Clinical Trials /

DEPLETHINK - LymphoDEPLEtion and THerapeutic Immunotherapy With NKR-2

NCT03466320

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: DEPLETHINK - LymphoDEPLEtion and THerapeutic Immunotherapy With NKR-2
  • Official Title: An Open-label, Phase I Study to Assess the Safety of NKR-2 Treatment Administration After a Non-myeloablative Preconditioning Chemotherapy in Relapse/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Patients.

Clinical Trial IDs

  • ORG STUDY ID: CYAD-N2T-005
  • NCT ID: NCT03466320

Conditions

  • AML
  • MDS

Interventions

DrugSynonymsArms
NKR-2cyclophosphamide 300 mg/m², fludarabine 30 mg/m²Segment 1 - T7-DL1

Purpose

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 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. The first segment will evaluate the preconditioning regimen consisting
      in cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily (CYFLU) administrated 3
      consecutive days daily at a specific interval prior to the NKR-2 administration. This segment
      is divided into three 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,

        -  Two different NKR-2 dose-levels i.e. dose-level 1 (1x108 NKR-2/injection) and dose-level
           2 (3x108 NKR-2/injection).

      The second segment (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 or 3x108
      NKR-2/injection) administered at the recommended interval (T3 or T7) after the CYFLU
      preconditioning.

      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 five weeks after NKR-2 administration, two 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 23 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.

      Secondary

      To document and characterize:

        -  The NKR-2 peripheral blood kinetics post-administration,

        -  Indicators of clinical activity,

        -  Additional indicators of safety.
    

Trial Arms

NameTypeDescriptionInterventions
Segment 1 - T7-DL1ExperimentalPreconditioning (consisting in cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily {CYFLU}) at days -9, -8 and -7. Dose 1: 1x108 NKR-2 (adjusted at 1.5x106 NKR-2/kg for patients with body weight ≤ 65 kg) administered at 7 days (T7) after the end of the preconditioning regimen
  • NKR-2
Segment 1 - T3-DL1ExperimentalPreconditioning (consisting in cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily {CYFLU}) at days -5, -4 and -3. Dose 1: 1x108 NKR-2 (adjusted at 1.5x106 NKR-2/kg for patients with body weight ≤ 65 kg) administered at 3 days (T3) after the end of the preconditioning regimen
  • NKR-2
Segment 1 - T3-DL2ExperimentalPreconditioning (consisting in cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily {CYFLU}) at days -5, -4 and -3. Dose 2: 3x108 NKR-2 (adjusted at 4.6x106 NKR-2/kg for patients with body weight ≤ 65 kg) administered at 3 days (T3) after the end of the preconditioning regimen
  • NKR-2
Segment 2 - extensionExperimentalThis extension segment will enroll more patients (to reach 9 evaluable patients in total) to further evaluate the selected treatment regimen, i.e., the recommended NKR-2 dose (1x108 or 3x108 NKR-2/injection) with the CYFLU preconditioning treatment administered at the recommended interval (T3 or T7) prior to NKR-2 administration.
  • NKR-2

Eligibility Criteria

        Inclusion Criteria:

          -  The patient must have signed the written ICF and must accept that, beyond the
             treatment period, and the treatment follow-up period, he/she will have to be monitored
             for a LongTerm Safety Follow-Up (LTSFU) for up to 15 years after enrollment.

          -  Both men and women of all races and ethnic groups are eligible.

          -  The patient must be > =18 and < = 70 years old at the time of signing the ICF.

        The patient must have either:

          -  A confirmed relapsed or refractory acute myeloid leukemia (AML) (> = 5% blasts in bone
             marrow or in peripheral blood) after one prior therapy defined as either

          -  Recurrence of disease after a complete remission (CR), or

          -  Failure to achieve CR with initial therapy. Note: Patient with AML M3 are excluded.

        A confirmed myelodysplastic syndrome (MDS) with:

          -  Revised International Prognostic Scoring System (R-IPSS) criteria for Intermediate,
             High-risk or Very High-risk disease or refractory anemia with excess blasts by WHO or
             MDS with TP53 mutation as detected by next-generation sequencing (NGS).

          -  Failure of prior treatment with at least 4 cycles of azacitidine or decitabine defined
             as no response to treatment, loss of response at any time point, or progressive
             disease/intolerance to therapy.

          -  The absolute peripheral blast count should be < 15,000 per micro liter.

        The patient must have evaluable disease defined by:

          -  Revised Recommendations of the International Working Group for Diagnosis,
             Standardization of Response Criteria, for AML patients,

          -  IWG 2006 Uniform Response Criteria for patients with Higher-Risk MDS.

          -  The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
             < = 2.

        The patient must have must have adequate hepatic and renal functions.

          -  Ejection fraction of > = 40%, as determined by echocardiography or a multigated
             acquisition (MUGA) scan.

          -  Women of child-bearing potential and men must agree to use effective contraception
             before, during and for at least 2 months after the last study treatment
             administration.

          -  The patient must, in the opinion of the Investigator, be able to adhere with the study
             visit schedule and all study procedures described in this protocol.

        Exclusion Criteria:

          -  The patient has a confirmed or suspected tumor involvement in the central nervous
             system (CNS). A neurological examination is to be performed systematically at
             baseline. In case signs or symptoms suggestive of potential CNS disease are observed,
             CNS imaging is to be performed. Peripheral neuropathy from prior therapy is
             acceptable.

          -  Patients who have received any cancer therapy (investigational agent or not),
             including but not limited to chemotherapy, small molecules, monoclonal antibodies
             (e.g., immune checkpoint blockade therapies), or radiotherapy within 2 weeks before
             the planned day for the apheresis.

          -  Patients who are planned to receive, concurrently receiving or have received any
             investigational agent within 3 weeks before the planned day for the first NKR-2
             administration.

          -  Patient is under systemic immunosuppressive drugs, unless specific cases authorized
             per protocol.

          -  Patients who have received prior allogeneic stem cell transplantation or chimeric
             antigen receptor therapy.

          -  Patients who are presenting persistent toxicities greater than or equal to CTCAE grade
             2 caused by previous cancer therapy (except for clinically non-significant toxicities,
             such as alopecia).

          -  Presence of any indwelling catheter or drain (e.g., percutaneous nephrostomy tube,
             indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter)
             may be permissible unless they have a catheter-associated infection that cannot be
             cleared with antibiotics. Ommaya reservoirs and dedicated central venous access
             catheters such as a Port-a-Cath, peripherally inserted central catheter, or Hickman
             catheter are permitted.

          -  Patients who underwent major surgery within 4 weeks before the planned day for the
             first NKR-2 administration.

          -  Patients who have received a live vaccine < = 6 weeks prior to the planned day for the
             first NKR-2 administration.

          -  Patients with uncontrolled intercurrent illness or serious uncontrolled medical
             disorder including but not limited to evidence of active pneumonitis on screening
             chest imaging, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia and/or pronounced disturbances of the electrical conduction system of the
             heart, or significant thromboembolic events.

          -  Patients with significant disorder of coagulation or receiving treatment with warfarin
             derivatives or heparin.

          -  Patients who have active infections necessitating use of antibiotics/antivirals
             treatment (prophylaxis is acceptable).

          -  Patients with a known history of hepatitis B (HBsAg positive) or C (anti-HCV
             positive).

          -  Patients who are known to be positive or screened positive for the human
             immunodeficiency virus (HIV).

          -  Patients with a family history of congenital or hereditary immunodeficiency.

          -  Patients with a history of allergic reactions or hypersensitivity attributed to Human
             serum albumin or Plasma-lyte A.

          -  Patient with history of idiopathic pulmonary fibrosis, organizing pneumonia,
             drug-induced pneumonitis, idiopathic pneumonitis and/or active or acute exacerbation
             of chronic obstructive pulmonary disease (COPD).

          -  Patients on supplemental home oxygen.

          -  Patients with history of any autoimmune disease including, but not limited to
             inflammatory bowel disease (including ulcerative colitis and Crohn's Disease),
             systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune
             vasculitis (e.g., Wegener's granulomatosis), CNS or motor neuropathy considered of
             autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple
             sclerosis). Patients with Graves disease and vitiligo will be allowed.

          -  Patients with a history of a malignancy other than the one evaluated in this study
             enrollment, with exception of the following circumstances:

          -  Patients with a history of malignancy who have been adequately treated and have been
             disease-free for at least 1 year, and

          -  Patients with adequately treated active non-invasive cancers (such as nonmelanomatous
             skin cancer or in-situ bladder, cervical and breast cancers).

          -  Patients with psychiatric/social situations or addictive disorders that may compromise
             the ability of the patients to give informed consent or to comply with the study
             procedures.

          -  Female patients who are pregnant or lactating.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The occurrence of Dose-limiting toxicities (DLT) during the study treatment until 3 weeks after first NKR-2 study treatment administration.
Time Frame:during the study treatment until 3 weeks after first NKR-2 study treatment administration.
Safety Issue:
Description:Dose-limiting toxicity refers to a specific adverse event that is experienced during treatment and until 3 weeks after first NKR-2 dose administration, is new and at least possibly related to NKR-2 study treatment administered following a preconditioning regimen

Secondary Outcome Measures

Measure:The NKR-2 cell kinetics endpoint of this Phase I study is: The evaluation of the circulating NKR-2 peripheral blood kinetics post-administration.
Time Frame:From day 1 (visit 4) until the end of the administration phase (day 85 = week 12 = Visit 22).
Safety Issue:
Description:NKR-2 detection in peripheral blood-isolated PBMC will be mandatory performed until the end of the administration phase. If positive at this visit, the evaluation will be performed during the follow-period visits and until 2 sequential tests are providing "undetectable" results, suggesting a lack of the NKR-2 persistence.
Measure:Additional Safety Endpoint: the occurence of Adverse Events ans Serious Adverse Events and any toxicity linked to study participation until the end of the administration phase, and until the end of the treatment follow-up
Time Frame:Until the end of the administration phase, and until the end of the treatment follow-up (at Month 24 - Visit 34).
Safety Issue:
Description:The occurrence of AEs and SAEs and any toxicity linked to study participation until the end of the administration phase, and until the end of the treatment follow-up (at Month 24 - Visit 34).
Measure:Clinical activity secondary endpoints: The incidence of CR, CRMRD-, CRi, MLFS, PR, or SD for AML patients.
Time Frame:From week 5 until Month 24.
Safety Issue:
Description:The incidence of CR, CRMRD-, CRi, MLFS, PR, or SD for AML patients at Week 5, Week 12, Week 19, Month 6, Month 9, Month 12, Month 18 and Month 24 post the first NKR-2 administration,
Measure:Clinical activity secondary endpoints: The incidence of CR, PR, marrow CR, cytogenic response, hematologic improvement or SD for MDS patients
Time Frame:From week 5 until Month 24.
Safety Issue:
Description:The incidence of CR, PR, marrow CR, cytogenic response, hematologic improvement or SD for MDS patients at Week 5, Week 12, Week 19, Month 6, Month 9, Month 12, Month 18 and Month 24 post the first NKR-2 administration
Measure:Clinical activity secondary endpoints: The objective clinical response rate (ORR) post the first NKR-2 administration
Time Frame:From week 5 until Month 24.
Safety Issue:
Description:The objective clinical response rate (ORR) post the first NKR-2 administration
Measure:Clinical activity secondary endpoints:The duration of response for patients with objective clinical response
Time Frame:From week 5 until Month 24.
Safety Issue:
Description:The duration of response for patients with objective clinical response
Measure:Clinical activity secondary endpoints: The ORR among subjects retreated with NKR-2.
Time Frame:From week 5 until Month 24.
Safety Issue:
Description:The ORR and duration of second response among subjects retreated with NKR-2.
Measure:Clinical activity secondary endpoints: The duration of second response among subjects retreated with NKR-2.
Time Frame:From week 5 until Month 24.
Safety Issue:
Description:The ORR and duration of second response among subjects retreated with NKR-2.
Measure:Clinical activity secondary endpoints: The overall survival (OS) from the study enrollment.
Time Frame:From study enrollment until Month 24.
Safety Issue:
Description:The overall survival (OS) from the study enrollment.
Measure:Clinical activity secondary endpoints: The relapse-free survival (RFS) from the study enrollment
Time Frame:From study enrollment until Month 24.
Safety Issue:
Description:The relapse-free survival (RFS) from the study enrollment
Measure:Clinical activity secondary endpoints: The event-free survival (EFS) from the study enrollment.
Time Frame:From study enrollment until Month 24.
Safety Issue:
Description:The event-free survival (EFS) from the study enrollment.
Measure:Clinical activity secondary endpoints: The cumulative incidence of relapse (CIR)
Time Frame:From study enrollment until Month 24.
Safety Issue:
Description:The cumulative incidence of relapse (CIR)
Measure:Clinical activity secondary endpoints: The cumulative incidence of death (CID)
Time Frame:From study enrollment until Month 24.
Safety Issue:
Description:The cumulative incidence of death (CID)
Measure:Clinical activity secondary endpoints: The non-relapse mortality (NMR) rate.
Time Frame:From study enrollment until Month 24.
Safety Issue:
Description:The non-relapse mortality (NMR) rate.
Measure:Mandatory correlative studies of this study are: The NKR-2 kinetics post-injection in the bone marrow.
Time Frame:From week 5 until month 24
Safety Issue:
Description:The aim of this specific research is to identify the presence of NKR-2 within and its kinetics post-administration according to the dose and preconditioning chemotherapy regimen. Genomic DNA isolated from these samples will be evaluated by qPCR using a validated assay (VCN) that detects a DNA signature unique to the NKR-2 transgene.
Measure:Mandatory correlative studies of this study are: Characterization of systemic cytokine level release post NKR-2 administration.
Time Frame:From day 1 until day 134 (week 19)
Safety Issue:
Description:One of the key effector functions of NKR-2 is the release of soluble cytokines during antigen engagement. Consequently, a surrogate marker of NKR-2 in vivo activity is potentially raised levels of cytokines relevant to T cell activation within the peripheral circulation.
Measure:Mandatory correlative studies of this study are: The evaluation of NKG2D ligand expression in patients' tumor cells prior to and after treatment.
Time Frame:From day 1 until day 134 (week 19)
Safety Issue:
Description:The research will evaluate NKG2D ligand expression in patient tumor samples. The aim of this project is to establish whether a correlation can be drawn between with the level of NKG2D ligand tumoral expression and NKR-2 activity.
Measure:Mandatory correlative studies of this study are: The evaluation of NKG2D ligand expression in patients' peripheral mononuclear cells prior to and after treatment.
Time Frame:From day 1 until day 134 (week 19)
Safety Issue:
Description:The research will evaluate NKG2D ligand expression in patient normal cells pre/post preconditioning chemotherapy and NKR-2 administrations. The aim of this project is to establish whether chemotherapy induce expression of NKG2D ligand expression and the possible correlation to any potential toxicity of the NKR-2 treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celyad (formerly named Cardio3 BioSciences)

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