A Study of Bleximenib in Combination With Acute Myeloid Leukemia (AML) Directed Therapies

Janssen (J&J Innovative Medicine)

Status and phase: Enrolling; Phase 1

Conditions: Leukemia, Myeloid, Acute

Treatments: Drug: Cytarabine; Drug: Bleximenib; Drug: Azacitidine (AZA); Drug: Daunorubicin or Idarubicin; Drug: Venetoclax (VEN)

Study type: Interventional

Funder types: Industry

Identifiers

NCT05453903

CR109124

2023-506582-58-00 (Registry Identifier)

75276617ALE1002 (Other Identifier)

2021-003999-14 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study is to determine the recommended Phase 2 dose (RP2D) candidate(s) of bleximenib in combination with AML directed therapies (dose selection) and further to evaluate safety and tolerability of bleximenib in combination with AML directed therapies at the RP2D(s) (dose expansion).

Enrollment: 200 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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

Exclusion criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

---

200 participants in 3 patient groups

Arm A: Relapsed/Refractory Setting

Experimental group

Description:

Participants with relapsed/refractory AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations will receive bleximenib in combination with either venetoclax (VEN) (Cohort A1: bleximenib+VEN) or azacitidine (AZA) (Cohort A2: bleximenib +AZA) or VEN+AZA (Cohort A3: bleximenib+VEN+AZA) or VEN + AZA (Cohort A4: bleximenib + VEN + AZA) in adolescent participants aged greater than or equal to (\>=) 12 years and less than (\<) 18 years of age, to select the recommended phase 2 dose (RP2D) of bleximenib in combination with VEN, AZA or VEN+AZA (dose selection). In dose expansion portion of the study, participants will receive bleximenib in combination with AML directed therapies at the RP2D(s).

Treatment:

Drug: Venetoclax (VEN)

Drug: Azacitidine (AZA)

Drug: Bleximenib

Arm B: Newly Diagnosed Chemotherapy Ineligible Setting

Experimental group

Description:

Participants will receive bleximenib in combination with VEN+AZA as frontline chemo therapy for newly diagnosed AML participants harboring KMT2A, NPM1, NUP98, or NUP214 alterations who are \>=75 years of age or \>=18 years of age to \<75 years of age with comorbidities that preclude the use of intensive induction chemotherapy.

Treatment:

Drug: Venetoclax (VEN)

Drug: Azacitidine (AZA)

Drug: Bleximenib

Arm C: Newly Diagnosed Chemotherapy Eligible Setting

Experimental group

Description:

Participants will receive combination of bleximenib with cytarabine+daunorubicin or idarubicin chemotherapy as frontline treatment regimen for participants \>= 18 to \<75 years of age with AML harboring NPM1, KMT2A, NUP98, or NUP214 alterations and eligible for intensive chemotherapy.

Treatment:

Drug: Daunorubicin or Idarubicin

Drug: Bleximenib

Drug: Cytarabine