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

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 (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).

Detailed Description
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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.

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

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: JNJ-75276617
* Drug: Venetoclax (VEN)
* Drug: Azacitidine (AZA)
* Drug: Cytarabine
* Drug: Daunorubicin or Idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AML according to World Health Organization (WHO) criteria: a) De novo or secondary AML; b) relapsed /refractory (Arm A only); c) harboring NPM1 / KMT2A alterations Pretreatment clinical laboratory values meeting the following criteria -listed below: White blood cell (WBC) count: less than or equal to <=25 x 10^9 per liter (/L), adequate liver and renal function 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 Must sign an informed consent form (ICF) indicating participant 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 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 (less than [<] 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 (uncomplicated Grade less than or equal to [≤]2 deep vein thrombosis is not considered exclusionary);(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

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Relapsed/Refractory Setting<br>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). | Drug: JNJ-75276617<br>* Participants will receive JNJ-75276617.<br>Drug: Venetoclax (VEN)<br>* Participants will receive VEN.<br>Drug: Azacitidine (AZA)<br>* Participants will receive AZA.<br>|
| Experimental: Arm B: Newly Diagnosed Chemotherapy Ineligible Setting<br>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. | Drug: JNJ-75276617<br>* Participants will receive JNJ-75276617.<br>Drug: Venetoclax (VEN)<br>* Participants will receive VEN.<br>Drug: Azacitidine (AZA)<br>* Participants will receive AZA.<br>|
| Experimental: Arm C: Newly Diagnosed Chemotherapy Eligible Setting<br>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. | Drug: JNJ-75276617<br>* Participants will receive JNJ-75276617.<br>Drug: Cytarabine<br>* Participants will receive cytarabine<br>Drug: Daunorubicin or Idarubicin<br>* Participants will receive daunorubicin or idarubicin<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) | 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. The DLTs are specific adverse events and are defined per protocol as any of the following: non-hematologic toxicity, or hematologic toxicity. | End of Cycle 1 (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of JNJ- 75276617 | Plasma samples will be analyzed to determine concentrations of JNJ-75276617 using a validated, specific, and sensitive method. | Up to 3 Years 3 months | 
| 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 | 
| Number of Participants with Differentiation of Leukemic Blasts | Number of participants with differentiation of leukemic blasts will be reported. | Up to 3 Years 3 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 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 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). | 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 x 109/L (500/μL) and platelet count >50 x 109/L (50,000/μL). | 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 x 109/L [1,000/μL]) or thrombocytopenia (<100 x 109/L [100,000/μL]). | 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. | Up to 3 Years 3 months | 
| Duration of response | 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. | Up to 3 Years 3 months | 
| Time to Response | Time to response is defined as time from first dose to achieving the first response of CR, CRh, CRi or overall response. | Up to 3 Years 3 months |