First-in-human study of SAR443579 infusion in male and female children and adult participants with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia (B-ALL), high risk-myelodysplasia (HR-MDS), or blastic plasmacytoid dendritic cell neoplasm (BPDCN)

JRCT ID: jRCT2031240490

Registered date:18/11/2024

Basic Information

• Recruitment status: Pending

Health condition(s) or Problem(s) studied

Acute lymphocytic leukemia
Acute myeloid leukemia refractory
Myelodysplastic syndromes
BPDCN

• Date of first enrollment: 03/02/2025
• Target sample size: 169
• Countries of recruitment: Australia,Japan,China,Japan,France,Japan,Netherlands,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

Drug: SAR443579
Pharmaceutical form: Powder for solution for infusion
Route of administration: Intravenous infusion

Study Arms:
Experimental: SAR443579
Dose Escalation: SAR443579 administered intravenously at escalating dose levels.
Dose Expansion: SAR443579 administered intravenously at the recommended dose and schedule determined from the dose escalation.

Outcome(s)

Primary Outcome

1. Escalation Part: Incidence of dose-limiting toxicity (DLT)
[Time Frame: Day 1 to Day 28]
DLTs encompass both hematologic and nonhematologic toxicities, prespecified adverse reactions observed post-administration of SAR443579 and assessed by both the investigator and the sponsor.
2. Japan Cohort C: Incidence of DLT in Japanese participants
[Time Frame: Day 1 to Day 28]
DLTs encompass both hematologic and nonhematologic toxicities, prespecified adverse reactions observed post-administration of SAR443579 and assessed by both the investigator and the sponsor.
3. Expansion/Optimization part (Cohorts A1, A2 & D), AML: Proportion of participants who have a CR + CRh + CRi according to the modified AML International Working Group (IWG) 2003 criteria
[Time Frame: Up to 6 months]
Measure of clinical response to treatment: Proportion of participants who have a CR + CRh + CRi according to the modified AML IWG 2003 criteria.
4. Expansion/Optimization part (Cohort B), MDS: Overall response rate (ORR) (CR + CR equivalent + partial remission [PR] + CR with limited count recovery [CRL] + CRh + hematologic improvement [HI]) according to the IWG 2023 MDS response criteria
[Time Frame: Up to 6 months]
Measure of clinical response to treatment: ORR (CR + CR equivalent + PR + CRL + CRh + HI) according to the IWG 2023 MDS response criteria.

Secondary Outcome

1. Expansion/Optimization part - Cohorts A, B and D: Recommended dose for expansion (RDE)
[Time Frame: Up to 12 months]
Recommended dose for expansion (RDE) of SAR443579.
2. Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Number of participants with treatment emergent adverse events (TEAEs)
[Time Frame: Up to 30 months]
Number of participants with treatment emergent adverse events (TEAEs).
3. Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Ctrough
[Time Frame: Day 1 to end of trial (maximum up to 30 months)]
Concentration observed just before treatment administration during repeated dosing (Ctrough).
4. Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Incidence of anti-drug antibody (ADA)
[Time Frame: Up to 30 months]
Percentage of participants with anti-drug antibody (ADA).
5. Escalation and Expansion/Optimization parts - Japan Cohort C, AML: Rate of CR + CRh + CRi per AML 2003 modified IWG response criteria
[Time Frame: Up to 6 months]
Measure of clinical response to treatment.
6. Escalation and expansion/Optimization parts - Japan Cohort C, MDS: CR rate and ORR rate per IWG 2023 MDS response criteria for escalation part and ORR rate per IWG 2023
[Time Frame: Up to 6 months]
Measure of clinical response to treatment.
7. Escalation and Expansion/Optimization parts - Japan Cohort C, B-ALL: Rate of CR + CRh + CRi as defined by National Comprehensive Cancer Network (NCCN)
[Time Frame: Up to 6 months]
Measure of clinical response to treatment.
8. Expansion/Optimization part - Cohorts A and D: ORR
[Time Frame: Up to 6 months]
Measure of clinical response to treatment.
9. Expansion/Optimization part - Cohorts A and D: Duration of CR + CRh + CRi (duration of composite complete remission)
[Time Frame: Up to 30 months]
Measure the length of clinical response to treatment.
10. Expansion/Optimization part - Cohorts A and D: Duration of CR + CRi + CRh + PR + morphological leukemia-free state (MLFS) (Duration of ORR)
[Time Frame: Up to 30 months]
Measure the length of clinical response to treatment.
11. Expansion/Optimization part - Cohorts A and D: Alternative CR rate
[Time Frame: Up to 6 months]
Measure of clinical response to treatment.
12. Expansion/Optimization part - Cohorts A and D: Duration of CR + CRh (Duration of alternative CR)
[Time Frame: Up to 30 months]
Measure the length of clinical response to treatment.
13. Expansion/Optimization part - Cohorts A and D: Event-free survival (EFS)
[Time Frame: Up to 6 months]
EFS is defined as the time interval from the first day of treatment assignment to the date of earliest evidence of relapse, treatment failure, or death.
14. Expansion/Optimization part - Cohorts A and D: Overall survival (OS)
[Time Frame: Up to 30 months]
OS is defined as time interval from the first day of treatment assignment to death from any cause.
15. Expansion/Optimization part - Cohorts A and D: Rate of HSCT
[Time Frame: Up to 30 months]
Rate of HSCT procedures immediately following study treatment administration but prior to subsequent therapy for treatment of AML.
16. Expansion/Optimization part - Cohorts A and D: Time to treatment failure (TTF)
[Time Frame: Up to 6 months]
TTF is defined as the time from first day of treatment assignment to discontinuation for any reason excluding remission, eg, relapsed disease, refractory disease, unacceptable adverse event (AE), participant preference or death.
17. Expansion/Optimization part - Cohorts A and D: Rate of conversion from transfusion dependence
[Time Frame: Day 0 to Day 56]
Rate of conversion from transfusion dependence during 56-day post-baseline period.
18. Expansion/Optimization part - Cohorts A and D: Rate of participants who are transfusion independent at baseline and remain independent during 56-day post-baseline period
[Time Frame: Day 0 to Day 56]
Rate of participants who are transfusion independent at baseline and remain independent during 56-day post-baseline period.
19. Expansion/Optimization part - Cohort B: Alternative CR rate
[Time Frame: Up to 6 months]
Alternative CR rate defined as proportion of participants with CR, CR equivalent, CR unilineage, CR bilineage, and CRh.
20. Expansion/Optimization part - Cohort B: Duration of ORR
[Time Frame: Up to 30 months]
The time interval from the first documented evidence of CR, CR equivalent, CRL, CRh, PR or HI to progressive disease (PD) or relapse from CR, CR equivalent, CRL, CRh, PR or HI as per 2023 IWG recommendations or death due to any cause, whichever comes first.
21. Expansion/Optimization part - Cohort B: EFS
[Time Frame: Up to 30 months]
EFS is defined as the time interval from the first day of treatment assignment to the date of protocol specified events.
22. Expansion/Optimization part - Cohort B: OS
[Time Frame: Up to 30 months]
OS is defined as time interval from the first day of treatment assignment to death from any cause.
23. Expansion/Optimization part - Cohort B: Rate of HSCT
[Time Frame: Up to 30 months]
Rate of HSCT procedures immediately following study treatment administration but prior to subsequent therapy.
24. Expansion/Optimization part - Cohort B: TTF
[Time Frame: Up to 30 months]
TTF is defined as the time interval from first day of treatment assignment to discontinuation for any reason excluding remission, eg, relapsed disease, disease progression, unacceptable AE, participant preference or death.
25. Expansion/Optimization part - Cohort B: Duration of alternative CR (CR + CR equivalent + CRL + CRh)
[Time Frame: Up to 30 months]
Measure the length of clinical response to treatment.
26. Expansion/Optimization part - Cohort B: Progression free survival (PFS)
[Time Frame: Up to 30 months]
The time interval from the first day of treatment assignment to the date of PD, relapse from CR (or CR equivalent), PR, CRL, CRh, or HI, death due to any cause, whichever comes first.

Key inclusion & exclusion criteria

• Age minimum: >= 1age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

- Participant must be at least 1 year (for France: 2 years) old at the time the trial participant or legal guardian signs the informed consent form and will be assigned as follows:
-- Adult arm: aged at least 18 years old.
-- Pediatric arm: aged 1 (for France: 2 years) to less than 18 years old.
- Adult and Pediatric Arms: Escalation and Expansion/Optimization Cohorts A1, A2, C, D: Confirmed diagnosis of primary or secondary acute myeloid leukemia (AML) (any subtype) according to World Health Organization (WHO) 2022 classification. Participants with AML must meet one of the following criteria, a), b), c) or d) and are limited to those with no available (or are ineligible) therapy with known clinical benefit.
a) Primary induction failure AML, defined as disease refractory to one of the following, i or ii.
i) An intensive induction attempt, per institution. Induction attempts include high-dose and/or standard-dose cytarabine +/- an anthracyclines/anthracenedione +/- an anti-metabolite, with or without growth factor or targeted therapy containing regimens.
ii) For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; Primary induction failure is defined as AML refractory to one of the following less intensive regimens, 1 or 2:
1. 4 cycles of hypomethylating agents or
2. 2 cycles of hypomethylating agents + venetoclax
b) Early relapse AML, defined as AML in relapse with complete remission (CR), CR with partial hematologic recovery (CRh) or CR with incomplete hematologic recovery (CRi) duration less than 6 months on prior induction treatment.
c) Leukemia in first or higher relapse.
d) For participants aged 1 (for France: 2 years) to less than 18 years old, primary induction failure is defined as disease refractory after two cycles of induction therapy.
- Adult Arm (Escalation and Expansion/Optimization Cohorts B and Japan Cohort C only): Confirmed diagnosis of myelodysplasia (MDS), meeting the following criteria:
a) intermediate or high-risk category as per a Revised International Prognostic Scoring System (IPSS-R) AND
b) confirmed CD123+ expression status determined by local institutional standards AND
c) limited to those with no available (or are ineligible) therapy with known clinical benefit.
- Pediatric arms escalation part and Japan Cohort C only: Confirmed diagnosis of CD123+ B-ALL without extramedullary lesions that have no available (or are ineligible) therapy with known clinical benefit. Participants with non-central nervous system chloromatous disease are not allowed in the study.
- Body weight at least 10 kg.
- Pediatric arm and escalation part only: Confirmed diagnosis of BPDCN according to WHO 2022 classification, who have relapsed or refractory disease with no available (or are ineligible) therapy with known clinical benefit.
- Japan participants (Cohort C): Participant must be at least 18 years old at the time the trial participant signs the informed consent form.

Exclude criteria

- Eastern Cooperative Oncology Group (ECOG) performance status greater than 2 (at least 18 years-old). Karnofsky Scale (16 to 17 years-old) less than 50% or Lansky Scale (less than 16 years-old) less than 50%.
- Ongoing or recent (within 5 years) evidence of significant autoimmune disease that requires or required treatment with systemic immunosuppressive treatments, which may suggest a risk for immune-related adverse events. The following are not exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that required only hormone replacement or psoriasis that does not require systemic treatment.
- History of an invasive malignancy within the last 3 years prior to first investigational medicinal product administration that requires active therapy (adjuvant hormonal therapy is allowed) other than the one treated in this study.
- Evidence of active central nervous system leukemia at the time of enrollment as evidenced by cytology or pathology. Except for participants aged 1 (for France: 2 years) to less than 18 years, central nervous system 1 disease (CNS1) and central nervous system 2 disease (CNS2) are allowed.
- Known acquired immunodeficiency syndrome (AIDS) (AIDS-related illnesses) or human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
- Prior treatment with an anti-CD123-directed agent (except for participants with BPDCN in the pediatric arm).
- Prior hematopoietic stem cell transplantation (HSCT) with relapse beyond 3 months or prior chimeric antigen receptor T cell (CAR-T) therapy in B-ALL with relapse beyond 2 months may be included only if off immunosuppression for a minimum of 4 weeks and no evidence of graft versus host disease (GVHD).
- Receiving at the time of first investigational medicinal product administration corticosteroid as a concomitant medication with corticosteroid dose more than 10 mg/day of oral prednisone or the equivalent.
- AML, BPDCN, or HR-MDS participants with prior treatment with cellular therapy, eg, CAR-T or chimeric antigen receptor NK cell (CAR-NK). Prior CAR-T therapy is allowed for participants with B-ALL.
- Concurrent treatment with other investigational drugs.
- Pregnant and breast-feeding women.
- History of solid organ transplant, including corneal transplant.
- Average corrected QT (QTc) (using the Fridericia correction calculation) greater than 470 millisecond at screening.
- Pediatric arm only: Participants with known inherited bone marrow failure syndromes (e.g., bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome). Participants with Down syndrome with adequate organ function as per Investigator discretion are allowed to participate in the study.
- Adult arm Expansion/Optimization- Participants with MDS evolving from a pre-existing myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), unclassifiable MDS/MPN and therapy-related MDS (t-MDS).
- Confirmed diagnosis of acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML) according to WHO 2022 classification.

Related Information

• Primary Sponsor: Tanaka Tomoyuki
• Secondary ID(s): NCT05086315,2023-508357-58