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Acute Myeloid LeukemiaPhase 1DHODHNCT04609826

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

A Phase 1 study testing JNJ-74856665, AZA and VEN in people with Acute Myeloid Leukemia and Myelodysplastic Syndromes, run by Janssen Research & Development, LLC at 20 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
JNJ-74856665, AZA and VEN
Could I receive a placebo?
No, everyone receives an active treatment
How many people
153 participants
Where
20 sitesin 4 countries
Study dates
26 Nov 2020to 25 Aug 2025
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

20 sites in 4 countries.

20 sites in 4 countries

Spain6 sites

  • Hosp Univ Vall D Hebron

    Barcelona, 08035

  • Hosp Clinic de Barcelona

    Barcelona, 08036

  • Inst. Cat. Doncologia-H Duran I Reynals

    Barcelona, 08908

  • Hosp Univ Fund Jimenez Diaz

    Madrid, 28040

  • Clinica Univ. de Navarra

    Pamplona, 31008

  • Hosp. Univ. Marques de Valdecilla

    Santander, 39008

Other trials in Spain

France5 sites

  • CHU de Nice Hopital de l Archet

    Nice, 06200

  • Hopital Saint Louis

    Paris, 75010

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

    Pessac, 33600

  • Institut Universitaire du Cancer Toulouse Oncopole

    Toulouse, 31059

  • CHRU Tours Hopital Bretonneau

    Tours, 37000

Other trials in France

South Korea5 sites

  • Severance Hospital Yonsei University Health System

    Seoul, 03722

  • Asan Medical Center

    Seoul, 05505

  • Samsung Medical Center

    Seoul, 06351

  • The Catholic University of Korea Seoul St Marys Hospital

    Seoul, 06591

  • Seoul National University Hospital

    Seoul, 3080

Other trials in South Korea

United Kingdom4 sites

  • Leicester Royal Infirmary

    Leicester, LE1 5WW

  • University College London Hospitals

    London, NW1 2BU

  • Kings College Hospital

    London, SE5 9RF

  • The Christie Nhs Foundation Trust

    Manchester, M20 4BX

Other trials in United Kingdom

About this study

Official title: A Phase 1, FIH, Dose Escalation Study of JNJ-74856665 (Dihydroorotate Dehydrogenase [DHODH] Inhibitor) Alone or in Combination in Participants With AML or MDS

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.

Read the detailed description

This is first-in-human (FIH) Phase 1, dose escalation study of JNJ-74856665 alone or in combination with Azacitidine or Venetoclax in participants with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). Participants with Chronic Myelomonocytic Leukemia (CMML) are also eligible and will either receive JNJ-74856665 as monotherapy or in combination with Azacitidine. 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 and is the second most common form of leukemia. MDS are a heterogeneous group of malignant hematopoietic stem cell disorders that are characterized by cytopenias, myeloid dysplasia, and a risk of transformation to AML. JNJ-74856665 is an orally bioavailable, potent, and selective dihydroorotate dehydrogenase (DHODH) inhibitor that binds to the enzyme's ubiquinone binding site promoting AML/MDS differentiation as well as cell cycle arrest and apoptosis. Azacitidine (5-azacytidine) is a nucleoside metabolic inhibitor that has been US Food and Drug Administration-approved for several MDS subtypes. Venetoclax (VEN) is a BCL-2 inhibitor that can restore activation of apoptosis in malignant cells, the survival of which often depends on dysregulation of this pathway. The study is divided into 3 periods: a Screening Phase (within 28 days before the first dose of study drug), a Treatment Phase (first dose of study drug until the completion of the end-of-treatment visit) and a Post-treatment Follow-up Phase (up to the end of study participation or end of study). The end of study is defined as the last study assessment for the last participant in the study. Total duration of study is up to 2 years and 10 months. Efficacy, safety, pharmacokinetics (PK), and biomarkers will be assessed at specified time points during this study. Participants safety and study conduct will be monitored throughout the study.

Being tested
JNJ-74856665, AZA, VEN
Medical subject headings
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • JNJ-74856665Drug

    JNJ-74856665 will be administered orally.

  • AZADrug

    AZA will be administered IV infusion or SC injection.

  • VENDrug

    VEN tablet will be administered orally.

Study groups in NCT04609826
Study groupRoleWhat they receive
Arm A: JNJ-74856665ExperimentalParticipants 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.
Receives: Drug: JNJ-74856665
Arm B: JNJ-74856665 + Azacitidine (AZA)ExperimentalParticipants will receive JNJ-74856665 orally in combination with AZA administered intravenously (IV) or subcutaneously (SC) in a 28-day cycle.
Receives: Drug: JNJ-74856665; Drug: AZA
Arm C: JNJ-74856665 + Venetoclax (VEN)ExperimentalParticipants will receive JNJ-74856665 orally in combination with VEN in a 28-day cycle.
Receives: Drug: JNJ-74856665; Drug: VEN
Arm D: JNJ-74856665ExperimentalParticipants will receive JNJ-74856665 orally in a 21-day cycle. Participants with transfusion dependent relapsed/refractory Myelodysplastic Syndrome (MDS) will be included.
Receives: Drug: JNJ-74856665

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 21 Days

  2. 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.

    Measured: Up to 28 Days

  3. 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.

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

  4. 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.

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

Secondary outcomes (10)

  1. Plasma Concentration of JNJ-74856665

    Plasma samples will be analyzed to determine concentrations of JNJ-74856665.

    Measured: Up to 2 years and 10 months

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

    Biomarker levels of intermediates including DHO, orotate, and uridine will be measured by liquid chromatography/mass spectrometry (LC-MS) for JNJ-74856665.

    Measured: Up to 2 years and 10 months

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

    Clinical response will be assessed per the modified European Leukemia Net (ELN) 2017 recommendations.

    Measured: Up to 2 years and 10 months

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

    Clinical response will be assessed per the modified International Working Group 2018 response criteria.

    Measured: Up to 2 years and 10 months

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

    Clinical response will be assessed per the modified International Working Group 2018 response criteria.

    Measured: Up to 2 years and 10 months

  6. Arm D: Red Blood Cell-Transfusion Independence (RBC-TI) Rate

    RBC-TI rate will be reported.

    Measured: Up to 2 years and 10 months

  7. Arm D: Overall Improvement Rate

    Overall improvement rate is defined as the percentage of participants achieving complete remission, partial remission, or hematologic improvement (HI) according to modified International Working Group (IWG) response criteria.

    Measured: Up to 2 years and 10 months

  8. Arms A, B, C and D: Time to Response (TTR)

    TTR defined for the responders as the time from the date of first dose of study treatment to the date of initial documentation of a first response as defined in the disease-specific response criteria.

    Measured: Up to 2 years and 10 months

  9. Arms A, B, C and D: Duration of Response (DOR)

    DOR will be calculated 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. For participants with disease that has not relapsed and who are alive, data will be censored at the last disease evaluation before the start of any subsequent anticancer therapy.

    Measured: Up to 2 years and 10 months

  10. Arms A, B, C and D: Transfusion Independence (TI)

    TI is defined as the absence of RBC and platelet transfusions for 8 weeks or longer after starting study treatment for participants with a primary diagnosis of AML or CMML-2, and 16 weeks or longer for participants with a primary diagnosis of MDS.

    Measured: Up to 2 years and 10 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Oct 2020
  2. Study start26 Nov 2020
  3. Primary completion25 Aug 2025
  4. Study completion25 Aug 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
153 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04609826
Sponsor's protocol ID
CR108874
Other IDs
74856665AML1001, 2020-002375-35, 2024-513918-35-00
Acronym
DHODH
Status last verified
Sep 2025
First submitted
30 Sep 2020
Last updated
1 Oct 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson \& Johnson is available at www.janssen.com/clinicaltrials/ 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

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing JNJ-74856665, AZA and VEN in people with Acute Myeloid Leukemia and Myelodysplastic Syndromes, run by Janssen Research & Development, LLC at 20 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 sites in Spain, France, South Korea, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Arms A and D: Number of Participants with Dose-Limiting Toxicity (DLT) (time frame: Up to 21 Days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04609826.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Oct 2025.

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