A study to evaluate S227928 as a Single Agent and in Combination with Venetoclax in Patients with R/R AML, MDS/AML, or CMML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Recherches Internationales Servier IRIS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Feb 2025 → 14 Oct 2025

Decision date (initial)

2025-01-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ADIR France Laboratorios Servier, S.L

External identifiers

EU CT number

2024-514356-33-00

ClinicalTrials.gov

NCT06563804

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

Phase I: To assess the safety and tolerability, and to determine the maximum tolerated dose (MTD), if appropriate, of S227928 as a single agent
Phase I: To assess the safety and tolerability, and to determine the Recommended Phase II Dose (RP2D) and/or the Maximum Tolerated Dose (MTD) of S227928 in combination with venetoclax.
Phase II: To assess the anti-leukemic activity of S227928 in combination with venetoclax in participants with R/R AML or MDS/AML (cohort 1).
Phase II: To assess the anti-leukemic activity of S227928 in combination with venetoclax in participants with R/R CMML (cohort 2).

Secondary objectives 9

1. Phase I: To characterize the pharmacokinetic (PK) profile of S227928 as a single agent and in combination with venetoclax.
2. Phase I: To evaluate the immunogenicity of S227928 as a single agent and in combination with venetoclax.
3. Phase I: To assess the anti-leukemic activity of S227928 as a single agent and in combination with venetoclax in participants with R/R AML or MDS/AML according to the European LeukemiaNet (ELN) 2022 criteria
4. Phase I: To assess the anti-leukemic activity of S227928 as a single agent and in combination with venetoclax in participants with R/R CMML according to the International Working Group (IWG) 2023 response criteria.
5. Phase II: To assess the anti-leukemic activity of S227928 in combination with venetoclax in participants with R/R AML or MDS/AML according to the ELN 2022 criteria (cohort 1)
6. Phase II: To assess the anti-leukemic activity of S227928 in combination with venetoclax in participants with R/R CMML according to the IWG 2023 response criteria (cohort 2).
7. Phase II: To further characterize the PK profile of S227928 in combination with venetoclax.
8. Phase II: To evaluate the immunogenicity of S227928 in combination with venetoclax.
9. Phase II: To confirm the safety and tolerability of S227928 in combination with venetoclax.

Conditions and MedDRA coding

"Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)/AML, or Chronic Myelomonocytic Leukemia (CMML)"

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Servier’s Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. Researchers can ask for a study protocol, patient-level and/or study-level clinical study data including clinical study reports. They can ask for all interventional clinical studies in patients: Submitted for new medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US). Where Servier or an affiliate are the Marketing Authorisation Holders (MAH). The date of the first Marketing Authorisation (MA) of the new medicine (or the new indication) in one of the EEA Member States will be considered within this scope. In addition, Servier’s data sharing policy includes all interventional clinical studies in patients: sponsored by Servier, with a first patient enrolled as of 1 January 2004 onwards, for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Adult participant (must be ≥ 18 years of age or according to local requirements).
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.except for European Countries where only ECOG performance status of 0 and 1 will be allowed.
3. Written informed consent must be obtained prior to any study-specific procedures.
4. Patients with pathologically confirmed AML, MDS/AML, or CMML as defined by the WHO 2022 classification or ICC, who have been previously treated with at least one prior standard treatment and have relapsed and/or refractory disease: a. Patients must not be candidates for further standard therapy, b. Treatment with agents for lower risk MDS such as erythropoietin or luspatercept are not considered anticancer therapies. c. Patients with R/R MDS with bone marrow blast count that does not meet ICC criteria for MDS/AML (i.e., bone marrow blast count <10%) will not be eligible for this study.
5. Circulating leukocytes < 10 x 10^9/L (use of hydroxycarbamide before study drug initiation is allowed to achieve this inclusion criterion).
6. Adequate renal and hepatic function within 7 days before study enrollment.

Exclusion criteria 12

1. Failure to recover to ≤ Grade 1 (Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0]) from acute non-hematologic toxicities due to previous therapy, prior to screening.
2. For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion): Both moderate and strong CYP3A4 inducers are prohibited, beginning 14 days before the start of IMP and continuing for the entire duration of treatment.
3. For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion): BCRP inhibitors, and medications which are substrates of P-gP, BCRP, or OATP1B1 with a narrow therapeutic index (NTIs) are prohibited, beginning 7 days prior to the start of IMP and continuing for the entire duration of treatment. If concomitant use of P-gp substrate is unavoidable, its dosing should be done at least 6 hours apart from venetoclax.
4. Diagnosis of myeloproliferative neoplasms (MPNs) or other non-CMML MDS/MPNs as defined by the WHO 2022 classification
5. Diagnosis of acute promyelocytic leukemia (French-American-British [FAB] M3 classification).
6. Diagnosis of acute leukemia of mixed or ambiguous lineage or histiocytic/dendritic cell neoplasms defined by the WHO 2022 classification.
7. Uncontrolled infections requiring systemic antibiotics and/or antifungal agents as per investigator’s judgment. Patients receiving prophylactic antibiotics and/or antifungal agents are eligible for this study.
8. Participants with a known clinically significant cardiovascular disease or condition, including: a. Uncontrolled arterial hypertension per the investigator’s judgment, b. New York Heart Association (NYHA) class III or IV congestive heart failure, c. Congenital or substance-induced long QT defined as heart rate-corrected QT (QTc) interval > 470 ms according to Fridericia’s formula, d. Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible), e. Severe uncorrected conduction disturbances (e.g., 3rd degree heart block). Patients with severe conduction disturbances corrected by a pacemaker are eligible, f. Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction),coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration, g. Troponin I > ULN or troponin T > ULN if troponin I cannot be assessed, h. Any factors that could increase the risk of QTc interval prolongation or risk of arrhythmic events such as heart failure, family history of QT syndrome, or family history of unexplained sudden death under 40 years of age.
9. Known active central nervous system involvement by AML, MDS/AML, or CMML
10. For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion), those with a malabsorption syndrome or other condition that precludes enteral route of administration.
11. For all participants receiving S227928 (as a single agent and in combination with Venetoclax): Although participants may be treated with strong inhibitors of CYP3A4 or of CYP2C8, they may not be treated with medications that are strong inhibitors of both CYP3A4 and CYP2C8, or with separate medications that when combined would cause strong inhibition of these two enzymes. In addition, participants may not be treated with a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2C8 and/or a moderate inhibitor of P-gp. These prohibitions begin 7 days prior to the start of IMP and continue for the entire duration of treatment. Triazole antifungal agents may be used, but only if they are in agreement with the criteria described above (i.e., they must not be dual strong inhibitors of both CYP3A4 and CYP2C8 or strong inhibitors of CYP3A4 and moderate inhibitors of either CYP2C8 or P-gp.
12. Participants previously treated with S227928 in Arm A will not be eligible for treatment in Arm B.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase I: Incidence and severity of dose-limiting toxicities (DLTs) of S227928 as a single agent and combined with venetoclax during the first cycle of treatment.
2. Phase I: Incidence of adverse events (AEs) and serious adverse events (SAEs), changes in vital signs, physical examination, laboratory tests, including cardiac markers,electrocardiogram (ECG), echocardiogram (ECHO) with or without global longitudinal strain (GLS) or multigated acquisition (MUGA) scan, and cardiac magnetic resonance imaging (MRI).
3. Phase I: Dose reductions/interruptions/delays or study withdrawal due to AEs.
4. Phase II: Complete Remission (CR).

Secondary endpoints 14

1. Plasma concentration vs. time profile and derived PK parameters (i.e., Cmax, Tmax, AUC) of S227928, total monoclonal antibody (mAb), and unconjugated S64315 and venetoclax (when applicable)
2. Phase I: Detection of anti-drug antibodies (ADAs) against S227928 and their titer, when applicable.
3. Phase I: Complete remission (CR), complete remission with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), CR with partial hematologic recovery (CRh), and partial remission (PR) for patients with AML and MDS/AML.
4. Phase I: Overall survival (OS), duration of response (DOR), and time to first remission (CR or CRh or CRi) for patients with AML and MDS/AML.
5. Phase I: Red-blood cell (RBC) and platelet transfusion independence for at least 8 weeks for patients with AML and MDS/AML.
6. Phase I: CR, CRh, CR with limited count recovery (CRL), CR equivalent, PR, hematologic improvement (HI); overall response rate (ORR)= CR + CR equivalent + CRh + CRL+ PR + HI for patients with CMML.
7. Phase I: Progression-free survival (PFS), event-free survival (EFS), and OS for patients with CMML.
8. Phase II: CRi, MLFS, CRh, PR; OS, EFS, DOR, time to first remission (CR or CRi or CRh); RBC and platelet transfusion independence for at least 8 weeks for patients with AML and MDS/AML.
9. Phase II: CRh, CRL, CR equivalent, PR, HI; ORR= CR + CR equivalent + CRh + CRL + PR + HI; PFS, EFS, and OS for patients with CMML.
10. Phase II: Plasma concentrations vs. time profile of S227928, total mAb, unconjugated S64315, and venetoclax and derived PK parameters (i.e., Cmax, Tmax, AUC) of S227928, total mAb and unconjugated S64315.
11. Phase II: Detection of ADAs against S22798 and their titer, when applicable.
12. Phase II: Incidence and severity of DLTs of S227928 in combination with venetoclax; Incidence of AEs and SAEs
13. Phase II: changes in vital signs, physical examination, laboratory tests including cardiac markers, ECG, ECHO with or without GLS or MUGA scan, and cardiac MRI.
14. Phase II: Dose reduction/interruptions/delays or study withdrawal due to AEs.

Investigational products

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

Test 10

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Recherches Internationales Servier IRIS

Sponsor organisation

Institut De Recherches Internationales Servier IRIS

Address

22 Route 128

City

Gif Sur Yvette

Postcode

91190

Country

France

Scientific contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Public contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Third parties 8

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

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

Documents 26 files

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

Application history

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