Tumor Infiltrating Lymphocytes Adjuvant Therapy of Melanoma (TIL)

TIL (Tumor Infiltrating Lymphocytes) and IL2 (Interleukin 2) Versus Abstention as Adjuvant Treatment in Melanoma With Only One Invaded Lymphnode After Lymphnodes Excision

The objective of this multicentric Phase III study is to confirm the results of the phase I-II study (Dreno B & Al. Cancer Immunol Immunother 2002; 51: 539-456) which demonstrated the preventive effect of a treatment by TIL (Tumor Infiltrating Lymphocytes) combined with IL2 (Interleukin 2; low dose injected subcutaneously) on the metastatic relapse in the stage III melanoma patients with only one invaded lymphnode.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: TIL + IL2

Detailed Description

In this open, multicentric (Grenoble, Montpellier, Nantes, Angers, Caen, Le Mans, Poitiers, Rennes, Tours) randomized study, selected patients with only one invaded lymphnode confirmed by anatomopathological exam will be randomized to one of the following arms: 1-Control group: patients of this group will not receive any treatment and will have the same clinical follow-up as the treated group. 2- TIL-IL2 group: treated patients will receive two injections of TIL combined with IL2. Tumor Infiltrating Lymphocytes will be obtained from a small piece of tumour tissue removed from the invaded lymphnode after surgery. TIL will be grown in larger number in laboratory during 6 weeks. Patients randomized in treatment arm will receive two injection of TIL (the first about 6 and the second about 10 weeks post-surgery). Administration of TIL will be combined with a low dose of IL2 (6 million U.I. per day) injected subcutaneously from J1 to J5 and J8 to J12 following the day of TIL infusion. The same dose and duration of IL2 treatment will be used for the second injection of TIL performed one month later. After 2 months adjuvant therapy, patients received no other treatment. Only a regular follow-up was performed.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Angers, France
    • CHU Angers
  • Caen, France
    • CHU Caen
  • Grenoble, France
    • Grenoble University Hospital
  • Le Mans, France
    • CH Le Mans
  • Montpellier, France
    • Montpellier University Hospital
  • Nantes, France, 44093
    • Nantes University Hospital
  • Poitiers, France
    • CHU Poitiers
  • Rennes, France
    • CHU Rennes
  • Tours, France
    • Chru Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 75 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Melanoma stage III (regional lymph node recurrence). Will be selected the patients with only one invaded lymph node confirmed by anatomopathological exam after lymph nodes excision.
• Absence of visceral metastases verified by physical examination, chest radiography, liver echography and brain-chest-liver CT-Scan.
• Age < 75 years, both genders
• ECOG 0-2, Karnofsky > 80%.
• Negative pregnancy test performed at the screening visit for fertile women.
• The potentially fertile women must use an oral contraception or an intra-uterine device (IUD) until three months following the last injection of the study treatment.
• The patients must have fully recovered from surgery.
• HIV 1/2: The patients must be negative for antibodies HIV 1 and HIV 2 and for Ag P24 or DGV HIV.
• HBV: The patients must be negative for the antigen, but can be positive for the antibodies but with a negative DNA PCR.
• HCV: The patients must be negative for the antibodies.
• HTLV ½: The patients must be negative for the antibodies.

• Following laboratory results:

  • Hemoglobin: ≥ 10 g/dl
  • WBC: ≥ 4000/µl
  • Lymphocytes: ≥ 700/µl
  • Platelet count: ≥ 100.000/µl
  • Serum creatinine: < 2.0 mg/dl or £ 177 mmol/l
  • Serum Bilirubin: < 2.0 mg/dl or £ 34.2 mmol/l
  • ASAT and ALAT: < 2.5 x the upper limit of normal.

Exclusion criteria:

• Patient with more than one invaded lymph node confirmed by anatomopathological exam.
• Presence of melanoma metastases discovered by clinical or radiological examination at the screening visit.
• Patients must not have received any Chemotherapy, immunotherapy or radiotherapy within the preceding 4 weeks (6 weeks since prior nitrosurea and mitomycin C therapies).
• Presence of cardiac affections (congestive cardiac insufficiency, coronaropathy, not controlled HTA).
• Any serious active medical illnesses, for example: Active systemic infections requiring of antibiotics, coagulation disorders or any other condition which requires concomitant medications not allowed during this study.
• Presence of the second active cancer other than surgically cured non-melanoma skin cancer or cervical carcinoma in-situ.
• Any affection requiring a systemic corticotherapy or a treatment by Interferon A.
• Any active auto-immune disease including the insulin-dependent diabetes or a immunodeficiency. The vitiligo is not an exclusion criteria.
• Thyroid dysfunction not responsive to therapy.
• Positive Serology for HIV, HVB, HVC or HTLV1/2.
• Woman pregnant or nursing or without an effective contraception.
• Incapacity to give written consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TIL+IL2; TIL + IL2	Drug: TIL + IL2; Patients are treated with 2 injections Of TIL (1st injection M1 and the second M2)The received concomitant IL2 at M1 and M2 on days Jo (injection TIL) to J5 and J8 to J12
NO_INTERVENTION: control; Patients are not treated

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determination of the duration of the relapse-free interval.	5 years
Physical examination, every 2 months until M18 then every 3 months until M36 then every 4 months up to 5 years, then once per year with a clinical examination only.	every 2 months until M18then every 3 months until M36 then every 4 months up to 5 years
Abdominal echography will be performed at the screening visit, M4, M8, M12 and then every 6 months until 5ans.	M4, M8, M12 and then every 6 months until 5ans.
CT-Scan will be performed before the first administration of study treatment (at the time of screening visit), every 6 months during 2 years and then every years up to 5 years.	every 6 months during 2 years and then every years up to 5 years.

Secondary Outcome Measures

Outcome Measure	Time Frame
Determine of overall survival	5 years
To define safety and toxicity of TIL/IL2 treatment	5 years
Evaluation of immunological responses	M0, J56, M12
Analysis of the clinical, biological and histological factors on the survival of the patients	at inclusion and each month

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Investigators: Principal Investigator: Brigitte DRENO, MD, Nantes University Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (ACTUAL): March 1, 2012
• Study Completion (ACTUAL): March 1, 2012

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (ESTIMATE): September 20, 2005

Study Record Updates

• Last Update Posted (ACTUAL): June 1, 2017
• Last Update Submitted That Met QC Criteria: May 31, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: immunotherapy; melanoma; TIL; Adjuvant therapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: BRD/04/01-D