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).

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

Leukemia, Myeloid, Acute

Acute Myeloid Leukemia

Leukemia

Blood Cancer

Hematologic Neoplasms

Hematologic Malignancies

Hematology

Hematological Malignancies

Cytarabine

Bleximenib

Venetoclax (VEN)

Azacitidine (AZA)

Daunorubicin or Idarubicin

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

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 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

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

Number of participants with depletion of leukemic blasts 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; Absence of extramedullary disease; Absolute neutrophil count (ANC) greater than or equal to (>=) 1.0*10^9/Liter (L) (1,000/microliter [mcL]); Platelet count >= 100 * 10^9/L (100,000/mcL).

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 * 10^9/L (500/mcL) and platelet count >50 * 10^9/L (50,000/mcL).

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*10^9/L [1,000/mcL]) or thrombocytopenia (<100 * 10^9/L [100,000/mcL]).

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, morphologic leukemia-free state (MLFS) or partial remission (PR).

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).

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.

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.

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).

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

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.

The University of Alabama at Birmingham

City of Hope

Massachusetts General Hospital

Albert Einstein College Of Medicine

Novant Health

Novant Health Forsyth Medical Center

MD Anderson

Monash Medical Centre

Peter MacCallum Cancer Centre

Westmead Hospital

Institut Paoli Calmettes

Institut Universitaire du Cancer Toulouse Oncopole

CHU de Tours - Hôpital de Bretonneau

Charité Universitätsmedizin Berlin

Universitätsklinikum Carl Gustav Carus Dresden

Universitaetsklinikum Heidelberg

Universitaetsklinikum Leipzig

Universitatsklinikum Ulm

Azienda Opedaliero-Universitaria Policlinico Sant'orsola Malpighi di Bologna

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

ASST Grande Ospedale Metropolitano Niguarda

IRCCS Istituto Clinico Humanitas

Hosp. de La Santa Creu I Sant Pau

Hosp. Clinic I Provincial de Barcelona

Hosp. Univ. Vall D Hebron

Hosp. Univ. Fund. Jimenez Diaz

Clinica Univ. de Navarra

University College London Hospitals NHSFT

Christie Hospital NHS Trust

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

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 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.

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 (>=) 75 years of age or >=18 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.

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

Trials at a glance

Trials at a glance

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

Outcome measures

Primary outcome measures

Secondary outcome measures