Clinical trial NCT06508489: A Study to Investigate Natural Killer Cell Engager (SAR443579) With Different Agents in Participants With Hematological Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: AML
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2024-07-18
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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:

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.

Primary outcomes:
measure: Number of participants with adverse events (AEs)/serious adverse events (SAEs)/adverse events of special interest (AESIs), laboratory abnormalities
timeFrame: Day 1 to 30 days after the last administration of study treatment
measure: Substudy 01: Incidence of dose limiting toxicities (DLTs) (escalation part)
timeFrame: Day 1 to Day 28
measure: Substudy 01: Complete Remission (CR) rate (optimization part)
timeFrame: Day 1 to 30 days after the last administration of study treatment
measure: Substudy 01: Complete Remission (CR) rate (expansion part)
timeFrame: Day 1 up to 6 months
Secondary outcomes:
measure: 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)
timeFrame: Day 1 to 30 days after the last administration of study treatment
measure: Incidence of anti-drug anti body (ADA) against SAR443579
timeFrame: Day 1 to 30 days after the last administration of study treatment
measure: Substudy 01: Percentage of participants with Minimal residual disease (expansion part)
timeFrame: Day 1 up to 6 months
measure: Substudy 01: Pharmacokinetic (PK) parameter of SAR443579: Ctrough
timeFrame: Day 1 up to 10 cycles (each cycle 28 days)
measure: Substudy 01: PK parameter of venetoclax: Cmax
timeFrame: Day 1 to Day 28
measure: Substudy 01: PK parameter of azacitidine: Cmax
timeFrame: Day 1 to Day 28
measure: Substudy 01: PK parameter of venetoclax: AUC
timeFrame: Day 1 to Day 28
measure: Substudy 01: PK parameter of azacitidine: AUC
timeFrame: Day 1 to Day 28
measure: Substudy 01: Composite Complete Remission (CRc) rate
timeFrame: Day 1 up to 6 months
measure: Substudy 01: Overall response rate (expansion part)
timeFrame: Day 1 up to 6 months
measure: Substudy 01: Duration of CR (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Duration of CRc (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Duration of overall response (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Alternative CR rate (expansion part)
timeFrame: Day 1 up to 6 months
measure: Substudy 01: Duration of alternative CR (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Event-free survival (EFS) (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Overall survival (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: 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)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Time to treatment failure (TTF) (expansion part)
timeFrame: Day 1 up to 24 months after the last administration from study treatment
measure: Substudy 01: Rate of conversion from transfusion dependence to transfusion independence (all parts)
timeFrame: Day 1 to Day 56
measure: Substudy 01: Rate of participants who are transfusion independent at baseline and remain independent during 56-day post-baseline period (all parts)
timeFrame: Day 1 to Day 56
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center- Site Number : 8400003
state: California
city: Bronx
country: United States
facility: Montefiore Medical Center- Site Number : 8400004
state: New York
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center - Ohio State Outpatient Care Upper Arlington- Site Number : 8400001
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University- Site Number : 8400006
state: Oregon
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center- Site Number : 8400008
state: Texas
city: Wollongong
country: Australia
facility: Investigational Site Number : 0360002
state: New South Wales
city: Melbourne
country: Australia
facility: Investigational Site Number : 0360001
state: Victoria
Study officials:
References: