A Study to Investigate Use of Off-the-shelf Natural Killer (NK) Cells (SAR445419) in Relapsed/Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This is a single group, Phase 1, single-arm, dose escalation study to determine the candidate dose(s), and evaluate safety, tolerability, and preliminary anti-tumor activity of SAR445419 administered after fludarabine and cytarabine conditioning for the treatment of relapsed or refractory acute myeloid leukemia (R/R AML). Adult participants with R/R AML will be eligible for treatment. The study is intended to assess the candidate dose(s) by the occurrence of dose-limiting toxicity (DLT) from start of chemotherapy until 28 days after the first administration of SAR445419. The duration of the study for a participant will include: Screening period up to 21 days prior to initiating chemotherapy, Treatment period of 5 days chemotherapy followed by SAR445419 administered for 2 weeks and end of treatment visit 56 days after first SAR445419 administration, Survival follow-up period up to 1 year after the last participant has started treatment with SAR445419.

Detailed Description
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Participants will be followed for 28 days (for DLT evaluations) after administration of the first SAR445419 dose (Day 1) for the primary endpoint and for 1 year after the first SAR445419 dose for selected secondary endpoints.

Official Title
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A Phase I, Single-arm, Open Label, Dose Escalation, Multicenter Study of Off-the-shelf Natural Killer (NK) Cells (SAR445419) in Participants With Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)

Conditions
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Acute Myeloid Leukaemia

Intervention / Treatment
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* Drug: SAR445419
* Drug: fludarabine
* Drug: cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 years of age inclusive Participants with confirmed diagnosis of relapsed or primary refractory acute myeloid leukemia (AML), according to World Health Organization (WHO) classification, including: Participants with relapsed AML after allogeneic stem cells transplantation, including those who have received donor lymphocyte infusions, Isolated central nervous system (CNS) or extramedullary disease, At least 1 prior line of therapy which includes chemotherapy, hypomethylating agents, venetoclax or targeted therapy. Participants with a weight ≥42 kg. Exclusion Criteria: Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed. Known acquired immunodeficiency syndrome (AIDS-related illnesses) or human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Pregnant or breast-feeding women, female participants of childbearing potential, and male participants with female partners of childbearing potential who are not willing to avoid pregnancy by using a highly effective method of contraception (2 barrier method or 1 barrier method with a spermicide, intrauterine device, or hormonal contraception with inhibition of ovulation, for 2 weeks prior to the first dose of SAR445419, during treatment, and 6 months after the last dose of fludarabine). A woman is considered of childbearing potential, i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. History of solid organ transplant, including corneal transplant. Receiving at the time of first SAR445419 administration corticosteroid as a concomitant medication with corticosteroid dose >10 mg/day of oral prednisone or the equivalent, except steroid inhaler, nasal spray, or ophthalmic solution Known contraindication to any of the non-investigational medicinal products (NIMPs) (fludarabine, cytarabine, acetaminophen and diphenhydramine). Concurrent treatment with other investigational drugs The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR445419<br>Treatment consists of chemotherapy with fludarabine 30mg/m2/day and cytarabine 2g/m2/day administered for 5 days (Day -6 to Day -2), followed by 6 doses of SAR445419 given thrice weekly for 2 weeks beginning Day 1. | Drug: SAR445419<br>* Cell suspension, by intraveneous (IV) injection<br>Drug: fludarabine<br>* Solution for injection , by IV injection<br>* Other names: fludara;Drug: cytarabine<br>* Solution for injection, by IV injection<br>* Other names: cytosar-U;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting (DLT) toxicity |  | from Day 1 to Day 28 | 
| Incidence of DLT from start of chemotherapy |  | From Day -6 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) |  | From baseline up to 1 year | 
| Median time to neutrophil and platelet count recovery | Median time to neutrophil and platelet count recovery post chemotherapy | From Day -6 up to 1 year | 
| Rate of HSCT | Percentage of participants going onto hematopoietic stem cell transplantation (HSCT) following SAR445419 treatment but prior to subsequent therapy for treatment of AML | From baseline up to 1 year | 
| Number of participants with infection |  | From baseline up to 1 year | 
| Number of participants by type of infection | Fungal, bacterial, viral, and particularly cytomegalovirus (CMV) infection or reactivation (opportunistic) infection | From baseline up to 1 year | 
| Percentage of participants with Composite Complete Remission (CRc) rate | Percentage of participants who have a complete remission (CR) or a complete remission with incomplete hematological recovery (CRi) as defined by the modified European LeukemiaNet (ELN) 2022 criteria for AML | From baseline up to Day 56 | 
| Percentage of participants with alternative complete remission rate | Percentage of participants with CR or a complete remission with partial hematological recovery (CRh) | From baseline up to Day 56 | 
| Percentage of participants with overall complete remission rate | Percentage of participants with CR or CRh or CRi or morphological leukemia-free state (MLFS) | From baseline up to Day 56 | 
| Duration of response | Time interval from first documented evidence of CR until progressive disease (PD) as per modified ELN 2022 criteria for AML or death due to any cause, whichever comes first | From baseline up to 1 year | 
| Duration of event-free survival | Time interval from date of first SAR445419 administration to induction failure, relapse or death due to any cause, whichever comes first | From baseline up to 1 year | 
| Overall survival rate at 6 months | Time from the first SAR445419 administration to death from any cause | From baseline up to 6 months | 
| Overall survival rate at 1 year | Time from the first SAR445419 administration to death from any cause | From baseline up to 1 year | 
| Time to treatment failure | Time from first SAR445419 administration to discontinuation for any reason excluding remission | From baseline up to 1 year |