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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: Venetoclax (VEN); Drug: Azacitidine (AZA); Drug: Bleximenib; Drug: Cytarabine; Drug: Daunorubicin or Idarubicin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Clayton, Australia, 3168
    • Monash Medical Centre
  • Melbourne, Australia, 3000
    • Peter MacCallum Cancer Centre
  • Westmead, Australia, 2145
    • Westmead Hospital
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Centre University Health Network
• France
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Rennes, France, 35033
    • Chu Rennes Hopital Pontchaillou
  • Toulouse, France, 31100
    • Institut Universitaire du Cancer Toulouse Oncopole
  • Tours, France, 37044
    • CHU de Tours - Hôpital de Bretonneau
• Germany
  • Berlin, Germany, 13353
    • Charite Universitaetsmedizin Berlin
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus Dresden
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg
  • Leipzig, Germany, 04103
    • Universitaetsklinikum Leipzig
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Italy
  • Bologna, Italy, 40138
    • Azienda Opedaliero-Universitaria Policlinico Sant'orsola Malpighi di Bologna
  • Meldola, Italy, 47014
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
  • Milan, Italy, 20162
    • ASST Grande Ospedale Metropolitano Niguarda
  • Rozzano, Italy, 20089
    • IRCCS Istituto Clinico Humanitas
• Spain
  • Barcelona, Spain, 08025
    • Hosp. de La Santa Creu I Sant Pau
  • Barcelona, Spain, 08036
    • Hosp Clinic de Barcelona
  • Barcelona, Spain, 8035
    • Hosp Univ Vall D Hebron
  • Madrid, Spain, 28040
    • Hosp Univ Fund Jimenez Diaz
  • Pamplona, Spain, 31008
    • Clinica Univ. de Navarra
• United Kingdom
  • London, United Kingdom, NW1 2PG
    • University College London Hospitals NHSFT
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital NHS Trust
  • Oxfordshire, United Kingdom, OX3 7LE
    • Oxford University Hospitals NHS Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • The University of Alabama at Birmingham
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10461
      • Albert Einstein College of Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health
    • Winston-Salem, North Carolina, United States, 27103
      • Novant Health Forsyth Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Relapsed/Refractory Setting; 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).	Drug: Venetoclax (VEN); Participants will receive VEN.; Drug: Azacitidine (AZA); Participants will receive AZA.; Drug: Bleximenib; Participants will receive bleximenib.; Other Names: JNJ-75276617
Experimental: Arm B: Newly Diagnosed Chemotherapy Ineligible Setting; 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.	Drug: Venetoclax (VEN); Participants will receive VEN.; Drug: Azacitidine (AZA); Participants will receive AZA.; Drug: Bleximenib; Participants will receive bleximenib.; Other Names: JNJ-75276617
Experimental: Arm C: Newly Diagnosed Chemotherapy Eligible Setting; 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.	Drug: Bleximenib; Participants will receive bleximenib.; Other Names: JNJ-75276617; Drug: Cytarabine; Participants will receive cytarabine.; Drug: Daunorubicin or Idarubicin; Participants will receive daunorubicin or idarubicin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events (AEs)	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.	Up to 3 Years 3 months
Number of Participants with Adverse Events (AEs) by Severity	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.	Up to 3 Years 3 months
Number of Participants with Dose-limiting Toxicity (DLT)	Number of participants with DLT will be reported according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.	End of Cycle 1 (28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Depletion of Leukemic Blasts	Number of participants with depletion of leukemic blasts will be reported.	Up to 3 Years 3 months
Plasma Concentration of Bleximenib	Plasma samples will be analyzed to determine concentrations of bleximenib using a validated, specific, and sensitive method.	Up to 3 Years 3 months
Percentage of Participants who Achieved Overall Response	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).	Up to 3 Years 3 months
Percentage of Participants who Achieve Complete Remission (CR)	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).	Up to 3 Years 3 months
Percentage of Participants who Achieve Complete Remission with Partial Hematologic Recovery (CRh)	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).	Up to 3 Years 3 months
Percentage of Participants who Achieve Complete Remission with Incomplete Hematologic Recovery (CRi)	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]).	Up to 3 Years 3 months

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Investigators: Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Publications and helpful links

General Publications

• Kwon MC, Thuring JW, Querolle O, Dai X, Verhulst T, Pande V, Marien A, Goffin D, Wenge DV, Yue H, Cutler JA, Jin C, Perner F, Hogeling SM, Shaffer PL, Jacobs F, Vinken P, Cai W, Keersmaekers V, Eyassu F, Bhogal B, Verstraeten K, El Ashkar S, Perry JA, Jayaguru P, Barreyro L, Kuchnio A, Darville N, Krosky D, Urbanietz G, Verbist B, Edwards JP, Cowley GS, Kirkpatrick R, Steele R, Ferrante L, Guttke C, Daskalakis N, Pietsch EC, Wilson DM, Attar R, Elsayed Y, Fischer ES, Schuringa JJ, Armstrong SA, Packman K, Philippar U. Preclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) in KMT2A- and NPM1-altered leukemias. Blood. 2024 Sep 12;144(11):1206-1220. doi: 10.1182/blood.2023022480.

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2022
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): March 3, 2027

Study Registration Dates

• First Submitted: July 8, 2022
• First Submitted That Met QC Criteria: July 8, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Cytarabine; Azacitidine; Daunorubicin; Idarubicin; venetoclax
• Other Study ID Numbers: CR109124; 2021-003999-14 (EudraCT Number); 75276617ALE1002 (Other Identifier: Janssen Research & Development, LLC); 2023-506582-58-00 (Registry Identifier: EUCT number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of Johnson & Johnson Innovative Medicine is available at innovativemedicine.jnj.com/our-innovation/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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No