapy, there are no new brain lesions, and the patient does not require ongoing corticosteroid treatment.
• Patients with an active second malignancy except for
• non-melanoma skin cancer that has been apparently cured or successfully resected
• carcinoma in situ as long as they have been adequately treated. 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.
• Active systemic infections or severe infections within four weeks prior to beginning of NMA chemotherapy.
• History of myocardial infarction or unstable angina within six months of enrolment
• 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.
• History of idiopathic pulmonary fibrosis or evidence of active pneumonitis (any origin)
• History of severe immediate hypersensitivity reaction to any of the agents used in this study.
• History of immediate hypersensitivity reaction to aminoglycosides (e.g. gentamicin or streptomycin).
• 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.
• Women who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead

Study Sites (1)

CHUV Oncology Department

Lausanne, Canton of Vaud, 1011, Switzerland

Location

MeSH Terms

Conditions

Melanoma

Interventions

Cyclophosphamide; fludarabine; Interleukin-2; Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins

Study Officials

• George Coukos, MD, PhD

  Department director

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: March 23, 2018
• Study Start: February 21, 2018
• Primary Completion: February 9, 2021
• Study Completion: June 6, 2024
• Last Updated: February 11, 2025

Record last verified: 2025-02

Locations

CH (1)