A Study of JNJ-75276617 in Participants With Acute Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine the recommended Phase 2 dose(s) (RP2D[s]) of JNJ-75276617 in Part 1 (Dose Escalation) and to determine safety and tolerability at the RP2D(s) in Part 2 (Dose Expansion).

Detailed Description
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Acute myeloid leukemia (AML) is a heterogeneous disease characterized by uncontrolled clonal expansion of hematopoietic progenitor cells (myeloid blasts) in the peripheral blood, bone marrow, and other tissues. Acute lymphoblastic leukemia (ALL) is a hematologic malignancy propagated by impaired differentiation, proliferation, and accumulation of lymphoid progenitor cells in the bone marrow and/or extramedullary sites. 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 primary goal of this FIH study is to establish the recommended Phase 2 dose (RP2D) of JNJ-75276617 with an acceptable safety profile. The total duration of the study is up to 2 years and 10 months. Safety assessment will include adverse events (AEs), serious adverse events (SAEs), physical examination, Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram, clinical safety laboratory assessment and pregnancy testing.

Official Title
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A First in Human Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Participants With Acute Leukemia

Conditions
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Acute Leukemias, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: JNJ-75276617


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory acute leukemia and has exhausted, or is ineligible for, available therapeutic options Acute leukemia harboring histone-lysine N-methyltransferase 2A (KMT2A) or nucleophosmin 1 gene (NPM1) alterations Pretreatment clinical laboratory values meeting the following criteria: (a) Hematology: white blood cell (WBC) count less than or equal to (<=) 30 * 10^9/liter (L) (hydroxyurea may be used to lower WBC count at screening and during study; (b) Chemistry: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 * upper limit of normal (ULN), total serum bilirubin <= 1.5 * ULN (participants with elevated bilirubinemia, such as Gilbert's syndrome, may enroll if conjugated bilirubin is within clinically acceptable range) and renal function; Estimated or measured glomerular filtration rate greater than or equal to (>=) 60 milliliter per minute (mL/min)/1.73 meter square (m^2) per four variable modified diet in renal disease (MDRD) equation Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1, or 2 A woman 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 A male must agree to all the following during the study and for 90 days after the last dose of study treatment: A male must agree to all the following during the study and for 90 days after the last dose of study treatment: (a) wear a condom when engaging in any activity that allows for passage of ejaculate to another person; (b) not to donate sperm or freeze for future use for the purpose of reproduction. In addition, the participant should be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak Exclusion Criteria: Acute promyelocytic leukemia according to World Health Organization (WHO) 2016 criteria Active central nervous system (CNS) disease Prior solid organ transplantation QTc according to Fridericia's formula (QTcF) for males >= 450 millisecond (msec) or for females >= 470 msec. Participants with a family history of Long QT syndrome are excluded Exclusion criteria related to stem cell transplant: a. Willing and able to undergo allogeneic stem cell transplant (if clinically indicated); b. Received prior treatment with allogenic bone marrow or stem cell transplant <=3 months before the first dose of study treatment; c. Has evidence of graft versus host disease; d. Received donor lymphocyte infusion <=1 month before the first dose of study treatment; e. Requires immunosuppressant therapy (exception: daily doses <=10 milligrams (mg) prednisone or equivalent are allowed for adrenal replacement) Chemotherapy, targeted therapy, immunotherapy, or radiotherapy within 4 weeks or 5 half-lives (whichever is shorter) before the planned first dose of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNJ-75276617<br>Participants in Part 1 (dose escalation) will receive JNJ-75276617 orally on a 28-day cycle. The dose levels will be escalated based on the dose limiting toxicities (DLT) evaluation by Study Evaluation Team (SET) until the recommended Phase 2 Doses (RP2Ds) has been identified. Participants in Part 2 (dose expansion) will receive JNJ-75276617 orally at one of the RP2D(s) determined in Part 1. Food effect cohort (optional) participants will receive JNJ-75276617 orally on Cycle 2 Day 1 under fasted condition and on Cycle 2 Day 2 under fed condition. | Drug: JNJ-75276617<br>* JNJ-75276617 is administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability | 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 2 years and 10 months | 
| Number of Participants with AEs by Severity | 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 2 years and 10 months | 
| Part 1: Percentage of Participants with Dose-Limiting Toxicity (DLT) | Percentage of participants with DLT will be assessed. The DLTs are specific adverse events and are defined as any of the following: high grade non-hematologic toxicity, or hematologic toxicity. | Up to 28 days Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of JNJ-75276617 | Plasma concentration of JNJ-75276617 will be reported. | Up to 2 years and 10 months | 
| Number of Participants with Depletion of Leukemic Blasts | Number of participants with depletion of leukemic blasts will be reported. | Up to 2 years and 10 months | 
| Number of Participants with Differentiation of Leukemic Blasts | Number of participants with differentiation of leukemic blasts will be reported. | Up to 2 years and 10 months | 
| Changes in Expression of Menin-histone-lysine N-methyltransferase 2A (KMT2A) Target Genes | Changes in expression of menin-KMT2A target genes will be reported. | Up to 2 years and 10 months | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieve complete remission (CR), CR with incomplete hematologic recovery (CRi) and CR with partial hematologic recovery (CRh). | Up to 2 years and 10 months | 
| Duration of Response (DOR) | DOR will be calculated among responders from the date of initial documentation of a response to the date of first documented evidence of relapse, as defined in the disease-specific response criteria, or death due to any cause, whichever occurs first. | Up to 2 years and 10 months | 
| Time to Response (TTR) | TTR is defined for the responders as the time from the date of the first dose of JNJ-75276617 to the date of the first documented response. | Up to 2 years and 10 months |