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Participants with relapsed/refractory AML harboring either NPM1 or KMT2A alterations will receive JNJ-75276617 in combination with either venetoclax (VEN) (Cohort A1: JNJ75276617+VEN) or azacitidine (AZA) (Cohort A2: JNJ-75276617+AZA) or VEN+AZA (Cohort A3: JNJ-75276617+VEN+AZA) to select the recommended phase 2 dose (RP2D) of JNJ-75276617 in combination with VEN, AZA or VEN+AZA (dose selection). In dose expansion portion of the study, participants will receive JNJ-75276617 in combination with AML directed therapies at the RP2D(s).

Participants will receive JNJ-75276617 in combination with VEN+AZA as frontline chemo therapy for newly diagnosed AML participants harboring either KMT2A or NPM1 alterations who are greater than or equal to (\>=)18 years of age to less than (\<) 75 years of age with comorbidities that preclude the use of intensive induction chemotherapy.

Participants will receive combination of JNJ-75276617 with cytarabine+daunorubicin or idarubicin chemotherapy as frontline treatment regimen for participants \>=18 to \<75 years of age with AML harboring either NPM1 or KMT2A alterations and eligible for intensive chemotherapy.

JNJ-75276617

Venetoclax (VEN)

Azacitidine (AZA)

Participants will receive daunorubicin or idarubicin

Daunorubicin or Idarubicin

Study Contact

Janssen Research & Development, LLC Clinical Trial

The purpose of this study is 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).

AML is a heterogenous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells (myeloid blasts) in the peripheral blood, bone marrow and other tissues and is the most common type of acute leukemia in adults. JNJ-75276617 is an orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between histone-lysine N-methyltransferase 2A (\[KMT2A\], also called mixed-lineage leukemia 1 \[MLL1\]; wild-type and fusion) and menin, with activity in leukemic cell lines and primary leukemia patient or patient-derived samples with either KMT2A alterations including gene rearrangements (KMT2A-r), duplications, and amplification, or nucleophosmin 1 gene (NPM1) alterations. The aim of this study is 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. The total study duration will be up to 2 years. 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.

A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies

A Phase 1b Study of JNJ-75276617 in Combination With AML-Directed Therapies for Participants With Acute Myeloid Leukemia Harboring KMT2A or NPM1 Alterations

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson \& Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.

Number of Participants with AEs by severity will be reported. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death related to adverse event.

Number of participants with DLT will be reported. The DLTs are specific adverse events and are defined per protocol as any of the following: non-hematologic toxicity, or hematologic toxicity.

Plasma samples will be analyzed to determine concentrations of JNJ-75276617 using a validated, specific, and sensitive method.

Number of participants with depletion of leukemic blasts will be reported.

Number of participants with differentiation of leukemic blasts will be reported.

Changes in expression of menin-KMT2A target genes will be reported.

Percentage of participants who achieve complete Remission (CR) will be reported. CR is defined as Bone marrow blasts less than (\<) 5 percent (%); Absence of circulating blasts and blasts with Auer rods; Absence of extramedullary disease; Absolute neutrophil count (ANC) greater than or equal to (\>=) 1.0 x 109/Liter (1,000/microliter \[μL\] ); Platelet count \>= 100 x 109/L (100,000/μL).

Percentage of participants who achieve complete remission with partial hematologic recovery (CRh) will be reported. CRh is defined as All criteria of CR with both ANC \>0.5 x 109/L (500/μL) and platelet count \>50 x 109/L (50,000/μL).

Percentage of participants who achieve complete remission with incomplete hematologic recovery (CRi) will be reported. CRi is defined as All CR criteria except for residual neutropenia (\<1.0 x 109/L \[1,000/μL\]) or thrombocytopenia (\<100 x 109/L \[100,000/μL\]).

Percentage of participants who achieve overall response will be reported. Overall response rate (ORR) is defined as the percentage of participants achieving CR, CRh, or CRi.

Duration of response is defined as time from achieving first response of CR, CRh, CRi or overall response to hematologic relapse or death of any cause.

Time to response is defined as time from first dose to achieving the first response of CR, CRh, CRi or overall response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies	NCT05453903	Leukemia, Myelo...	JNJ-75276617 Venetoclax (VEN... Azacitidine (AZ... Cytarabine Daunorubicin or...	18 Years -	Janssen Research & Development, LLC
A Study of JNJ-75276617 in Combination With Acute Myeloid Leukemia (AML) Directed Therapies	NCT05453903	Leukemia, Myelo...	JNJ-75276617 Venetoclax (VEN... Azacitidine (AZ... Cytarabine Daunorubicin or...	18 Years -	Janssen Research & Development, LLC

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