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

  • STATUS
    Recruiting
  • End date
    Jun 30, 2026
  • participants needed
    20
  • sponsor
    Centre Hospitalier Universitaire Vaudois
Updated on 19 July 2020

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.

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.

Details
Treatment cyclophosphamide, Fludarabine, Nivolumab, Interleukin-2, TIL
Clinical Study IdentifierNCT03475134
SponsorCentre Hospitalier Universitaire Vaudois
Last Modified on19 July 2020

Adding a note
adding personal notes guide

Select a piece of text and start making personal notes.

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Metastatic Melanoma?
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. 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 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 postmenopausal 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. 20\. 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

Exclusion Criteria

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
\. 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)
Clear my responses

How to participate?

Step 1 Connect with a site
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar
Name

Primary Contact

site
Name

Phone Email

0/250
Please verify that you are not a bot.
Step 2 Get screened

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more
Step 3 Enroll in the clinical study

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more
Step 4 Get your study results

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

Study

user name

Annotated by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No made yet