Early discontinuation based on strategic sponsor decision not driven by any safety concerns

This is a parallel, Phase 1/Phase 2, randomized, open label, multi-cohort, multi-center study assessing the safety, tolerability and preliminary efficacy of SAR443579 with different agents for treatment in adolescent and/or adult participants with CD123 expressing hematological malignancies.

This protocol is structured as a master protocol (containing common protocol elements). Individual sub-studies will explore SAR443579 with combination partners, which may include approved or investigational agents.

Experimental sub-studies will be tested through 3 parts:

Part 1: dose finding (such as dose escalation/ safety run-in). Part 2: dose optimization (when applicable). Part 3: dose expansion. In each sub-study, a dose escalation will identify preliminary recommended dose for expansion (pRDE) of SAR443579 and its respective combination partner. Following the determination of the preliminary RDE, additional participants will be enrolled in the dose expansion part, or if dose optimization needs to be further evaluated, additional participants will be enrolled in the "dose optimization/expansion" part. Dose optimization and dose expansion part could involve randomization depending on specific sub-study design.

Study will consist of a screening period, treatment period, and follow-up period.

Participants will receive study treatment until documented disease progression, unacceptable adverse events, participant's decision to stop study treatment, or completion of the maximum cycles allowed in the sub-studies, or the participant meets other criteria for discontinuation per study protocol (whichever occurs first).

Substudy 01:

Title: A Phase 1/Phase 2, open-label, multi-center study, assessing the safety, tolerability and the preliminary efficacy of SAR443579 administered in combination with azacitidine + venetoclax in adult participants with CD123 expressing newly diagnosed Acute Myeloid Leukemia (ND-AML) that are ineligible for intensive chemotherapy

Short title: A study to investigate natural killer cell engager (SAR443579) in combination with azacitidine + venetoclax in adult participants with newly diagnosed acute myeloid leukemia

The expected duration of the study for a participant is approximately about 2.5 years. The study duration includes a screening period, an induction and maintenance. After the end of study treatment participants will enter the follow-up period for up to 2 years.

Planned number of participants:

22 participants planned to be screened, 8 being adults and 14 being elderly; 9-18 participants planned to be enrolled (dose escalation part)

Enrollment will be paused upon completion of Part 1: Dose Escalation. The available data will be reviewed and the recommended doses and schedule for optimization will be selected by the study board. Enrollment in the Part 2: Dose optimization and Part 3: Dose expansion will be provided in a future protocol amendment.

Inclusion Criteria:

- Participants with CD123-expressing hematological neoplasm per the 5th edition of the WHO Classification of Hematolymphoid Tumors.

Substudy 01:

• Participants must be ≥18 years of age
• Confirmed diagnosis of Acute Myeloid Leukemia
• Ineligible for intensive chemotherapy. Ineligible for intensive chemotherapy is defined by the following criteria:

A) ≥ 75 years of age, OR

B) 18 to 74 years of age and meeting one or more of the following:

1. Eastern Cooperative Oncology Group (ECOG) performance status 2-3.

2. Cardiac history of congestive heart failure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) ≤50% or symptomatic coronary heart disease confirmed by coronarography or cardiac imaging.

3. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume (FEV1) ≤65%.

4. Creatinine clearance ≥30 to <45 mL/min calculated by modification of diet in renal disease (MDRD) formula.

5. Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0x upper limit of normal (ULN).

   • Subject with an Eastern Cooperative Oncology Group (ECOG) performance status as follows:

a) 0 to 2 for participants ≥75 years of age or b) 0 to 3 for participants 18 to 74 years of age.

• For participants ≥75 years of age, adequate renal function demonstrated by a creatinine clearance ≥30 mL/min, calculated by modification of diet in renal disease (MDRD)

• Subject with adequate liver function demonstrated by the following:

  1. For participants 18 to 74 years of age, aspartate aminotransferase (AST) ≤3.0 × ULN, alanine aminotransferase (ALT) ≤3.0 × ULN and bilirubin ≤3.0 × ULN, unless considered due to leukemic organ involvement ˂5 × ULN.
  2. For participants ≥75 years of age, aspartate aminotransferase (AST) ≤3.0 × ULN, alanine aminotransferase (ALT) ≤3.0 × ULN and bilirubin ≤1.5 × ULN, unless considered due to leukemic organ involvement ˂5 × ULN.

Exclusion Criteria:

• Any clinically significant, uncontrolled medical conditions (including any serious active systemic infection that is not controlled)

• Known second malignancy either progressing or requiring active treatment within the last 3 years prior to first IMP administration

• Known acquired immunodeficiency syndrome (AIDS-related illnesses) or HIV disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or SARS-CoV-2 infection. With exception for:

  1. HBV as determined by positive test for hepatitis B surface antigen (HBsAg) and/or HBV DNA. Participant who tests positive for anti-hepatitis B core (HBc) antigen IgG (with or without testing positive for anti-HBs), but tests negative for HBsAg and HBV DNA, is eligible.
  2. A participant who tests positive for anti-HCV antibodies and has undetectable HCV RNA without receiving antiviral treatment for HCV is eligible.

• Active, known, or suspected clinically significant autoimmune disease that has required systemic treatment in the past 2 years prior to first IMP administration, except controlled by replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)

• Predicted life expectancy ≤3 months.

• Medical conditions requiring treatment with medications with narrow therapeutic index that are substrates of CYP enzymes and that cannot be closely monitored to allow for dose adjustment.

• Ongoing adverse event of NCI CTCAE [Version 5.0] Grade 2 or greater severity cause by any prior anti-cancer therapy

Substudy 01:

• Patient with Acute Promyelocytic Leukemia (APL)

• Known active central nervous system involvement with AML at the time of enrollment as evidenced by cytology or pathology

• Cardiovascular disease of New York Heart Association (NYHA) Class ≥2.

• Malabsorption syndrome or other condition that precludes enteral route of administration

• A baseline QTc interval of (using the Fridericia correction calculation) >470 msec.

• Subject has received treatment with at least one of the following:

  1. A hypomethylating agent, venetoclax and/or chemo therapeutic agent for AML other than hydroxyurea used for disease control prior to the initiation of study therapy.
  2. Experimental therapies for AML.
  3. Concomitant medications of strong and moderate CYP3A inducers within 7 days prior to the initiation of study treatment.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org