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

Leukemia, Myeloid, Acute Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05453903
• Other study ID #: CR109124
• Secondary ID: 2021-003999-1475
• Status: Recruiting
• Phase: Phase 1
• Start date: October 4, 2022
• Est. completion date: March 5, 2026

Study information

• Verified date: May 2024
• Source: Janssen Research & Development, LLC
• Contact: Study Contact
• Phone: 844-434-4210
• Email: Participate-In-This-Study[@]its.jnj.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: March 5, 2026
• Est. primary completion date: May 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• JNJ-75276617
Participants will receive JNJ-75276617.
• Venetoclax (VEN)
Participants will receive VEN.
• Azacitidine (AZA)
Participants will receive AZA.
• Cytarabine
Participants will receive cytarabine
• Daunorubicin or Idarubicin
Participants will receive daunorubicin or idarubicin

Locations

Country	Name	City	State
Australia	Monash Medical Centre	Clayton
Australia	Peter MacCallum Cancer Centre	Melbourne
Australia	Westmead Hospital	Westmead
France	Institut Paoli Calmettes	Marseille Cedex 9
France	Institut Universitaire du Cancer Toulouse Oncopole	Toulouse Cedex 9
France	CHU de Tours - Hôpital de Bretonneau	Tours
Germany	Charite Universitatsmedizin Berlin	Berlin
Germany	Universitatsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Universitaetsklinikum Leipzig	Leipzig
Germany	Universitatsklinikum Ulm	Ulm
Italy	Azienda Opedaliero-Universitaria Policlinico Sant'orsola Malpighi di Bologna	Bologna
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	IRCCS Istituto Clinico Humanitas	Rozzano
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. de La Santa Creu I Sant Pau	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Univ. Fund. Jimenez Diaz	Madrid
Spain	Clinica Univ. de Navarra	Pamplona
United Kingdom	University College London Hospitals NHSFT	London
United Kingdom	Christie Hospital NHS Trust	Manchester
United Kingdom	Oxford University Hospitals NHS Trust	Oxfordshire
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Novant Health	Charlotte	North Carolina
United States	City of Hope	Duarte	California
United States	MD Anderson	Houston	Texas
United States	Albert Einstein College Of Medicine	New York	New York
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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