DEPLETHINK - LymphoDEPLEtion and THerapeutic Immunotherapy With NKR-2
Condition: AML; MDS
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This open-label Phase I study aims at assessing primarily the safety of the NKR-2 treatment
      administered after a non-myeloablative preconditioning regimen in r/r AML/MDS patients.

      This Phase I study will contain two different sequential segments. The first segment will
      determine the recommended investigational treatment option (schedule of preconditioning and
      NKR-2 dose) and the second segment will expand to a larger number of r/r AML/MDS patients.
    

Detailed description: 
      This open-label Phase I/II study aims at assessing primarily the safety and the clinical
      activity of the NKR-2 treatment administered after a non-myeloablative preconditioning
      regimen in r/r AML/MDS patients.

      The Phase I part of the study will contain two different sequential segments. The first
      segment (dose escalation segment) will determine the recommended investigational treatment
      option (schedule of preconditioning and NKR-2 dose) and the second segment (extension
      segment) will expand to a larger number of r/r AML/MDS patients.

      The Phase II part of the study will also contain two sequential segments, assessing the
      clinical activity of the NKR-2 treatment administrated as per the recommended investigational
      treatment option (schedule of preconditioning and NKR-2 dose).

      The Phase I dose escalation segment will evaluate the preconditioning regimen consisting in
      cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily (CYFLU) administrated 3 consecutive
      days at a specific interval prior to the NKR 2 administration. This segment is divided into
      four sequential cohorts to evaluate respectively:

        -  Two different intervals between the preconditioning regimen and the NKR-2 administration
           i.e. NKR-2 administered 3 days (T3) or 7 days (T7) after the end of the preconditioning
           regimen,

        -  Three different NKR-2 dose-levels i.e. dose-level 1 (1x108 NKR 2/injection), dose-level
           2 (3x108 NKR-2/injection) and dose-level 3 (1x109 NKR-2/injection).

      The Phase I extension segment will enroll more r/r AML/MDS patients (to reach 9 evaluable
      patients in total) to further evaluate the recommended NKR-2 dose (1x108, 3x108 or 1x109
      NKR-2/injection) administered at the recommended interval (T3 or T7) after the CYFLU
      preconditioning.

      The Phase II will enroll more r/r AML/MDS patients (13 patients in total in the segment 1 and
      30 new patients in the segment 2) to further evaluate the recommended NKR-2 dose (1x108,
      3x108 or 1x109 NKR-2/injection) administered at the recommended interval (T3 or T7) after the
      CYFLU preconditioning to assess the clinical activity.

      Each patient will receive a single administration of NKR-2 following the preconditioning
      regimen. Depending on the clinical response as evaluated at the first tumor assessment,
      scheduled three weeks after NKR-2 administration, three situations may arise:

        -  If the patient is presenting a complete remission, partial remission, or stable disease,
           and meets all criteria for a consolidation cycle, then three new injections of NKR-2 at
           the recommended dose defined in the ongoing THINK study (THINK RecD), without prior
           preconditioning, will be administered with a two weeks interval,

        -  If the patient is in PD, or does not meet all criteria for the consolidation cycle
           he/she will not receive any other NKR-2 injection but will follow other visits as
           scheduled.

      For each patient who received at least one NKR-2 administration, the overall study duration
      will be 15 years after first NKR-2 administration.

      The duration of the administration phase and treatment follow-up will be 24 months.

      Patients will be asked to complete a total of maximum 20 visits during the treatment
      administration phase, and maximum 6 visits during the treatment follow-up phase. During the
      long-term safety follow-up, yearly visits will be scheduled (up to Y15).

      Rationale for the study:

      NKR-2 has the potential to treat many distinct tumor-types because of a broad expression and
      important prevalence of the NKG2D ligands expression in various tumor types including in r/r
      AML/MDS. This Phase I study will explore the hypothesis that the administration of modified
      T-cells targeting NKG2D-ligands expressed by AML/MDS cells, after a prior nonmyeloablative
      preconditioning treatment, in patients refractory to and/or relapsing after prior therapies,
      is safe and, considering the poor outcomes and lack of therapeutic strategies for this
      patient population, may have a strategic advantage over current approaches and provide
      potential clinical benefit.

      Objectives of the study:

      Primary

      To document and characterize:

        -  The safety of the NKR-2 treatment administration in r/r AML/MDS patients after a
           non-myeloablative preconditioning. (Phase I part)

        -  The objective response rate (ORR) post the first NKR-2 administration. (Phase II part)

      Secondary

      To document and characterize:

        -  The NKR-2 peripheral blood kinetics post-administration,

        -  Indicators of clinical activity,

        -  Additional indicators of safety.
    

Intervention name(s): NKR-2
Intervention type(s): Biological
Intervention description(s): This Phase I study will explore the hypothesis that the administration of modified T-cells targeting NKG2D-ligands expressed by AML/MDS cells, after a prior nonmyeloablative preconditioning treatment, in patients refractory to and/or relapsing after prior therapies, is safe and, considering the poor outcomes and lack of therapeutic strategies for this patient population, may have a strategic advantage over current approaches and provide potential clinical benefit.
Other intervention name(s): cyclophosphamide 300 mg/m²; fludarabine 30 mg/m²
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment