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

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ClinicalTrials.gov Identifier: NCT05453903
Recruitment Status : Recruiting
First Posted : July 12, 2022
Last Update Posted : March 24, 2023
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Description
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Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: JNJ-75276617 Drug: Venetoclax (VEN) Drug: Azacitidine (AZA) Phase 1

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 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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of JNJ-75276617 in Combination With AML Directed Therapies for Participants With Acute Myeloid Leukemia Harboring KMT2A or NPM1 Alterations
Actual Study Start Date : October 4, 2022
Estimated Primary Completion Date : May 15, 2024
Estimated Study Completion Date : January 2, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A: Relapsed/Refractory Setting
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
Participants will receive JNJ-75276617 orally for each 28-day cycle.

Drug: Venetoclax (VEN)
Participants will receive VEN tablet orally with continuous daily dosing.

Drug: Azacitidine (AZA)
Participants will receive intravenous (IV) infusion or subcutaneous (SC) injection of AZA daily for 7 days of each 28-day cycle.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants with Adverse Events (AEs) [ Time Frame: Up to 2 Years ]
    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.

  2. Number of Participants with Adverse Events (AEs) by Severity [ Time Frame: Up to 2 Years ]
    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.

  3. Number of Participants with Dose-limiting Toxicity (DLT) [ Time Frame: Up to 28 days of Cycle 1 (each cycle is of 28 days) ]
    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.


Secondary Outcome Measures :
  1. Plasma Concentration of JNJ- 75276617 [ Time Frame: Up to 2 Years ]
    Plasma samples will be analyzed to determine concentrations of JNJ-75276617 using a validated, specific, and sensitive method.

  2. Number of Participants with Depletion of Leukemic Blasts [ Time Frame: Up to 2 Years ]
    Number of participants with depletion of leukemic blasts will be reported.

  3. Number of Participants with Differentiation of Leukemic Blasts [ Time Frame: Up to 2 Years ]
    Number of participants with differentiation of leukemic blasts will be reported.

  4. Changes in Expression of Menin-histone-lysine N-methyltransferase 2A (KMT2A) Target Genes [ Time Frame: Up to 2 Years ]
    Changes in expression of menin-KMT2A target genes will be reported.

  5. Percentage of Participants who Achieve Complete Remission (CR) [ Time Frame: Up to 2 Years ]
    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).

  6. Percentage of Participants who Achieve Complete Remission with Partial Hematologic Recovery (CRh) [ Time Frame: Up to 2 Years ]
    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).

  7. Percentage of Participants who Achieve Complete Remission with Incomplete Hematologic Recovery (CRi) [ Time Frame: Up to 2 years ]
    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]).

  8. Percentage of Participants who Achieved Overall Response [ Time Frame: Up to 2 Years ]
    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.

  9. Duration of response [ Time Frame: Up to 2 Years ]
    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.

  10. Time to Response [ Time Frame: Up to 2 Years ]
    Time to response is defined as time from first dose to achieving the first response of CR, CRh, CRi or overall response.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of AML according to World Health Organization (WHO) 2016 criteria a) De novo or secondary AML; b) relapsed /refractory (Arm A); 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05453903


Contacts
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Contact: Study Contact 844-434-4210 Participate-In-This-Study@its.jnj.com

Locations
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Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
More Information
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Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT05453903    
Other Study ID Numbers: CR109124
2021-003999-14 ( EudraCT Number )
75276617ALE1002 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: July 12, 2022    Key Record Dates
Last Update Posted: March 24, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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
URL: https://www.janssen.com/clinical-trials/transparency

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Azacitidine
 Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors