Clinical Trials /

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

NCT04609826

Description:

The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74856665 as monotherapy (Arm A) and in combination with azacitidine (AZA) (Arm B).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of JNJ-74856665 in Participants With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
  • Official Title: A Phase 1, First in Human (FIH), Dose Escalation Study of JNJ-74856665 (Dihydroorotate Dehydrogenase [DHODH] Inhibitor) Alone or in Combination in Participants With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: CR108874
  • SECONDARY ID: 2020-002375-35
  • SECONDARY ID: 74856665AML1001
  • NCT ID: NCT04609826

Conditions

  • Leukemia, Myeloid, Acute
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
JNJ-74856665Arm A: JNJ-74856665
AZAArm B: JNJ-74856665 + AZA

Purpose

The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74856665 as monotherapy (Arm A) and in combination with azacitidine (AZA) (Arm B).

Detailed Description

      This is first-in-human (FIH) Phase 1), dose escalation study of JNJ-74856665 alone or in
      combination with Azacitidine in participants with Acute Myeloid Leukemia (AML) or
      Myelodysplastic Syndrome (MDS). 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 been US Food and Drug Administration-approved for several MDS subtypes. 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 3.7 years. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: JNJ-74856665ExperimentalParticipants will receive JNJ-74856665 orally once daily in a 21-day cycle. The dose levels will be escalated based on the decisions of the Study Evaluation Team (SET) until a RP2D has been identified.
  • JNJ-74856665
Arm B: JNJ-74856665 + AZAExperimentalParticipants will receive JNJ-74856665 once daily in combination with AZA administered intravenously (IV) or subcutaneously (SC) once daily for 7 days starting on Day 1 of each 28-day cycle.
  • JNJ-74856665
  • AZA

Eligibility Criteria

        Inclusion Criteria:

          -  A diagnosis of: Arm A: AML according to the World Health Organization (WHO) 2016
             criteria with relapsed or refractory disease and have exhausted, or are ineligible for
             therapeutic options, or high-risk or very high-risk MDS according to revised
             International Prognostic Scoring System (IPSS-R) and relapsed or refractory disease
             after at least 1 course of hypomethylating therapy or induction therapy; Arm B: newly
             diagnosed AML or relapsed or refractory AML (2016 WHO classification) (bone marrow)
             unsuitable for intensive treatment (including stem cell transplantation) with a
             curative intent, but eligible to receive AZA treatment or high-risk or very high-risk
             MDS according to IPSS-R unsuitable for intensive treatment (including stem cell
             transplantation) with a curative intent, but eligible to receive AZA treatment

          -  Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1

          -  Women of childbearing potential 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 woman of childbearing potential must agree to all the following during the study and
             for 30 days 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-feed

          -  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

        Exclusion Criteria:

          -  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 or AZA or the
             excipients of these treatments
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Arm A: Number of Participants with Dose-Limiting Toxicity (DLT)
Time Frame:Up to 21 Days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Plasma Concentration of JNJ-74856665
Time Frame:Up to 3.7 years
Safety Issue:
Description:Plasma samples will be analyzed to determine concentrations of JNJ-74856665 in Arm A and Arm B.
Measure:Plasma Concentration of AZA
Time Frame:Up to 3.7 years
Safety Issue:
Description:Plasma samples will be analyzed to determine concentrations of AZA in Arm B.
Measure:Biomarker Levels of Intermediates Including Dihydroorotate (DHO), Orotate, and Uridine of JNJ-74856665 with or Without AZA.
Time Frame:Up to 3.7 years
Safety Issue:
Description:Biomarker levels of intermediates including DHO, orotate, and uridine will be measured by liquid chromatography/mass spectrometry (LC-MS) for JNJ-74856665 with or without AZA in Arm A and Arm B.
Measure:Arm A and Arm B: Clinical Response of all Participants with a Primary Disease of AML
Time Frame:Up to 3.7 years
Safety Issue:
Description:Clinical response will be assessed per the modified European Leukemia Net (ELN) 2017 recommendations.
Measure:Arm A and Arm B: Clinical Response of all Participants with a Primary Disease of MDS
Time Frame:Up to 3.7 years
Safety Issue:
Description:Clinical response will be assessed per the modified International Working Group 2018 response criteria.
Measure:Arm A and Arm B: Time to Response (TTR)
Time Frame:Up to 3.7 years
Safety Issue:
Description: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.
Measure:Arm A and Arm B: Duration of Response (DOR)
Time Frame:Up to 3.7 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Janssen Research & Development, LLC

Last Updated

February 26, 2021