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NCT03475134 | SNCTP000002237

Etude de phase I pour évaluer la faisabilité et la sécurité d’un transfert adoptif de lymphocytes T autologues infiltrant la tumeur en combinaison avec de l’IL-2 suivi d’un rattrapage avec Nivolumab chez des patients atteints d’un mélanome métastatique avancé

Data source: BASEC (Imported from 16.10.2019), WHO (Imported from 13.10.2019)
Changed: 08.10.2019
Disease category: Melanom

Brief description of trial (Source of data: BASEC)

Cette étude s’adresse à des patients atteints d’un mélanome avancé ou métastatique et est effectuée pour évaluer la faisabilité d'un traitement combiné d’immunothérapie et pour s’assurer qu’il peut être administré en toute sécurité.

Cette thérapie (TIL-ACT) consiste à prélever les cellules immunes qui ont infiltré la tumeur du patient, particulièrement les lymphocytes T cytotoxiques (ou TILs, qui sont capables d'éliminer les cellules tumorales), puis à les faire proliférer en laboratoire avant de les perfuser au même patient. Comme ces cellules proviennent de la tumeur du patient, elles vont la reconnaître plus rapidement.

Cette étude d’immunothérapie dite de phase I prévoit d’inclure 10 patients qui recevront tous une chimiothérapie de lymphodéplétion (pour éliminer les lymphocytes T de la circulation et ainsi favoriser la greffe des TILs), puis la perfusion de leur propres TILs (pour attaquer la tumeur) ainsi que de l’IL-2 (pour augmenter l’activité anti-tumorale des TILs), et si le patient remplit certaines conditions, ceci sera suivi d’un traitement de rattrapage par le nivolumab (pour maintenir les TILs actifs contre la tumeur). La partie du traitement de lymphodéplétion et de la perfusion des TILs durera un mois environ. Le traitement de nivolumab démarrera dans l’année qui suit pour une durée maximale de 2 ans. Les patients seront suivis pendant 5 ans après perfusion des TILs (qui constitue le jour 0).
La chimiothérapie lympho-déplétive composée de fludarabine et de cyclophosphamide, l’IL-2 et le nivolumab sont autorisés en Suisse mais ne sont pas utilisés conformément au mode d’emploi (autre dosage ou autre indication). La perfusion des lymphocytes T infiltrant la tumeur constitue une thérapie innovante qui n’est pas encore autorisée en Suisse.

Health conditions investigated (Source of data: BASEC)

Mélanome métastatique

Health conditions (Source of data: WHO)

Metastatic Melanoma

Rare disease (Source of data: BASEC)

Yes

Intervention investigated (e.g. drug, therapy or campaign) (Source of data: BASEC)

Chimiothérapie lympho-déplétive suivie du transfert adoptif autologue de lymphocytes T, d'un traitement avec de l'interleukine-2 et, au besoin, d'un traitement de rattrapage avec le nivolumab.

Interventions (Source of data: WHO)

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

Criteria for participation in trial (Source of data: BASEC)

- Patient ayant donné son consentement pour le traitement TIL-ACT avant le début des procédures spécifiques à l'étude

- Diagnostique de mélanome confirmé histologiquement

- Patient présentant un mélanome de stade IV et dont la maladie a progressé suite à au moins un traitement standard de 1ère ligne.

-Patient ayant subit une résection tumorale ou une biopsie préalable et chez qui une pre-REP de TILs est disponible et adéquate pour une expansion REP ultérieure

Exclusion criteria (Source of data: BASEC)

- Mélanome uvéal (oculaire) primaire

- Patient présentant une pathologie maligne active secondaire (sauf exceptions) (la pathologie maligne n'est pas considérée comme active si la thérapie est terminée et que le médecin la considère comme traitée ou avec moins de 30% de risque de rechute à 5 ans après le diagnostique).

- Infections systémiques actives ou graves dans les 4 semaines précédant la chimiothérapie.

Inclusion/Exclusion Criteria (Source of data: WHO)


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:

• 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.

5. 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.

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 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.

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 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 rec

Further information on the trial in WHO primary registry

https://clinicaltrials.gov/show/NCT03475134

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT03475134

Further information on trial

Date trial registered

16.02.2018

Incorporation of the first participant

21.02.2018

Recruitment status

Recruiting

Academic title (Source of data: WHO)

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

Type of trial (Source of data: WHO)

Interventional

Design of the trial (Source of data: WHO)

Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).

Phase (Source of data: WHO)

Phase 1

Primary end point (Source of data: WHO)

Toxicity of TIL-ACT;Feasibility of TIL-ACT - successful infusion;Feasibility of TIL-ACT - successful Rapid Expansion Protocol (REP)

Secundary end point (Source of data: WHO)

Overall survival (OS);Progression free survival (PFS) in the nivolumab rescue phase;Progression free survival (PFS) for TIL-ACT;Objective response rate (ORR);Toxicity of nivolumab rescue;Feasibility of nivolumab rescue following TIL-ACT

Contact information (Source of data: WHO)

Please refer to primary and secondary sponsors

Trial sites

Trial sites in Switzerland (Source of data: BASEC)

Lausanne

Countries (Source of data: WHO)

Switzerland

Contact for further information on the trial

Details of contact in Switzerland (Source of data: BASEC)

Lana Kandalaft
+41 21 314 78 23
lana.kandalaft@chuv.ch

Contact for general information (Source of data: WHO)

George Coukos, MD, PhD;Lana Kandalaft, PharmD, PhD;George Coukos
Department director
+41213147823;+41213140627
lana.kandalaft@chuv.ch;george.coukos@chuv.ch

Contact for scientific information (Source of data: WHO)

George Coukos, MD, PhD;Lana Kandalaft, PharmD, PhD;George Coukos
Department director
+41213147823;+41213140627
lana.kandalaft@chuv.ch;george.coukos@chuv.ch

Principal Sponsor/Investigator

Principal sponsor (Source of data: WHO)

Centre Hospitalier Universitaire Vaudois

Further trial identification numbers

BASEC ID (Source of data: BASEC)

2016-02189

Secondary ID (Source of data: WHO)

CHUV-DO-ATATIL-2016