Relapsed or Refractory Acute Leukemia, Relapsed or Refractory Acute Myeloid Leukemia
Conditions
Keywords
NPM1c, KMT2At, NUP98t, AML, ALL, Acute Leukemia, Relapsed Refractory, S243249
Brief summary
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
DRUGS243249 600mg
Taken twice daily by mouth
DRUGS243249 400mg
Taken twice daily by mouth
DRUGS243249 450mg
Taken twice daily by mouth
DRUGS243249 300mg
Taken twice daily by mouth
Sponsors
Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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) |
| 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to response (TTR) | Through Long-term Follow-up (Approximately 5 years) | Measured from the date of first dose administration until the first achievement of CR/CRh, CR, CR/CRh MRD negativity, CRc and ORR |
| Transfusion independence 56 days (TI-56) | Through Long-term Follow-up (Approximately 5 years) | 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. |
| Transfusion independence 112 days (TI-112) | Through Long-term Follow-up (Approximately 5 years) | 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. |
| 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) | Through Safety Follow-up (Approximately 3 years) | EQ-5D-5L scores range from 0-5 with 5 representing the best QoL. |
| QoL measured via Hematological malignancy specific patient-reported outcome (HM-PRO) | Through Safety Follow-up (Approximately 3 years) | 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. |
| Health economic outcomes measured via EQ-5D-5L | Through Safety Follow-up (Approximately 3 years) | EQ-5D-5L scores range from 0-1 with 1 representing the best health economic outcomes. |
| Plasma concentration of S243249 and relevant metabolites | Through Cycle 6 Day 1 (each cycle is 28 days) | Plasma samples will be analyzed to determine concentrations of S243249 and relevant metabolites |
| Health economic outcomes measured via HM-PRO | Through Safety Follow-up (Approximately 3 years) | HM-PRO scores range from 0 to 48, with a higher score representing the largest impact on health economic outcomes. |
| Tmax | Through Cycle 6 Day 1 (each cycle is 28 days) | Time to observed maximum plasma concentration of S243249 and relevant metabolites |
| Cmax | Through Cycle 6 Day 1 (each cycle is 28 days) | Maximum plasma concentration of S243249 and relevant metabolites |
| AUC0-t | Through Cycle 6 Day 1 (each cycle is 28 days) | Area under the plasma concentration-time curve from time 0 to time t of S243249 and relevant metabolites |
| Ability to proceed to hematopoietic stem cell transplantation (HSCT) as assessed by the investigator | Through Long-term Follow-up (Approximately 5 years) | — |
| Overall response rate (ORR) | Through Long-term Follow-up (Approximately 5 years) | CR + CRh + Complete remission with incomplete hematological recovery (CRi) + Morphologically leukemic state (MLFS) + Partial remission (PR) |
| Composite complete remission (CRc) rate | Through Long-term Follow-up (Approximately 5 years) | CRc is CR + CRh + CRi |
| 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) | Through Long-term Follow-up (Approximately 5 years) | 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 |
Contacts
CONTACTInstitut de Recherches Internationales Servier (I.R.I.S.)
Outcome results
None listed