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Metastatic MelanomaPhase 1NCT03475134

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

A Phase 1 study testing TIL, Cyclophosphamide and Fludarabine in people with Metastatic Melanoma, run by Centre Hospitalier Universitaire Vaudois at 1 site in Switzerland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Melanoma
What is being tested?
TIL, Cyclophosphamide and Fludarabine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
1 siteSwitzerland
Study dates
21 Feb 2018to 6 Jun 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • 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.
  • 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.
  • 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.
  • Adequate cardiovascular function, with documented left ventricular ejection fraction (LVEF) ≥ 45%
  • 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.
  • 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.
  • Patients' toxicities from previous treatments must have recovered to a grade 1 or less according to NCI CTCAE 5.0, 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 immunosuppressive doses, 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.
  • For women of childbearing potential (WOCBP: sexually mature women who have not undergone a hysterectomy, have not been naturally post-menopausal for at least 12 consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 mIU/ml (milli international units/ml)):
  • Agreement to follow instructions for contraception for the couple from screening until month number 6 of the study, in case of women not receiving nivolumab; for women receiving nivolumab, they are required to follow instructions for contraception for the couple, during participation in the trial and for the 5 months after last nivolumab infusion.
  • Negative pregnancy test (urine or serum) during screening.
  • For men participating in the trial and their female partners: agreement to follow instructions for contraception for the couple 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 follow instructions for contraception for the couple, during participation in the trial and for the 7 months after last nivolumab infusion.

Who cannot join

  • 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.
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  • 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.
  • Subjects for whom there are concerns that they will not reliably comply with the requirements for contraception should not be enrolled into the study.
  • Any serious underlying medical condition that could interfere with study medication.
  • Any mental or other impairment that may compromise compliance with the requirements of the study.
  • 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).

Trial locations and contacts

1 site in 1 country.

Switzerland1 site

  • CHUV Oncology Department

    Lausanne, Canton of Vaud, 1011

Other trials in Switzerland

About this study

Official title: 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

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.

Read the 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. Between 3 and 24 hours after the infusion of TILs, optional IL-2 will be started as a bolus administration every eight hours at minimum form the start of each administration, for a maximum of eight doses, with a maximum interval of 24 hours. 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.

Being tested
TIL, Cyclophosphamide, Fludarabine, Interleukin-2, Nivolumab
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TILOther

    Adoptive transfer of Autologous Tumor-Infiltrating Lymphocytes

  • CyclophosphamideDrug

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

  • FludarabineDrug

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

  • Interleukin-2Drug

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

  • NivolumabDrug

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

Study groups in NCT03475134
Study groupRoleWhat they receive
TIL-ACT +/- Nivolumab rescueExperimentalNon-myeloablative lymphodepleting chemotherapy (cyclophosphamide and fludarabine), Tumor Infiltrating Lymphocyte (TIL)-Adoptive Cell Therapy (ACT), Interleukin-2 (IL-2), Nivolumab rescue
Receives: Other: TIL; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Interleukin-2; Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 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.

  2. 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)

    Measured: 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.

  3. Toxicity of TIL-ACT

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

    Measured: 37 days after chemotherapy start (TLT period)

Secondary outcomes (6)

  1. Feasibility of nivolumab rescue following TIL-ACT

    Number of patients included in the 'nivolumab rescue' population

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

  2. Toxicity of nivolumab rescue

    Number of patients receiving nivolumab with adverse events as assessed by CTCAE version 5.0

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

  3. Objective response rate (ORR)

    Best overall response

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

  4. Progression free survival (PFS) for TIL-ACT

    Time from start of NMA chemotherapy until objective tumor progression (using RECIST criteria and iRECIST) or death if not documented progression.

    Measured: 5 years

  5. Progression free survival (PFS) in the nivolumab rescue phase

    Time from start of nivolumab treatment until objective tumor progression (using RECIST criteria and iRECIST) or death if not documented progression.

    Measured: 5 years

  6. Overall survival (OS)

    Time from start of NMA chemotherapy until death

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Mar 2018
  2. Study start21 Feb 2018
  3. Primary completion9 Feb 2021
  4. Study completion6 Jun 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03475134
Sponsor's protocol ID
CHUV-DO-ATATIL-2016
Status last verified
Feb 2025
First submitted
16 Feb 2018
Last updated
11 Feb 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Ferreira HJ, Stevenson BJ, Pak H, Yu F, Almeida Oliveira J, Huber F, Taillandier-Coindard M, Michaux J, Ricart-Altimiras E, Kraemer AI, Kandalaft LE, Speiser DE, Nesvizhskii AI, Muller M, Bassani-Sternberg M. Immunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides. Nat Commun. 2024 Mar 15;15(1):2357. doi: 10.1038/s41467-024-46408-3.

    PubMed 38490980

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing TIL, Cyclophosphamide and Fludarabine in people with Metastatic Melanoma, run by Centre Hospitalier Universitaire Vaudois at 1 site in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 40 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03475134, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Feb 2025.

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