A Phase Ib Study of Bleximenib in Combination With AML-Directed Therapies for Participants With Acute Myeloid Leukemia Harboring KMT2A or NPM1 Alterations
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Study Summary
To determine the recommended Phase 2 dose (RP2D) candidate(s) of JNJ-75276617 in combination with AML directed therapies (dose selection) and further to evaluate safety and tolerability of JNJ-75276617 in combination with AML directed therapies at the RP2D(s) (dose expansion). To determine the RP2D(s), safety, pharmacokinetic, pharmacodynamic and preliminary clinical activity of JNJ-75276617 in combination with AML directed therapies for adult participants with relapsed/refractory or newly diagnosed AML with NPM1 or KMT2A gene alterations and will include dose selection and subsequent combination specific dose expansion. Safety evaluations include adverse events (AE) monitoring, clinical laboratory tests, electrocardiograms (ECGs), vital sign measurements, physical examination findings, and eastern cooperative oncology group (ECOG) performance status score. Dose Selection: Determine the recommended Phase 2 dose (RP2D) candidate(s) of JNJ-75276617 in combination with AML directed therapies Dose Expansion: Further evaluate safety and tolerability of JNJ-75276617 in combination with AML directed therapies at the RP2D(s) To determine the safety and preliminary efficacy of bleximenib in combination with intensive cytarabine + daunorubicin/idarubicin, followed by cytarabine consolidation for ND NPM1m or KMT2Ar AML participants (pts) eligible for IC. . The safety dataset includes all dosed pts, with adverse events (AEs) reported per CTCAE v5. The efficacy dataset, as assessed by investigators (per modified ELN 2017), comprises ND pts with NPM1m or KMT2Ar who received ≥50 mg bleximenib BID in combination with ‘7+3’ IC and completed at least 1 disease evaluation.
Response criteria was assessed by each investigator according to European LeukemiaNet (ELN) recommendations.
ASH 2025:
In Cohort A1, pts with R/R AML received VEN in combination with oral bleximenib at 15–100 mg twice daily (BID) continuously. VEN dosing was guided by the label, with ramp-up followed by a plateau dose of 400 mg daily in 28-day cycles. Bleximenib started on Day 4, after VEN ramp-up. Safety analysis includes all dosed pts. Relative dose intensity (RDI) is the total bleximenib dose received divided by total planned doses of bleximenib for a 28-day cycle. Intention-totreat efficacy analysis includes NPM1m or KMT2Ar AML pts receiving bleximenib 50 mg or 100 mg BID in combination with VEN, including pts who discontinued prior to first disease evaluation.
To report updated safety and efficacy data.
- Adolescent participants (defined as greater than or equal to [>=] 12 and less than [<] 18 years of age) are only eligible for the relapsed/refractory (R/R) cohort (Arm A, cohort A4)
- Diagnosis of AML according to World Health Organization (WHO) criteria: a) De novo or secondary AML; b) relapsed/refractory (Arm A only); c) harboring KMT2A, NPM1, NUP98, or NUP214 alterations; d) Participants may receive emergency leukapheresis and/or cytarabine as cytoreductive therapy according to local practice guidelines
- Pretreatment clinical laboratory values meeting the following criteria -listed below: White blood cell (WBC) count: less than or equal to (<=) 25*10^9 per liter (/L), adequate liver and renal function
- Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or 2. Adolescent participants only: Performance status >70 by Lansky scale (for participants <16 years of age) or >70 Karnofsky scale (for participants >16 years of age)
- A female of childbearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study treatment
- Must sign an informed consent form (ICF) indicating participant (or their legally authorized representative) understands the purpose of the study and procedures required for the study and is willing to participate in the study
- Willing and able to adhere to the prohibitions and restrictions specified in this protocol
- Acute promyelocytic leukemia, diagnosis of Down syndrome associated leukemia or juvenile myelomonocytic leukemia according to WHO 2016 criteria
- Leukemic involvement of the central nervous system
- Recipient of solid organ transplant
- Cardiovascular disease that is uncontrolled, increases risk for Torsades de Pointes or that was diagnosed within 6 months prior to the first dose of study treatment including, but not limited to: (a) Myocardial infarction; (b) Severe or unstable angina; (c) Clinically significant cardiac arrhythmias, including bradycardia (<50 beats per minute); (d) Uncontrolled (persistent) hypertension: (example, blood pressure greater than [>] 140/90 millimeters of mercury [mm Hg]; (e) Acute neurologic events such as stroke or transient ischemic attack, intracranial or subarachnoid hemorrhage, intracranial trauma; (f) Venous thromboembolic events (example, pulmonary embolism) within 1 month prior to the first dose of study treatment ;(g) Congestive heart failure (NYHA class III to IV); (h) Pericarditis or clinically significant pericardial effusion; (i) Myocarditis; (j) Endocarditis (k) Clinically significant hypokalemia, hypomagnesemia, hypocalcemia (corrected for hypoalbuminemia)
- Any toxicity (except for alopecia, stable peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapy that has not resolved to baseline or to grade 1 or less
- Pulmonary compromise that requires the need for supplemental oxygen use to maintain adequate oxygenation
- Participants with diagnosis of Fanconi anemia, Kostmann syndrome, Shwachman diamond syndrome, or any other known bone marrow failure syndrome
Clinical Study Information for Healthcare Providers
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