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

Official title

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

Overview

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.

Interventions

• Drug S243249 600mg
  Taken twice daily by mouth
• Drug S243249 400mg
  Taken twice daily by mouth
• Drug S243249 450mg
  Taken twice daily by mouth
• Drug S243249 300mg
  Taken twice daily by mouth

Primary outcome measures

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

Secondary outcome measures (12)

• Overall response rate (ORR) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Composite complete remission (CRc) rate [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• CR rate [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Rate of CR/CRh Minimal residual disease (MRD) negativity [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Duration of response (DOR) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Time to response (TTR) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Transfusion independence 56 days (TI-56) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Transfusion independence 112 days (TI-112) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Event free survival (EFS) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Cumulative relapse rate (CIR) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Cumulative mortality (CID) [Time frame: Through Long-term Follow-up (Approximately 5 years)]
• Overall survival (OS) [Time frame: Through Long-term Follow-up (Approximately 5 years)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07722312 · BN104-102 · 2025-524689-74-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗