A Study to Investigate Use of Off-the-shelf Natural Killer (NK) Cells (SAR445419) in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Study Overview
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Brief Summary
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This is a multicenter, parallel multicohort, phase 2, single-arm study for adjunctive treatment in participants with high-risk myeloid malignancies undergoing allogeneic HSCT. The purpose of this study is to assess the safety and preliminary efficacy of off-the-shelf (OTS) ex vivo expanded NK cells (SAR445419) in improving relapse free survival (RFS).

Detailed Description
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The expected duration of the study for a participant is about 2 years.

Official Title
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A Phase 2, Single Arm, Multicohort, Open Label, Multicenter Trial of Off-the-shelf Natural Killer (NK) Cells (SAR445419) in Patients With High-risk Myeloid Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Allogenic Stem Cell Transplantation

Intervention / Treatment
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* Drug: SAR445419


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 (Cohort A - MAC) or 18-75 (Cohort B - RIC) Participants with high-risk AML/MDS who are scheduled to undergo stem cell transplantation with matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor sourced HSCT Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≤ 3 (cohort A / MAC participants only) Adequate major non-hematopoietic organ system function Karnofsky performance score ≥70% Body weight ≥45 kg Exclusion Criteria: AML beyond CR1 Presence of FLT3 mutations Uncontrolled bacterial, viral, or fungal infections at time of enrollment Positive test for human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS) Positive hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection Diagnosis of prior immunodeficiency or organ transplantation requiring immunosuppressive therapy Active or chronic autoimmune condition requiring systemic immunosuppressive or immunomodulatory therapy Prior allogeneic transplantation HSCT graft DSA ≥3000 MFI Current use of systemic corticosteroids at physiologic doses ≤ 0.2 mg/kg/day of prednisone or equivalent Use of checkpoint inhibitor therapy within 4 weeks prior to the start of HSCT conditioning regimen The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Interventional Model Description: This is a parallel multicohort, phase 2, single-arm study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High risk AML and MDS<br>Participants with high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic HSCT will receive 3 doses of SAR445419. A myeloablative conditioning (MAC) and a reduced intensity conditioning (RIC) cohort will be included. | Drug: SAR445419<br>* Pharmaceutical form: cell suspension Route of administration: Intravenous (IV) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of relapse free survival (RFS) post allogeneic hematopoietic stem cell transplantation (HSCT) | Percentage of patients who are relapse free and alive at 12 months from the date of HSCT and who received at least the first 2 planned doses of SAR445419 | 12 months post HSCT | 
| Frequency of cytomegalovirus (CMV) reactivation/infection in CMV seronegative participants who receive a CMV seronegative HSCT graft |  | From baseline up to 2 years | 
| Frequency of life-threatening (grade 4) infusion related reactions (IRR) or cytokine release syndrome (CRS) that does not resolve to grade 1 within 72 hours despite therapy |  | From baseline up to 2 years | 
| Frequency of life threatening (grade 4) tumor lysis syndrome (TLS) |  | From baseline up to 2 years | 
| Frequency of life-threatening (grade 4) immune cell-associated neurotoxicity syndrome (ICANS) that does not resolve to grade 1 within 72 hours despite therapy |  | From baseline up to 2 years | 
| Frequency of grade 3-4 acute graft versus host disease (aGVHD) |  | From baseline up to 2 years | 
| Frequency of non-relapse mortality (NRM) |  | 100 days post HSCT | 
| Frequency of graft failure | Frequency of primary or secondary graft failure | 100 days post HSCT | 
| Frequency of overall mortality |  | 100 days post HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events (AEs) | AEs characterized by type and severity as graded by the national cancer institute common terminology criteria for adverse events (NCI CTCAE) v.5.0, timing, seriousness, and relationship to study treatments. All AEs will be captured from signing of informed consent until 30 days after the last SAR445419 administration. All serious AEs (SAEs) and AEs of special interest (AESIs) will be captured until the end of the study. | From baseline up to 2 years | 
| Number of participants with acute Graft-Versus-Host-Disease (aGVHD) | The cumulative incidence of grade 2-4 and 3-4 aGVHD | 6, 12, 18 and 24 months post-HSCT | 
| Number of participants with chronic Graft-Versus-Host-Disease (cGVHD) | The cumulative incidence of cGVHD graded as mild, moderate or severe | 6, 12, 18 and 24 months post-HSCT | 
| Proportion of participants who are alive and do not need ongoing immune suppression to control GVHD |  | 6, 12, 18 and 24 months post-HSCT | 
| Cumulative incidence of relapse |  | 6, 12, 18 and 24 months post-HSCT | 
| Rate of relapse free survival (RFS) |  | 6, 12, 18 and 24 months post-HSCT | 
| Rate of overall survival (OS) |  | 6, 12, 18 and 24 months post-HSCT | 
| Rate of non-relapse mortality (NRM) |  | 6, 12, 18 and 24 months post-HSCT | 
| Rate of GVHD-free relapse-free survival (GRFS) |  | 6, 12, 18 and 24 months post-HSCT | 
| Time to hematologic recovery (platelet and neutrophil count recovery) post-HSCT |  | From baseline up to approximately 180 days | 
| Frequency of donor cell engraftment | The proportion of patients with full chimerism (≥95% donor cells), mixed chimerism (5-95% donor cells) and graft rejection (<5% donor cells) | 28 and 100 days, and 6 and 12 months post-HSCT | 
| Frequency of primary graft failure |  | 28 days post-HSCT | 
| Frequency of secondary graft failure |  | 100 days and 12, 18 and 24 months post-HSCT | 
| Cumulative incidence of CMV reactivation or infection and symptomatic BK-virus (BKV) hemorrhagic cystitis |  | 100 days and 6 and 12 months post-HSCT | 
| Cumulative incidence of grade 2-4 and grade 3-4 infections during the on-treatment period |  | Until 30 days after the last administration of SAR445419 | 
| Change from baseline in Quality of life in Acute Myeloid Leukemia (AML-QoL) score | AML-QoL is a 27 item questionnaire to measure quality of life in patients with Acute Myeloid Leukemia and high-risk Myelodysplastic Syndrome, covering seven different domains and with lower scores indicating better quality of life. AML-QoL uses 5-point Likert type scale ranging from 1: Never to 5: Almost always for the 26 items included in domains and ranging from 1: Excellent to 5: Poor for the QOL item. | 28 and 100 days and 6, 9 and 12 months post HSCT | 
| Change from baseline in Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) score | FACT-BMT is a 50 item questionnaire to measure quality of life in bone marrow transplant patients covering five different domains and with higher scores indicating better quality of life. FACT-BMT questionnaire uses likert type scale with responses measuring from 0-4 (where 0 = not at all; 1 = a little bit; 2 = somewhat, 3 = quite; and 4 = very much) | 28 and 100 days and 6, 9 and 12 months post HSCT | 
| Change from baseline in Patient Global Impression of Severity (PGIS) score | PGIS scale is a single-item with a self-reported categorical scale to assess patient's impression of disease severity. PGIS contains response options ranging from 0 (none) to 4 (severe). | 28 and 100 days and 6, 9 and 12 months post HSCT | 
| Change from baseline in Patient Global Impression of Change (PGIC) score | PGIC scale is a single item with a self-reported categorical scale designed to assess patient's impression of change in disease symptom severity. PGIC contains response options ranging from 0 (no-change) to 7 (considerable improvement). | 28 and 100 days and 6, 9 and 12 months post HSCT | 
| Change from baseline in Functional Assessment of Chronic Illness Therapy GP5 question (FACIT-GP5) score | FACIT-GP5 is single item to assess global side effect bother. FACIT-GP5 uses likert type scale with responses Scores range from 0 (not at all bothered by side effect) to 4 (very much bothered by side effects). | 7, 14 and 35 days post-HSCT |