A Study to Investigate Natural Killer Cell Engager (SAR443579) With Different Agents in Participants With Hematological Malignancies

PHASE1PHASE2RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Participants with CD123-expressing hematological neoplasm per the 5th edition of the WHO Classification of Hematolymphoid Tumors.
  • 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 caused by any prior anti-cancer therapy
  • 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 chemotherapeutic 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.
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2024-08-13

    Primary completion: 2029-02-12

    Study completion finish: 2029-02-12

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE1

      PHASE2

    trial

    Trial ID

    NCT06508489

    Intervention or treatment

    BIOLOGICAL: SAR443579

    DRUG: venetoclax

    DRUG: azacitidine

    Conditions

    • Acute Myeloid Leukemia

    Find a site

    Closest Location:

    Investigational Site Number : 0360001

    Research sites nearby

    Select from list below to view details:

    • Investigational Site Number : 0360001

      Melbourne, Victoria, Australia

    • Investigational Site Number : 0360002

      Wollongong, New South Wales, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Substudy 01: SAR443579 + azacitidine + venetoclax
    • Part 1: Safety run-in: SAR443579 treatment will begin with an identified starting dose. Safety run-in will proceed according to the incidence of DLTs.
    BIOLOGICAL: SAR443579
    • Pharmaceutical form: Powder for solution for infusion Route of administration: intravenous infusion

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Number of participants with adverse events (AEs)/serious adverse events (SAEs)/adverse events of special interest (AESIs), laboratory abnormalitiesNot SpecifiedDay 1 to 30 days after the last administration of study treatment
    Substudy 01: Incidence of dose limiting toxicities (DLTs) (escalation part)Not SpecifiedDay 1 to Day 28
    Substudy 01: Complete Remission (CR) rate (optimization part)Proportion of participants who have a CR (Complete Remission) determined by the Investigator according to 2022 European Leukemia Net (ELN) recommendations for diagnosis and management of AMLDay 1 to 30 days after the last administration of study treatment
    Substudy 01: Complete Remission (CR) rate (expansion part)Proportion of participants who have a CR (Complete Remission) determined by the Investigator according to 2022 European Leukemia Net (ELN) recommendations for diagnosis and management of AMLDay 1 up to 6 months

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) and clinically significant laboratory abnormalities (expansion part)According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)Day 1 to 30 days after the last administration of study treatment
    Incidence of anti-drug anti body (ADA) against SAR443579Not SpecifiedDay 1 to 30 days after the last administration of study treatment
    Substudy 01: Percentage of participants with Minimal residual disease (expansion part)As defined by 2022 ELN recommendations for AMLDay 1 up to 6 months
    Substudy 01: Pharmacokinetic (PK) parameter of SAR443579: CtroughConcentrations observed at the end the dosing period during repeated administration for SAR443579Day 1 up to 10 cycles (each cycle 28 days)
    Substudy 01: PK parameter of venetoclax: CmaxMaximum concentration observed for venetoclaxDay 1 to Day 28
    Substudy 01: PK parameter of azacitidine: CmaxMaximum concentration observed for azacitidineDay 1 to Day 28
    Substudy 01: PK parameter of venetoclax: AUCArea under the blood concentration versus time curve extrapolated to infinity for venetoclaxDay 1 to Day 28
    Substudy 01: PK parameter of azacitidine: AUCArea under the blood concentration versus time curve extrapolated to infinity for azacitidineDay 1 to Day 28
    Substudy 01: Composite Complete Remission (CRc) rateProportion of participants who have a CR (Complete Remission) + CRh (complete remission with partial hematologic recovery) + CRi (Complete Remission with Incomplete Hematologic Recovery) determined by the Investigator according to 2022 European Leukemia Net (ELN) recommendations for diagnosis and management of AML. (CRc = CR + CRh + CRi)Day 1 up to 6 months
    Substudy 01: Overall response rate (expansion part)Proportion of participants who have a CR or CRi or CRh or PR or MLFS (morphological leukemia-free state) according to the 2022 ELN criteria.Day 1 up to 6 months
    Substudy 01: Duration of CR (expansion part)Defined as the time interval from the first documented evidence of CR until disease relapse as per 2022 ELN recommendations or death due to any cause, whichever comes firstDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Duration of CRc (expansion part)Defined as the time interval from first documented evidence of CRc (CR, CRh or CRi) until disease relapse as per 2022 ELN recommendations or death due to any cause, whichever comes firstDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Duration of overall response (expansion part)Defined as the time from the first documented evidence of CR or CRi or CRh or PR or MLFS until disease relapse as per 2022 ELN recommendations or death due to any cause, whichever comes firstDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Alternative CR rate (expansion part)Defined as the proportion of participants with CR+CRh (complete remission with partial hematological recovery)Day 1 up to 6 months
    Substudy 01: Duration of alternative CR (expansion part)Defined as the time from the first documented evidence of CR or CRh until disease relapse as per 2022 ELN recommendations or death due to any cause, whichever comes firstDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Event-free survival (EFS) (expansion part)Defined as the time interval from the first day of treatment assignment to the date of earliest evidence of relapse, treatment failure, or deathDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Overall survival (expansion part)Defined as time interval from the first day of treatment assignment to death from any causeDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Rate of hematopoietic stem cell transplantation (HSCT) procedures immediately following study treatment administration but prior to subsequent therapy for treatment of AML (all parts)The HSCT rate is defined as the proportion of such participants who undergo HSCT through study treatment but before subsequent therapy, among the safety/exposed populationDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Time to treatment failure (TTF) (expansion part)Defined as the time from first day of treatment assignment to discontinuation for any reason excluding remission, for example relapsed disease, refractory disease, unacceptable AE, participant preference or deathDay 1 up to 24 months after the last administration from study treatment
    Substudy 01: Rate of conversion from transfusion dependence to transfusion independence (all parts)The transfusion dependency (TD) at baseline is based on the receipt of any red blood cell or platelets transfusions within at least 28 days prior to the start of study treatment. For post baseline treatment, transfusion independency (TI) will be defined as the absence of transfusion during any 56 consecutive day period during treatment.Day 1 to Day 56
    Substudy 01: Rate of participants who are transfusion independent at baseline and remain independent during 56-day post-baseline period (all parts)Transfusion independency (TI) will be defined as the absence of transfusion during any 56 consecutive day period during treatment.Day 1 to Day 56

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    References

    Clinical Trials Gov: A Study to Investigate Natural Killer Cell Engager (SAR443579) With Different Agents in Participants With Hematological Malignancies

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