DEPLETHINK - LymphoDEPLEtion and THerapeutic Immunotherapy With NKR-2

NCT03466320 | Completed Phase 1 FDA Drug

• 1 other identifier: CYAD-N2T-005
• Study Type: interventional
• Target: 21
• Locations: 2 countries
• Sites: 7

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.

Conditions

AML; MDS

Outcome Measures

Primary Outcomes (1)

• The occurrence of Dose-limiting toxicities (DLT) 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

  during the study treatment until 3 weeks after first NKR-2 study treatment administration.

Secondary Outcomes (18)

• The NKR-2 cell kinetics endpoint of this Phase I study is: The evaluation of the circulating NKR-2 peripheral blood kinetics post-administration.

  From day 1 (visit 4) until the end of the administration phase (day 85 = week 12 = Visit 22).

• 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

  Until the end of the administration phase, and until the end of the treatment follow-up (at Month 24 - Visit 34).

• Clinical activity secondary endpoints: The incidence of CR, CRMRD-, CRi, MLFS, PR, or SD for AML patients.

  From week 5 until Month 24.

• Clinical activity secondary endpoints: The incidence of CR, PR, marrow CR, cytogenic response, hematologic improvement or SD for MDS patients

  From week 5 until Month 24.

• Clinical activity secondary endpoints: The objective clinical response rate (ORR) post the first NKR-2 administration

  From week 5 until Month 24.

Study Arms (7)

Phase I Dose Escalation Segment 1 - T7-DL1

EXPERIMENTAL

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

Phase I Dose Escalation Segment 1 - T3-DL1

EXPERIMENTAL

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

Phase I Dose Escalation Segment 1 - T3-DL2

EXPERIMENTAL

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

Phase I Dose Escalation Segment 1 - T3-DL3

EXPERIMENTAL

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

Phase I Dose Escalation - extension

EXPERIMENTAL

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

Phase II Segment 1

EXPERIMENTAL

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

Phase II Segment 2

EXPERIMENTAL

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

Interventions

NKR-2 BIOLOGICAL

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.

Also known as: cyclophosphamide 300 mg/m², fludarabine 30 mg/m²

Phase I Dose Escalation - extension; Phase I Dose Escalation Segment 1 - T3-DL1; Phase I Dose Escalation Segment 1 - T3-DL2; Phase I Dose Escalation Segment 1 - T3-DL3; Phase I Dose Escalation Segment 1 - T7-DL1; Phase II Segment 1; Phase II Segment 2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Both men and women of all races and ethnic groups are eligible.
• The patient must be ≥ 18 and ≤ 75 years old at the time of signing the ICF.
• The patient must not be eligible for standard of care therapy and have one of the following hematological malignancy:
• 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.
• \. 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.
• \. 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.
• \. 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.

You may not qualify if:

• The patient has a confirmed or history of tumor involvement in the central nervous system (CNS).
• 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)
• 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).
• 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 (Day 1).
• Patients who have received a live vaccine ≤ 6 weeks prior to each 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 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.
• Patients with significant disorder of coagulation or receiving treatment with warfarin derivatives or heparin.
• 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).
• Patients who are known to be positive or screened positive for 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.

Sponsors & Collaborators

• Celyad Oncology SA: lead
• IQVIA Biotech: collaborator

Study Sites (7)

University of Colorado

Aurora, Colorado, 80045, United States

Location

H. Lee Moffitt Cancer Center and Research Institute Hospital, Inc.,

Tampa, Florida, 33612, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

New York School of Medicine

New York, New York, 10016, United States

Location

Universitair Ziekenhuis Antwerpen

Antwerp, 2650, Belgium

Location

Institute Jules Bordet

Brussels, Belgium

Location

UZ Gent

Ghent, Belgium

Location

MeSH Terms

Interventions

Cyclophosphamide; fludarabine

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Frederic Lehmann, MD

  Celyad Oncology SA

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: March 15, 2018
• Study Start: September 18, 2018
• Primary Completion: February 1, 2021
• Study Completion: February 1, 2021
• Last Updated: May 4, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); BE (3)