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DEPLETHINK - LymphoDEPLEtion and THerapeutic Immunotherapy With NKR-2 (DEPLETHINK)

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ClinicalTrials.gov Identifier: NCT03466320
Recruitment Status : Recruiting
First Posted : March 15, 2018
Last Update Posted : May 24, 2019
Sponsor:
Collaborator:
Novella Clinical
Information provided by (Responsible Party):
Celyad (formerly named Cardio3 BioSciences)

Brief 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.


Condition or disease Intervention/treatment Phase
AML MDS Biological: NKR-2 Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase I/II Study to Assess the Safety and Clinical Activity of NKR-2 Treatment Administration After a Non-myeloablative Preconditioning Chemotherapy in Relapse/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Patients.
Actual Study Start Date : September 18, 2018
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021


Arm Intervention/treatment
Experimental: Phase I Dose Escalation Segment 1 - T7-DL1

Preconditioning (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

Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²

Experimental: Phase I Dose Escalation Segment 1 - T3-DL1

Preconditioning (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

Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²

Experimental: Phase I Dose Escalation Segment 1 - T3-DL2

Preconditioning (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

Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²

Experimental: Phase I Dose Escalation Segment 1 - T3-DL3

Preconditioning (consisting in cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily {CYFLU}) at days -5, -4 and -3.

Dose 3: 1x109 NKR-2 (adjusted at 1.5x107 NKR-2/kg for patients with body weight ≤ 65 kg) administered at 3 days (T3) after the end of the preconditioning regimen

Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²

Experimental: Phase I Dose Escalation - extension
This 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 or 1x109NKR-2/injection) with the CYFLU preconditioning treatment administered at the recommended interval (T3 or T7) prior to NKR-2 administration.
Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²

Experimental: Phase II Segment 1
This extension segment will enroll more patients (to reach 13 evaluable patients in total) to further evaluate the selected treatment regimen, i.e., the recommended NKR-2 dose (1x108 or 3x108 or 1x109NKR-2/injection) with the CYFLU preconditioning treatment administered at the recommended interval (T3 or T7) prior to NKR-2 administration.
Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²

Experimental: Phase II Segment 2
Enrollment in the Phase II part of the study will be divided in 2 consecutive segments, with 13 patients in total in the segment 1 and 30 new patients in segment 2 (43 patients in total) if the study is not terminated due to futility, according a Simon's two-stage optimal design
Biological: NKR-2
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 Names:
  • cyclophosphamide 300 mg/m²
  • fludarabine 30 mg/m²




Primary Outcome Measures :
  1. 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. ]
    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 :
  1. 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). ]
    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.

  2. 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). ]
    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).

  3. 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. ]
    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,

  4. 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. ]
    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

  5. Clinical activity secondary endpoints: The objective clinical response rate (ORR) post the first NKR-2 administration [ Time Frame: From week 5 until Month 24. ]
    The objective clinical response rate (ORR) post the first NKR-2 administration

  6. Clinical activity secondary endpoints:The duration of response for patients with objective clinical response [ Time Frame: From week 5 until Month 24. ]
    The duration of response for patients with objective clinical response

  7. Clinical activity secondary endpoints: The ORR among subjects retreated with NKR-2. [ Time Frame: From week 5 until Month 24. ]
    The ORR and duration of second response among subjects retreated with NKR-2.

  8. Clinical activity secondary endpoints: The duration of second response among subjects retreated with NKR-2. [ Time Frame: From week 5 until Month 24. ]
    The ORR and duration of second response among subjects retreated with NKR-2.

  9. Clinical activity secondary endpoints: The overall survival (OS) from the study enrollment. [ Time Frame: From study enrollment until Month 24. ]
    The overall survival (OS) from the study enrollment.

  10. Clinical activity secondary endpoints: The relapse-free survival (RFS) from the study enrollment [ Time Frame: From study enrollment until Month 24. ]
    The relapse-free survival (RFS) from the study enrollment

  11. Clinical activity secondary endpoints: The event-free survival (EFS) from the study enrollment. [ Time Frame: From study enrollment until Month 24. ]
    The event-free survival (EFS) from the study enrollment.

  12. Clinical activity secondary endpoints: The cumulative incidence of relapse (CIR) [ Time Frame: From study enrollment until Month 24. ]
    The cumulative incidence of relapse (CIR)

  13. Clinical activity secondary endpoints: The cumulative incidence of death (CID) [ Time Frame: From study enrollment until Month 24. ]
    The cumulative incidence of death (CID)

  14. Clinical activity secondary endpoints: The non-relapse mortality (NMR) rate. [ Time Frame: From study enrollment until Month 24. ]
    The non-relapse mortality (NMR) rate.

  15. 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 ]
    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.

  16. 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) ]
    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.

  17. 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) ]
    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.

  18. 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) ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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 Long-Term Safety Follow-Up (LTSFU) for up to 15 years after enrollment.
  2. Both men and women of all races and ethnic groups are eligible.
  3. The patient must be ≥ 18 and ≤ 75 years old at the time of signing the ICF.
  4. The patient must not be eligible for standard of care therapy and have one of the following hematological malignancy:

4.a. A confirmed relapsed or refractory acute myeloid leukemia (AML) (i.e. ≥ 5% blasts in bone marrow or in peripheral blood) after at least one prior therapy defined as either

  • Recurrence of disease after a first complete remission (CR1) and not eligible for a second course of induction therapy, or
  • Recurrence of disease after a second complete remission (CR2), or
  • Failure to achieve CR after induction chemotherapy. Note: Patient with AML M3 are excluded. 4.b. 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 (i.e. ≥ 5% blasts in bone marrow or ≥ 2% blasts in peripheral blood) 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.

    5. The absolute peripheral blast count should be < 15,000/L. 6. 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. 7. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status below or equal to 2.

    8. The patient must have adequate hepatic and renal functions as assessed by standard laboratory criteria 9. The patient must have a left ventricular ejection fraction (LVEF) of more than or equal to 40%, as determined by echocardiography or a multigated acquisition (MUGA) scan.

    10. The patient must have a good pulmonary function with a Forced Expiratory Volume in the first second (FEV-1)/Forced Vital Capacity (FVC) more than or equal to 0.7 with FEV-1 more than or equal to 50% predicted (GOLD 1 or 2 severity) as determined by the spirometry performed at baseline , unless related to the AML/MDS disease as judged by the Investigator.

    11. 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.

    12. 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:

  1. The patient has a confirmed or history of tumor involvement in the central nervous system (CNS).
  2. 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 (Day -21)
  3. 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 (Day 1).
  4. Patient is under systemic immunosuppressive drugs, unless specific cases authorized per protocol.
  5. Patients who have received prior allogeneic stem cell transplantation or chimeric antigen receptor therapy.
  6. 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).
  7. 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.
  8. Patients who underwent major surgery within 4 weeks before the planned day for the first NKR-2 administration (Day 1).
  9. Patients who have received a live vaccine ≤ 6 weeks prior to each NKR 2 administration.
  10. 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 history (or evidenced after the electrocardiogram planned at screening) and/or pronounced disturbances of the electrical conduction system of the heart, or significant thromboembolic events.
  11. Patients with significant disorder of coagulation or receiving treatment with warfarin derivatives or heparin.
  12. Patients who have active infections including, but not limited to viral, bacterial or fungal infections necessitating use of antibiotics/antivirals/antifungal treatment (prophylaxis is acceptable).
  13. Patients who are known to be positive or screened positive for hepatitis B (HBsAg positive) or C (anti-HCV positive).
  14. Patients who are known to be positive or screened positive for the human immunodeficiency virus (HIV).
  15. Patients with a family history of congenital or hereditary immunodeficiency.
  16. Patients with a history of allergic reactions or hypersensitivity attributed to Human serum albumin or Plasma-lyte A.
  17. 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).
  18. Patients on supplemental home oxygen.
  19. 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.
  20. 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 non-melanomatous skin cancer or in-situ bladder, cervical and breast cancers).
  21. 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.
  22. Female patients who are pregnant or lactating.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03466320


Contacts
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Contact: Florence Renard 32(0) 10 39 41 92 frenard@celyad.com
Contact: Kimberly Phillips 1 781 820 8575 kphillips@celyad.com

Locations
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United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045
United States, New York
New York School of Medicine Recruiting
New York, New York, United States, 10016
Belgium
Institute Jules Bordet Recruiting
Brussels, Belgium
UZ Gent Recruiting
Gent, Belgium
Sponsors and Collaborators
Celyad (formerly named Cardio3 BioSciences)
Novella Clinical
Investigators
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Study Director: Frederic Lehmann, MD Celyad (formerly named Cardio3 BioSciences)

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Responsible Party: Celyad (formerly named Cardio3 BioSciences)
ClinicalTrials.gov Identifier: NCT03466320     History of Changes
Other Study ID Numbers: CYAD-N2T-005
First Posted: March 15, 2018    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites