A Study of JNJ-74856665 in Participants With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

NCT04609826 | Completed Phase 1

• 4 other identifiers: CR10887474856665AML10012020-002375-352024-513918-35-00
• Study Type: interventional
• Target: 153
• Locations: 4 countries
• Sites: 20

Brief Summary

The purpose of this study is to determine the safety, tolerability, maximum tolerated doses (MTDs) and recommended Phase 2 doses (RP2Ds) of JNJ-74856665 as monotherapy and/or in combinations.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia

Outcome Measures

Primary Outcomes (4)

• Arms A and D: Number of Participants with Dose-Limiting Toxicity (DLT)

  Number 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 21 Days

• Arms B and C: Number of Participants with DLT

  Number 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

• Arms A, B, C and D: 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.

  After last dose of study treatment (up to 6 months)

• Arms A, B, C and D: Number of Participants with AEs by Severity

  Number of participants with AEs by severity will be reported as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

  After last dose of study treatment (up to 6 months)

Secondary Outcomes (10)

• Plasma Concentration of JNJ-74856665

  Up to 2 years and 10 months

• Biomarker Levels of Intermediates Including Dihydroorotate (DHO), Orotate, and Uridine of JNJ-74856665

  Up to 2 years and 10 months

• Arm A, Arm B and Arm C: Clinical Response of all Participants with a Primary Disease of Acute Myeloid Leukemia (AML)

  Up to 2 years and 10 months

• Arm A, Arm B and Arm C: Clinical Response of all Participants with a Primary Disease of Myelodysplastic Syndrome (MDS)

  Up to 2 years and 10 months

• Arm A, Arm B and Arm C: Clinical Response of all Participants with a Primary Disease of chronic myelomonocytic leukemia-2 (CMML-2)

  Up to 2 years and 10 months

Study Arms (4)

Arm A: JNJ-74856665

EXPERIMENTAL

Participants will receive JNJ-74856665 orally in a 21-day cycle. The dose levels will be escalated based on the decisions of the Study Evaluation Team (SET) until a recommended Phase 2 dose (RP2D) has been identified.

Drug: JNJ-74856665

Arm B: JNJ-74856665 + Azacitidine (AZA)

EXPERIMENTAL

Participants will receive JNJ-74856665 orally in combination with AZA administered intravenously (IV) or subcutaneously (SC) in a 28-day cycle.

Drug: JNJ-74856665; Drug: AZA

Arm C: JNJ-74856665 + Venetoclax (VEN)

EXPERIMENTAL

Participants will receive JNJ-74856665 orally in combination with VEN in a 28-day cycle.

Drug: JNJ-74856665; Drug: VEN

Arm D: JNJ-74856665

EXPERIMENTAL

Participants will receive JNJ-74856665 orally in a 21-day cycle. Participants with transfusion dependent relapsed/refractory Myelodysplastic Syndrome (MDS) will be included.

Drug: JNJ-74856665

Interventions

JNJ-74856665 DRUG

JNJ-74856665 will be administered orally.

Arm A: JNJ-74856665; Arm B: JNJ-74856665 + Azacitidine (AZA); Arm C: JNJ-74856665 + Venetoclax (VEN); Arm D: JNJ-74856665

AZA DRUG

AZA will be administered IV infusion or SC injection.

Arm B: JNJ-74856665 + Azacitidine (AZA)

VEN DRUG

VEN tablet will be administered orally.

Arm C: JNJ-74856665 + Venetoclax (VEN)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of: Arms A and C: Acute Myeloid Leukemia (AML) according to the World Health Organization (WHO) 2016 criteria with relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options; or newly transformed secondary AML according to the WHO 2016 criteria and have exhausted standard therapeutic options for AML during their treatment prior to transformation; or high-risk or very high-risk Myelodysplastic Syndrome (MDS) according to the WHO 2016 criteria and the revised International Prognostic Scoring System (IPSS-R) with relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options; or Arm A only: chronic myelomonocytic leukemia-2 (CMML-2) according to the WHO 2016 criteria with relapsed or refractory disease and have exhausted or are ineligible for standard therapeutic options; Arm B: Eligible participants must be considered unsuitable for intensive treatment with a curative intent (including stem cell transplantation), but eligible to receive Azacitidine (AZA) treatment with the following underlying diseases: AML (newly diagnosed or relapsed/refractory) according to the 2016 WHO classification only if Venetoclax (VEN) + hypomethylating agent (HMA) (or low-dose cytarabine) is not indicated or available; or high-risk or very high-risk MDS according to the 2016 WHO classification and IPSS-R; or CMML-2 according to the WHO 2016 criteria; Arm D: Very low, low, or intermediate-risk MDS according to the 2016 WHO classification and IPSS-R and the following: Transfusion dependence defined as requiring at least 3 red blood cell (RBC) units transfused within 16 weeks prior to C1D1; pre-transfusion hemoglobin (Hb) should be less than (\<) 9.0 grams per decilitre (g/dL) to count towards the 3 units total, Relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment or endogenous serum erythropoietin (EPO) level greater than (\>) 500 milliunits per milliliter (mU/mL). Exception: Del(5q) karyotype is allowed, provided prior treatment with lenalidomide has failed or participant was ineligible to receive lenalidomide
• Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
• Women of childbearing potential (WOCBP) must have a negative highly sensitive serum (beta-human chorionic gonadotropin) at screening and again within 48 hours prior to the first dose of study treatment. A urine or serum test is acceptable at subsequent time points
• A WOCBP must agree to all the following during the study and for 6 months after the last dose of study treatment: a) use a barrier method of contraception; b) use a highly effective preferably user-independent method of contraception; c) not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction; d) not plan to become pregnant; e) not breast-feeding
• 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; c) not plan to father a child. 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

You may not qualify if:

• Acute promyelocytic leukemia according to World Health Organization 2016 criteria
• Known central nervous system involvement
• Prior treatment with a dihydroorotate dehydrogenase (DHODH) inhibitor for an oncology indication or intolerance to a DHODH inhibitor given for non-oncology indication
• Toxicities (except for alopecia, peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapies that have not resolved to baseline or to Grade 1 or less
• Known allergies, hypersensitivity, or intolerance to JNJ-74856665, AZA, or VEN or the excipients of these treatments

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (20)

CHU de Nice Hopital de l Archet

Nice, 06200, France

Location

Hopital Saint Louis

Paris, 75010, France

Location

Centre Hospitalier Universitaire (CHU) de Bordeaux Hopital HautLeveque Centre Francois Magendie

Pessac, 33600, France

Location

Institut Universitaire du Cancer Toulouse Oncopole

Toulouse, 31059, France

Location

CHRU Tours Hopital Bretonneau

Tours, 37000, France

Location

Severance Hospital Yonsei University Health System

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

The Catholic University of Korea Seoul St Marys Hospital

Seoul, 06591, South Korea

Location

Seoul National University Hospital

Seoul, 3080, South Korea

Location

Hosp Univ Vall D Hebron

Barcelona, 08035, Spain

Location

Hosp Clinic de Barcelona

Barcelona, 08036, Spain

Location

Inst. Cat. Doncologia-H Duran I Reynals

Barcelona, 08908, Spain

Location

Hosp Univ Fund Jimenez Diaz

Madrid, 28040, Spain

Location

Clinica Univ. de Navarra

Pamplona, 31008, Spain

Location

Hosp. Univ. Marques de Valdecilla

Santander, 39008, Spain

Location

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

Location

University College London Hospitals

London, NW1 2BU, United Kingdom

Location

Kings College Hospital

London, SE5 9RF, United Kingdom

Location

The Christie Nhs Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2020
• First Posted: October 30, 2020
• Study Start: November 26, 2020
• Primary Completion: August 25, 2025
• Study Completion: August 25, 2025
• Last Updated: October 1, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

KR (5); ES (6); FR (5); GB (4)