S243249 Monotherapy in Patients With Relapsed or Refractory Acute Leukemia With a KMT2A or NUP98 Translocation or Relapsed or Refractory AML With NPM1c Mutation

A Phase 1/2, Dose Optimization and Dose Expansion, Multicenter, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Menin Inhibitor S243249 Monotherapy in Patients With Relapsed or Refractory Acute Leukemia With a KMT2A or NUP98 Translocation or Patients With Relapsed or Refractory Acute Myeloid Leukemia With NPM1c Mutation

The objective of this study is to establish the efficacy, safety, and tolerability of S243249 and to establish the recommended phase 2 dose (RP2D) of S243249 monotherapy in participants with relapsed/refractory (R/R) acute leukemia with select mutations. Phase 1 dose optimization will determine the RP2D to be used in Phase 2 dose expansion. The study will include a screening period, a treatment period consisting of continuous 28-day cycles of treatment, a safety follow-up period and a long-term follow-up period. Participants may undergo blood tests, electrocardiogram (ECG), bone marrow aspirations, vital sign checks, questionnaires, and physical exams.

Study Overview

• Status: Not yet recruiting
• Conditions: Relapsed or Refractory Acute Myeloid Leukemia; Relapsed or Refractory Acute Leukemia
• Intervention / Treatment: Drug: S243249 600mg; Drug: S243249 400mg; Drug: S243249 450mg; Drug: S243249 300mg

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier (I.R.I.S.); Phone Number: +33 1 55 72 60 00; Email: scientificinformation@servier.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged ≥ 18 years old.
• Negative serum pregnancy (β-hCG) test in women of childbearing potential at screening
• Cytomorphology-confirmed diagnosis of R/R acute leukemia (including AML, ALL, and mixed lineage leukemia) according to the WHO criteria in 2022. R/R acute leukemia must meet at least one of the following conditions:
• Primary refractory disease, defined as non-response to 2 courses of standard induction therapy.
• R/R disease, defined as > 5% blasts on bone marrow aspirate (BMA) / bone marrow biopsy (BMB) after completing prior therapy.
• Relapse after allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT, or immunotherapy such as chimeric antigen receptor T cell therapy (CAR-T) and T cell engager (TCE).
• Participants with secondary AML or AML transformed from myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), etc., can be included in the study, if they meet the above criteria after the disease has transformed into AML.
• Confirmation of KMT2At, NUP98t, or NPM1c mutation using next generation sequencing (NGS), fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR) based test in an accredited local or central lab within 28 days before start of treatment.
• Peripheral blood white blood cell (WBC) count ≤ 25 mm3 (hydroxyurea, steroids, or vincristine to reduce peripheral WBC count is permitted).
• Participants will be at least 2 weeks from prior therapy (except hydroxyurea, vincristine, or steroids and prespecified prephase therapy) and recovered from nadir to no worse than Grade 1 nonhematological toxicity from the prior treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Adequate electrolytes, liver, kidney, and cardiac function
• Sexually active male or female participants of childbearing potential must agree to use 2 medically accepted forms of effective contraception, e.g., oral, parenteral, or implanted contraceptives; intrauterine devices; and barrier methods with spermicides, during the study and for 3 or 6 months after the final administration of investigational medicinal product (IMP), in males and females respectively. Egg donation is not allowed during the study or within 6 months of the last dose of S243249.
• Male participants with women of childbearing potential (WOCBP) partners must use a condom during the study and for at least 3 months after the final administration of IMP.

Exclusion Criteria:

• Active central nervous system (CNS) leukemia (including imaging abnormalities and cerebrospinal fluid (CSF) smear or flow cytometry indicating leukemia cells)).
• Active disseminated intravascular coagulation (DIC).
• Active uncontrolled infection (prophylaxis because of absolute neutrophil count [ANC] is excepted).
• Diagnosis of acute promyelocytic leukemia (APL, M3).
• Corrected QT interval calculated by Fridericia (QTcF) > 450 msec on screening ECG.
• Participants with an increased pro-arrhythmic risk such as those with congenital long QT syndrome.
• Uncontrolled or severe cardiovascular disease, , within 12 months.
• Uncontrolled serious arrhythmias.
• Clinically significant pericardial disease.
• History of other malignancy within the past 5 years.
• Participants who receive autologous hematopoietic stem cell transplantation (ASCT) or CAR-T therapy within 60 days of the first dose of S243249 or have not yet recovered from toxicity related to ASCT or CAR-T therapy.
• Participants who receive allogeneic HSCT within 100 days of the first dose of S243249, still have active acute or chronic graft versus host disease (GVHD), or still require immune-modulating therapy.
• Have an active infection of hepatitis B or hepatitis C.
• Have advanced liver disease or cirrhosis.
• Uncontrolled human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome related illness.
• Pregnant and/or breast-feeding (lactating) women.
• Participant has received anti-leukemia treatment, including chemotherapy, radiation therapy, targeted small molecule agents, biologic agents, immunotherapy, or any other investigational therapy (excluding hydroxyurea, or vincristine for cytoreduction) within 2 weeks prior to the first dose of S243249.
• Previous treatment targeting menin, dose optimization phase only.
• Any concomitant participation in another therapeutic clinical trial is prohibited. Any participation in another nontherapeutic clinical trial could be approved by the medical monitor.
• Participants taking medications known to prolong the QT/QTc interval (with the exception of necessary azole antifungals).
• Ongoing toxicity from prior anti-leukemia therapy that has not resolved to Grade 1 7 days prior to the first dose of S243249 has to be approved by the medical monitor.
• Uncontrolled active infection
• Known allergy or hypersensitivity to menin inhibitors or any component of S243249.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Optimization: Cohort 1; For participants without strong CYP3A4 inhibitors	Drug: S243249 600mg; Taken twice daily by mouth
Experimental: Phase 1 Dose Optimization: Cohort 2; For participants without strong CYP3A4 inhibitors	Drug: S243249 400mg; Taken twice daily by mouth
Experimental: Phase 1 Dose Optimization: Cohort 3; For participants with strong CYP3A4 inhibitors	Drug: S243249 450mg; Taken twice daily by mouth
Experimental: Phase 1 Dose Optimization: Cohort 4; For participants with strong CYP3A4 inhibitors	Drug: S243249 300mg; Taken twice daily by mouth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Adverse Events (AEs)	Through Safety Follow-up (Approximately 3 years)
Severity of AEs	Through Safety Follow-up (Approximately 3 years)
Number of changes in laboratory values	Through Safety Follow-up (Approximately 3 years)
Number of changes in electrocardiogram (ECG)	Through Safety Follow-up (Approximately 3 years)
Number of changes in vital signs	Through Safety Follow-up (Approximately 3 years)
Number of AEs leading to dose interruption	Through Safety Follow-up (Approximately 3 years)
Number of AEs leading to dose modification	Through Safety Follow-up (Approximately 3 years)
Number of AEs leading to dose delays	Through Safety Follow-up (Approximately 3 years)
Number of AEs leading to permanent treatment discontinuation	Through Safety Follow-up (Approximately 3 years)
Complete remission (CR) + Complete remission with partial recovery of hematology (CRh) rate	Through Long-term Follow-up (Approximately 5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	CR + CRh + Complete remission with incomplete hematological recovery (CRi) + Morphologically leukemic state (MLFS) + Partial remission (PR)	Through Long-term Follow-up (Approximately 5 years)
Composite complete remission (CRc) rate	CRc is CR + CRh + CRi	Through Long-term Follow-up (Approximately 5 years)
CR rate		Through Long-term Follow-up (Approximately 5 years)
Rate of CR/CRh Minimal residual disease (MRD) negativity		Through Long-term Follow-up (Approximately 5 years)
Duration of response (DOR)	Measured from the date of first achievement of CR/CRh, CR, CR/CRh MRD negativity, CRc and ORR until hematologic relapse or death from any cause	Through Long-term Follow-up (Approximately 5 years)
Time to response (TTR)	Measured from the date of first dose administration until the first achievement of CR/CRh, CR, CR/CRh MRD negativity, CRc and ORR	Through Long-term Follow-up (Approximately 5 years)
Transfusion independence 56 days (TI-56)	The absence of red blood cells and platelet transfusions lasting for 56 consecutive days during which the patient is either on Investigational medicinal product (IMP) or following discontinuation from IMP but before the start of new therapy.	Through Long-term Follow-up (Approximately 5 years)
Transfusion independence 112 days (TI-112)	The absence of red blood cells and platelet transfusions lasting for 112 consecutive days during which the patient is either on IMP or following discontinuation from IMP but before the start of new therapy.	Through Long-term Follow-up (Approximately 5 years)
Event free survival (EFS)		Through Long-term Follow-up (Approximately 5 years)
Cumulative relapse rate (CIR)		Through Long-term Follow-up (Approximately 5 years)
Cumulative mortality (CID)		Through Long-term Follow-up (Approximately 5 years)
Overall survival (OS)		Through Long-term Follow-up (Approximately 5 years)
Quality of Life (QoL) measured via EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L)	EQ-5D-5L scores range from 0-5 with 5 representing the best QoL.	Through Safety Follow-up (Approximately 3 years)
QoL measured via Hematological malignancy specific patient-reported outcome (HM-PRO)	HM-PRO Part A scores range from 0 to 48 and Part B scores from 0 to 36, with a higher score representing the largest impact on quality of life.	Through Safety Follow-up (Approximately 3 years)
Health economic outcomes measured via EQ-5D-5L	EQ-5D-5L scores range from 0-1 with 1 representing the best health economic outcomes.	Through Safety Follow-up (Approximately 3 years)
Health economic outcomes measured via HM-PRO	HM-PRO scores range from 0 to 48, with a higher score representing the largest impact on health economic outcomes.	Through Safety Follow-up (Approximately 3 years)
Ability to proceed to hematopoietic stem cell transplantation (HSCT) as assessed by the investigator		Through Long-term Follow-up (Approximately 5 years)
Plasma concentration of S243249 and relevant metabolites	Plasma samples will be analyzed to determine concentrations of S243249 and relevant metabolites	Through Cycle 6 Day 1 (each cycle is 28 days)
Tmax	Time to observed maximum plasma concentration of S243249 and relevant metabolites	Through Cycle 6 Day 1 (each cycle is 28 days)
Cmax	Maximum plasma concentration of S243249 and relevant metabolites	Through Cycle 6 Day 1 (each cycle is 28 days)
AUC0-t	Area under the plasma concentration-time curve from time 0 to time t of S243249 and relevant metabolites	Through Cycle 6 Day 1 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Servier

Study record dates

Study Major Dates

• Study Start (Estimated): September 20, 2026
• Primary Completion (Estimated): August 11, 2029
• Study Completion (Estimated): August 25, 2030

Study Registration Dates

• First Submitted: July 13, 2026
• First Submitted That Met QC Criteria: July 22, 2026
• First Posted (Actual): July 23, 2026

Study Record Updates

• Last Update Posted (Actual): July 23, 2026
• Last Update Submitted That Met QC Criteria: July 22, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: AML; ALL; Acute Leukemia; Relapsed Refractory; NPM1c; KMT2At; NUP98t; S243249
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Recurrence; Leukemia, Myeloid, Acute
• Other Study ID Numbers: BN104-102; 2025-524689-74-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for 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 any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorization in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No