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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sanofi-Aventis Recherche & Developpement

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Jul 2022 → 13 Jun 2025

Decision date (initial)

2024-03-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Sanofi-Aventis Recherche et Développement

External identifiers

EU CT number

2023-508357-58-00

EudraCT number

2021-004287-98

WHO UTN

U1111-1266-7399

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Pharmacokinetic, Efficacy, Dose response

Escalation part:

-- Adults Arm: To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and preliminary Recommended Dose(s) for Expansion (RDEs) of SAR443579 administered as a single agent in participants with relapsed or refractory acute myeloid leukemia (R/R AML), and high risk myelodysplastic syndrome (HR-MDS)

-- Pediatrics: To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and RDEs of SAR443579 administered as a single agent in participants with R/R AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN), or B-ALL

- Japan Cohort C: To confirm the tolerability of SAR443579 in Japanese participants

- Expansion/Optimization part (Cohorts A1, A2, B & D): To assess the anticancer activity of SAR443579 administered as a single agent at the preliminary Recommended Dose(s) for Expansion (RDEs) and confirm the RDE in participants with R/R AML and MDS.

Secondary objectives 8

1. To identify the preliminary RDEs (escalation part) and confirm the RDE (expansion/optimization part cohorts A, B and D)
2. To characterize the overall safety and tolerability profile of SAR443579 (escalation & expansion/optimization parts)
3. To characterize the pharmacokinetic (PK) profile of SAR443579 when administered as a single agent (escalation and expansion/optimization parts)
4. To evaluate the potential immunogenicity of SAR443579 (escalation and expansion/optimization parts)
5. To assess preliminary evidence of hematologic response (except BPDCN) (escalation part and expansion/optimization, and Japan Cohort C)
6. To assess additional parameters of SAR443579 anticancer activity in AML participants at the RDE (expansion/optimization part; cohorts A and D)
7. To assess transfusion independence rate (TI) after treatment with SAR443579 at the RDE (expansion/optimization part, Cohorts A and D)
8. To assess additional parameters of SAR443579 anticancer activity in MDS participants at the RDE (expansion/optimization part, Cohort B)

Conditions and MedDRA coding

Acute lymphocytic leukaemia- Acute myeloid leukaemia refractory - Myelodysplastic syndrome - Blastic plasmacytoid dendritic cell neoplasia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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.
2. Adult and Pediatric Arms: Escalation and Expansion/Optimization Cohorts A1, A2, C, D: Confirmed diagnosis of primary or secondary 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 (PIF) 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 antimetabolite, 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; PIF is defined as AML refractory to one of the following less intensive regimens, 1 or 2:1. 4 cycles of hypomethylating agents (HMA) or 2. 2 cycles HMA + venetoclax b) Early relapse (ER) AML, defined as AML in relapse with CR, CRh or 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.
3. Adult Arm (Escalation and Expansion/Optimization Cohorts B and Japan Cohort C only): Confirmed diagnosis of 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
4. Pediatric arms escalation part and Japan Cohort C only: Confirmed diagnosis of CD123+ BALL without extramedullary lesions that have no available (or are ineligible) therapy with known clinical benefit. Participants with non-CNS chloromatous disease are not allowed in the study.
5. Body weight at least 10 kg.
6. Pediatric arm and escalation part only: Confirmed diagnosis of BPDCN according to World Health Organization (WHO) 2022 classification, who have relapsed or refractory disease with no available (or are ineligible) therapy with known clinical benefit.
7. Japan participants (Cohort C): Participant must be at least 18 years old at the time the trial participant signs the informed consent form

Exclusion criteria 16

1. Eastern Cooperative Oncology Group (ECOG) performance status greater than 2 (at least 18 years-old). Karnovsky Scale (16-17 years-old) less than 50% or Lansky Scale (less than 16 years-old) less than 50%.
2. 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.
3. History of an invasive malignancy within the last 3 years prior to first IMP administration that requires active therapy (adjuvant hormonal therapy is allowed) other than the one treated in this study.
4. 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 CNS2 disease are allowed.
5. Known acquired immunodeficiency syndrome (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.
6. Prior treatment with an anti-CD123-directed agent (except for participants with BPDCN in the pediatric arm).
7. Prior HSCT with relapse beyond 3 months or prior 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 GVHD.
8. Receiving at the time of first investigational medicinal product (IMP) administration corticosteroid as a concomitant medication with corticosteroid dose more than 10 mg/day of oral prednisone or the equivalent.
9. AML, BPDCN, or HR-MDS participants with prior treatment with cellular therapy, eg, chimeric antigen receptor T cell (CAR-T) or chimeric antigen receptor NK cell (CARNK). Prior CAR-T therapy is allowed for participants with B-ALL.
10. Concurrent treatment with other investigational drugs
11. Pregnant and breast-feeding women
12. History of solid organ transplant, including corneal transplant
13. Average QTc (using the Fridericia correction calculation) greater than 470 millisecond (msec) at screening.
14. 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.
15. Adult arm Expansion/Optimization- Participants with MDS evolving from a preexisting myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), unclassifiable MDS/MPN and therapy-related MDS (t-MDS).
16. Confirmed diagnosis of acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML) according to WHO 2022 classification.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Escalation Part: Incidence of dose-limiting toxicity (DLT)
2. Japan Cohort C: Incidence of DLT in Japanese participant
3. Expansion/Optimization part (Cohorts A1, A2 & D), AML: Proportion of participants who have a CR + CRh + CRi according to the modified AML IWG 2003 criteri
4. Expansion/Optimization part (Cohort B), MDS: Overall response rate (CR + CR equivalent + PR + CRL + CRh + HI) according to the IWG 2023 MDS response criteria

Secondary endpoints 26

1. Expansion/Optimization part – Cohorts A, B and D: Recommended dose for expansion (RDE)
2. Escalation and Expansion/Optimization parts – Cohorts A, B, C and D: Number of participants with TEAEs
3. Escalation and Expansion/Optimization parts – Cohorts A, B, C and D: Ctrough
4. Escalation and Expansion/Optimization parts – Cohorts A, B, C and D: Incidence of ADA
5. Escalation and Expansion/Optimization parts – Japan Cohort C, AML: Rate of CR + CRh + CRi per AML 2003 modified IWG response criteria
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
7. Escalation and Expansion/Optimization parts – Japan Cohort C, B-ALL: Rate of CR + CRh + CRi as defined by National Comprehensive Cancer Network (NCCN)
8. Expansion/Optimization part – Cohorts A and D: Overall response rate (ORR)
9. Expansion/Optimization part – Cohorts A and D: Duration of CR + CRh + CRi (Duration of CRc)
10. Expansion/Optimization part – Cohorts A and D: Duration of CR + CRi + CRh + PR + MLFS (Duration of overall response rate)
11. Expansion/Optimization part – Cohorts A and D: Alternative CR rate
12. Expansion/Optimization part – Cohorts A and D: Duration of CR + CRh (Duration of alternative CR)
13. Expansion/Optimization part – Cohorts A and D: Event-free survival (EFS)
14. Expansion/Optimization part – Cohorts A and D: Overall survival (OS)
15. Expansion/Optimization part – Cohorts A and D: Rate of hematopoietic stem cell transplantation (HSCT)
16. Expansion/Optimization part – Cohorts A and D: Time to treatment failure (TTF)
17. Expansion/Optimization part – Cohorts A and D: Rate of conversion from transfusion dependence
18. Expansion/Optimization part – Cohorts A and D: Rate of participants who are transfusion independent at baseline and remain independent during 56-day postbaseline period
19. Expansion/Optimization part – Cohort B: Alternative CR rate
20. Expansion/Optimization part – Cohort B: Duration of ORR
21. Expansion/Optimization part – Cohort B: Eventfree survival (EFS)
22. Expansion/Optimization part – Cohort B: Overall survival (OS)
23. Expansion/Optimization part – Cohort B: Rate of hematopoietic stem cell transplantation (HSCT)
24. Expansion/Optimization part – Cohort B: Time to treatment failure (TTF)
25. Expansion/Optimization part – Cohort B: Duration of alternative CR (CR + CR equivalent + CRL + CRh)
26. Expansion/Optimization part – Cohort B: Progression free survival (PFS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sanofi-Aventis Recherche & Developpement

Sponsor organisation

Sanofi-Aventis Recherche & Developpement

Address

82 Avenue Raspail

City

Gentilly

Postcode

94250

Country

France

Scientific contact point

Organisation

Sanofi-Aventis Recherche & Developpement

Contact name

Clinical Sciences and Operations

Public contact point

Organisation

Sanofi-Aventis Recherche & Developpement

Contact name

Clinical Sciences and Operations

Third parties 9

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications