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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

Datenbasis: BASEC (Import vom 20.03.2019), WHO (Import vom 17.03.2019)
Geändert: 15.03.2019
Krankheitskategorie: Melanom

Zusammenfassende Beschreibung der Studie (Datenquelle: 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.

Untersuchte Krankheiten (Datenquelle: BASEC)

Mélanome métastatique

Health conditions (Datenquelle: WHO)

Metastatic Melanoma

Seltene Krankheit (Datenquelle: BASEC)

Ja

Untersuchte Intervention (z.B. Medikament, Therapie, Kampagne) (Datenquelle: 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 (Datenquelle: WHO)

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

Kriterien zur Teilnahme an der Studie (Datenquelle: 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

Ausschlusskriterien (Datenquelle: 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 (Datenquelle: 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:

- Pre-REP TIL cultures obtained are required to have 5-50 x10^6 cells, =70% viable
(if cryopreserved, this viability criterion applies to pre-thawing sample).

- In cases where more than one collected material is available for a given patient,
the Center of Experimental Therapeutics (CTE) Good Manufacturing Practices
(GMP) Manufacturing facility (in agreement with the sponsor) will decide which
material will be used for further expansion.

- Pre-REP TIL (only for cryopreserved material) must meet quality control (QC)
release criteria as specified in the Investigator's Brochure (IB).

5. Male or female age = 18 to = 70 years at the time of informed consent.

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 4.03, 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 any dose, 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 24
consecutive months or have a serum follicle-stimulating hormone (FSH) < 40 mIU/ml
(milli international units/ml)):

- Agreement to use 2 acceptable methods of contraception from screening until month
number 6 of the study, in case of women not receiving nivolumab; for women
receiving nivolumab, they are required to use two forms of acceptable
contraception, 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 use 2
acceptable methods of effective con

Weitere Angaben zur Studie im WHO-Primärregister

https://clinicaltrials.gov/show/NCT03475134

Weitere Angaben zur Studie aus der Datenbank der WHO (ICTRP)

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

Weitere Informationen zur Studie

Registrationsdatum der Studie

16.02.2018

Einschluss der ersten teilnehmenden Person

21.02.2018

Rekrutierungsstatus

Recruiting

Wissenschaftlicher Titel (Datenquelle: 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

Studientyp (Datenquelle: WHO)

Interventional

Design der Studie (Datenquelle: WHO)

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

Phase (Datenquelle: WHO)

Phase 1

Primäre Endpunkte (Datenquelle: WHO)

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

Sekundäre Endpunkte (Datenquelle: 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

Kontakt für Auskünfte (Datenquelle: WHO)

Please refer to primary and secondary sponsors

Studiendurchführungsorte

Durchführungsorte in der Schweiz (Datenquelle: BASEC)

Lausanne

Durchführungsländer (Datenquelle: WHO)

Switzerland

Kontakt für weitere Auskünfte zur Studie

Angaben zur Kontaktperson in der Schweiz (Datenquelle: BASEC)

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

Kontakt für allgemeine Auskünfte (Datenquelle: WHO)

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

Kontakt für wissenschaftliche Auskünfte (Datenquelle: WHO)

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

Studienverantwortliche

Hauptsponsor (Datenquelle: WHO)

Centre Hospitalier Universitaire Vaudois

Weitere Studienidentifikationsnummern

BASEC ID (Datenquelle: BASEC)

2016-02189

Secondary ID (Datenquelle: WHO)

CHUV-DO-ATATIL-2016