A Phase 1/Phase 2, Randomized, Open-label, Multi Cohort, Multi Center, Study Assessing the Safety, Tolerability and Preliminary Efficacy of SAR443579 a Natural Killer Cell Engager (NKCE) Targeting CD123, Administered With Different Agents in Participants With CD123 Expressing Hematological Malignancies
Overview
- Phase
- Phase 1
- Intervention
- SAR443579
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Sanofi
- Enrollment
- 7
- Locations
- 7
- Primary Endpoint
- Number of participants with adverse events (AEs)/serious adverse events (SAEs)/adverse events of special interest (AESIs), laboratory abnormalities
- Status
- Terminated
- Last Updated
- 8 months ago
Overview
Brief Summary
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).
Detailed Description
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.
Investigators
Eligibility Criteria
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:
- •Eastern Cooperative Oncology Group (ECOG) performance status 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.
- •Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume (FEV1) ≤65%.
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:
- •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.
- •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:
Arms & Interventions
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.
Intervention: SAR443579
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.
Intervention: venetoclax
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.
Intervention: azacitidine
Outcomes
Primary Outcomes
Number of participants with adverse events (AEs)/serious adverse events (SAEs)/adverse events of special interest (AESIs), laboratory abnormalities
Time Frame: Day 1 to 30 days after the last administration of study treatment
Substudy 01: Complete Remission (CR) rate (optimization part)
Time Frame: Day 1 to 30 days after the last administration of study treatment
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 AML
Substudy 01: Complete Remission (CR) rate (expansion part)
Time Frame: Day 1 up to 6 months
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 AML
Substudy 01: Incidence of dose limiting toxicities (DLTs) (escalation part)
Time Frame: Day 1 to Day 28
Secondary Outcomes
- Incidence of anti-drug anti body (ADA) against SAR443579(Day 1 to 30 days after the last administration of study treatment)
- Substudy 01: Pharmacokinetic (PK) parameter of SAR443579: Ctrough(Day 1 up to 10 cycles (each cycle 28 days))
- Substudy 01: Duration of alternative CR (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Overall survival (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Percentage of participants with Minimal residual disease (expansion part)(Day 1 up to 6 months)
- Substudy 01: PK parameter of venetoclax: Cmax(Day 1 to Day 28)
- Substudy 01: PK parameter of azacitidine: Cmax(Day 1 to Day 28)
- 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)(Day 1 to 30 days after the last administration of study treatment)
- Substudy 01: Overall response rate (expansion part)(Day 1 up to 6 months)
- Substudy 01: Duration of CR (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Duration of CRc (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Composite Complete Remission (CRc) rate(Day 1 up to 6 months)
- Substudy 01: Alternative CR rate (expansion part)(Day 1 up to 6 months)
- Substudy 01: Rate of participants who are transfusion independent at baseline and remain independent during 56-day post-baseline period (all parts)(Day 1 to Day 56)
- Substudy 01: PK parameter of venetoclax: AUC(Day 1 to Day 28)
- Substudy 01: PK parameter of azacitidine: AUC(Day 1 to Day 28)
- Substudy 01: Duration of overall response (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Event-free survival (EFS) (expansion part)(Day 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)(Day 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)(Day 1 to Day 56)
- Substudy 01: Time to treatment failure (TTF) (expansion part)(Day 1 up to 24 months after the last administration from study treatment)