Etude : TK008 /



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Acronyme
Nom
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme : TK008

Nom :

Traitement :

Type d'étude : Ciblage moléculaire / Innovation thérapeutique

Dernière MÀJ : 24/05/2019
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : TK008: Randomized Phase III Trial of Haploidentical HCT With or Without an Add Back Strategy of HSV-Tk Donor Lymphocytes in Patients With High Risk Acute Leukemia

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C92 - Leucémie myéloïde

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C91 - Leucémie lymphoïde
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : Delayed immune-reconstitution remains one of the main limitation of haploidentical stem cell transplantation. The risk of severe infections remains high for several months and CD3+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA (Human Leukocyte Antigen) disparity, and a reduced thymic function in adults and differences in host/donor antigen presenting cells are contributing causes.

The infusions of HSV-TK engineered lymphocytes may represent a significant therapeutic improvement in haploidentical HCT (hematopoietic cell transplantation), because it remarkably may enhance both GvL (Graft versus Leukemia) activity, thus reducing the occurrence of disease relapse, and post-transplant immune reconstitution in the absence of chronic immune suppression, thus decreasing the rate of both post-transplant opportunistic infections and transplant-related mortality. Furthermore, the efficient control of GvHD achieved via the suicide mechanism allows also the multiple infusion of HSV-TK-treated donor lymphocytes, when needed, that might further improve post-transplant host immune reconstitution, and survival in patients receiving haplo-HCT. Finally, this therapeutic approach can become a valuable option for all candidates, including patients with advanced disease and older age.

The proposed clinical trial represents an innovative therapeutic treatment for patients affected by high risk acute leukemia, who have undergone haploidentical stem cell transplantation.

Study arms:
- Experimental: A
HSV-TK engineering donor Lymphocytes
Intervention: Genetic: HSV-Tk
- Active Comparator: B
T-cell depleted or T-cell replete strategies
Intervention: Other: T-cell depleted or T-cell replete strategies

Intervention:
- Genetic: HSV-Tk
Infusion of approximately 1±0.2 x 10^7 HSV-Tk genetically modified CD3+ cells/Kg between day +21 and day +49 after haploidentical HCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
- Other: T-cell depleted or T-cell replete strategies
Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T cells (1 x 10^4/Kg) or unmanipulated haploidentical stem cell transplantation followed by high-dose cyclophosphamide as part of GvHD prophylaxis

Current primary outcome:
Disease-free survival (DFS) [ Time Frame: from the date of randomization, assessed up to 12 months ], measured from the date of randomization until the date of relapse (or progression), or death from any cause, whichever occurs first.

Current secondary outcomes:
- Overall Survival (OS) [ Time Frame: from the date of randomization to the date of death, assessed up to 12 months ]
- any death without previous occurrence of a documented relapse (or progression).
- Chronic GvHD-free/relapse-free survival (GRFS) [ Time Frame: from the date of randomization to the date of death, assessed up to 12 months ]
the time from the date of randomization to chronic GvHD, relapse/progression or death from any cause, whichever occurs first.
- Immune reconstitution (IR) [ Time Frame: weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12 ]
the time to reach a level of circulating CD3+ ≥ 100/µl for two consecutive observations
- Engraftment rate [ Time Frame: day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12 ]
defined as the persistent blood cells count above predefined level
- Cumulative incidence of grade 2, 3, or 4 acute GVHD (aGvHD) [ Time Frame: from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months ]
diagnosed and graded according to standard criteria
- Cumulative incidence of chronic GvHD (cGvHD) [ Time Frame: from the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months ]
diagnosed and graded according to standard NIH consensus criteria
- Duration of GvHD episodes [ Time Frame: From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months ]
diagnosed and graded according to standard NIH consensus criteria
- Cumulative incidence of relapse (CIR) [ Time Frame: from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months ]
defined on the basis of morphologic evidence of leukaemia in bone marrow or other sites.
- Incidence and duration of infectious episodes and infectious disease mortality [ Time Frame: from randomization to the date of resolution, assessed up to 12 months ]
diagnosis, monitoring and treatment of infectious relevant events
- Evaluate the acute and long-term toxicity related to the HSV-Tk infusions [ Time Frame: from HSV-Tk infusions to the date of resolution, assessed up to 12 months ]
Toxicity profile of HSV-Tk infusions
- Quality of life (QoL) and Medical Care Utilization (MCU) in both arms [ Time Frame: from randomization up to 12 months ]
Medical resource use data collected will be used in health economic analyses where it may be combined with other data from other sources such as cost data or other clinical parameters.
- Non-relapse mortality (NRM) [ Time Frame: from the date of randomization to the date of death, assessed up to 12 months ]
- Defined for all patients as any death without previous occurrence of a documented relapse (or progression)

Phase : III

Stade : NA

NA
Critères d'inclusion
Critères de non-inclusion
Critères d'inclusion et de non-inclusion
Critères d'inclusion : - Age ≥ 18 years
- Any of the following conditions:
* AML and ALL in 1st complete remission (CR1)
* AML and ALL in 2nd or subsequent CR
* secondary AML in CR
* AML and ALL in 1st or 2nd relapse or primary refractory
- Family donor with patient-donor number of HLA mismatches ≥ 2 (full haploidentical), or family donors sharing one HLA-haplotype with the patient
- Stable clinical conditions and life expectancy > 3 months
- PS ECOG < 2
- Serum creatinine < 1.5 x ULN
- Bilirubin < 1.5 x ULN; transaminases < 3 x ULN
- Left ventricular ejection fraction > 45%
- QTc interval < 450 ms
- DLCO > 50%
- Patients, or legal guardians, and donors must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects

Critères de non-inclusion : - Patients with life-threatening condition or complication other than their basic condition
- Contraindication to haploidentical HCT as defined by the Investigator
- Patients with active CNS disease
- Pregnant or lactation.

Exclusion criteria for HSV-Tk infusion:
- Infections requiring administration of ganciclovir or valganciclovir at the time of infusion
- GvHD requiring systemic immunosuppressive therapy
- Ongoing systemic immunosuppressive therapy after haploidentical HCT
- Administration of G-CSF after haploidentical HCT

HSV-Tk cells can be administered after an adequate patient wash-out period (24 hours)
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT00914628
Promoteur :
MolMed S.p.A
Type de sponsor : Industriel
Via Olgettina, 58 - 20132 Milano, Italy
00000 HORS FRANCE

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Ibrahim YAKOUB-AGHA

TEC / ARC / IDE :
Secrétariat de recherche
fanny.miquel@
chru-lille.fr
03.20.44.57.13

Ouverture de l'essai : OUVERT

MAJ : 23/05/2019