JNJ-74856665 for AML and MDS

(DHODH Trial)

No longer recruiting at 40 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Janssen Research & Development, LLC

Must be taking: Azacitidine

Must not be taking: Dihydroorotate dehydrogenase inhibitors

Disqualifiers: Acute promyelocytic leukemia, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years and 10 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates a new treatment, JNJ-74856665, for individuals with certain blood disorders, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The trial aims to determine the safety of this treatment and identify the optimal dose, either alone or in combination with other drugs like Venetoclax (VEN) or Azacitidine (AZA). Suitable candidates often have AML or MDS that has not responded to standard treatments or cannot undergo intensive therapies. Participants will receive JNJ-74856665 in various combinations and cycles based on their specific condition. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that JNJ-74856665 is undergoing its first human trials to assess safety. This early study aims to determine the appropriate dose and evaluate tolerability. Detailed safety information is not yet available due to the study's early stage.

In laboratory tests, JNJ-74856665 demonstrated significant effectiveness against leukemia cells, suggesting potential efficacy. However, safety data from human trials is still being collected. The study also examines how JNJ-74856665 interacts with other drugs like Venetoclax and Azacitidine. These combinations are being tested to evaluate their combined effectiveness and identify any side effects.

Currently, the exact safety profile of JNJ-74856665 in humans remains unknown. The ongoing study is crucial for gaining further insights into its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about JNJ-74856665 for treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) because it offers a fresh approach. Unlike traditional chemotherapy, which targets rapidly dividing cells, JNJ-74856665 works by a novel mechanism that may target cancer cells more precisely. This treatment is being tested alone and in combination with other drugs like Venetoclax and Azacitidine, potentially boosting its effectiveness and offering more versatile treatment options. Additionally, its oral administration could provide a more convenient alternative to treatments that require intravenous delivery. These innovations could lead to better outcomes and improved quality of life for patients with these challenging conditions.

What evidence suggests that this trial's treatments could be effective for AML and MDS?

Research shows that JNJ-74856665 is a promising new treatment for certain blood cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It blocks an enzyme called DHODH, which cancer cells need to survive. Studies have demonstrated that JNJ-74856665 has strong anti-cancer effects in both lab tests and animal studies. In this trial, some participants will receive JNJ-74856665 with azacitidine, a treatment already approved for MDS and AML, which may be more effective, especially in patients with higher numbers of cancer cells. Other participants will receive JNJ-74856665 combined with venetoclax, another cancer drug, which might provide a powerful way to treat these blood conditions. Early results are promising, suggesting it could be a valuable addition to current treatments. ^{1 2 3 4 6}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for adults with certain blood disorders like AML or MDS who've tried other treatments without success, or can't use them. It's also for those unsuitable for intensive treatment but can take AZA, and some with lower-risk MDS needing regular blood transfusions. Participants must be in good physical condition and women/men agree to contraception.

Inclusion Criteria

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

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I am allergic to JNJ-74856665, AZA, VEN, or their ingredients.

I have been diagnosed with a specific type of leukemia.

My cancer has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive JNJ-74856665 alone or in combination with Azacitidine or Venetoclax in 21 or 28-day cycles

Up to 2 years and 10 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 months

What Are the Treatments Tested in This Trial?

Interventions

• AZA
• JNJ-74856665
• VEN

Trial Overview

The study tests JNJ-74856665 alone or combined with AZA (Azacitidine) or VEN (Venetoclax), aiming to find the safest doses. The focus is on how well patients tolerate these drugs and what effects they have on their diseases.

How Is the Trial Designed?

Group I: Arm D: JNJ-74856665 Experimental Treatment 1 Intervention

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

Group II: Arm C: JNJ-74856665 + Venetoclax (VEN) Experimental Treatment 2 Interventions

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

Group III: Arm B: JNJ-74856665 + Azacitidine (AZA) Experimental Treatment 2 Interventions

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

Group IV: Arm A: JNJ-74856665 Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

The treatment landscape for acute myeloid leukemia (AML) has significantly improved with the FDA's approval of eight new drugs in the last two years, offering new therapeutic options for patients.

These new therapies, including FLT3 inhibitors and IDH inhibitors, represent a shift towards targeted treatments, which may enhance efficacy and provide more personalized approaches to managing this complex disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Time Has Come for Targeted Therapies for AML: Lights and Shadows. Fiorentini, A., Capelli, D., Saraceni, F., et al.[2020]

In a phase II trial involving 26 patients with relapsed/refractory AML treated with sargramostim (GM-CSF) and bexarotene, 31% showed hematologic improvement in neutrophils, although no complete or partial remissions were achieved.

Another trial with 10 patients using GM-CSF and entinostat resulted in 10% achieving partial remission and 20% showing hematologic improvement, indicating that while the treatments were well tolerated, their clinical efficacy was modest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies. Norsworthy, KJ., Cho, E., Arora, J., et al.[2022]

Azacitidine is an approved treatment for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), showing benefits even in patients with higher blast counts, as demonstrated in recent phase III trials.

Oral azacitidine (CC-486) has shown promising biological activity and tolerability in early studies, potentially offering a more convenient treatment option for patients with MDS and AML, with ongoing investigations into extended dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cogle, CR., Scott, BL., Boyd, T., et al.[2023]

Azacitidine (AZA) was found to be more effective than conventional care in treating patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), with overall response rates of 27% for MDS, 20% for AML, and 20% for CMML among 83 patients studied.

The treatment showed a median overall survival of 75% at 12 months for MDS and CMML patients, and 60% for AML patients, indicating a promising efficacy, although the most common side effects included myelosuppression and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia. Helbig, G., Chromik, K., Woźniczka, K., et al.[2021]

In a Phase II study involving 20 elderly patients (median age 76) with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS), a combination treatment of hydroxyurea, azacitidine, and low-dose gemtuzumab ozogamicin resulted in a high complete remission rate of 70%.

The treatment was found to be safe, with only one early death (5%) due to disease progression, and the median survival for patients was 10 months, indicating that this regimen could be a promising option for this high-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Nand, S., Godwin, J., Smith, S., et al.[2019]

Oral azacitidine (Oral-AZA) has been approved for treating adult patients with acute myeloid leukemia (AML) in first complete remission, showing a significant median overall survival advantage of 9.9 months compared to placebo in the QUAZAR AML-001 trial.

Oral-AZA offers a more convenient dosing regimen than injectable azacitidine, allowing for extended treatment cycles, which may improve patient adherence and outcomes in maintenance therapy for AML and potentially in myelodysplastic syndromes (MDS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Azacitidine (CC-486) for the Treatment of Myeloid Malignancies. Garcia-Manero, G., Döhner, H., Wei, AH., et al.[2022]

Azacitidine (AZA) is the standard frontline treatment for higher-risk myelodysplastic syndrome (MDS) and has been shown to significantly improve overall survival compared to conventional care in a phase III trial.

There is a need for further research to identify better prognostic factors for response to AZA and to explore combination therapies with other effective drugs to enhance treatment outcomes for patients with MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of advanced myelodysplastic syndrome with demethylating agents: azacitidine. Adès, L., Itzykson, R., Fenaux, P.[2013]

In a study of 415 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), certain subtypes (AML-MRC-M and AML-MRC-H) showed better overall survival rates compared to other subtypes, indicating that not all AML-MRC patients are high-risk.

Intensive therapy significantly improved overall survival and event-free survival in patients with AML-MRC-M and AML-MRC-H, suggesting that tailored treatment approaches based on specific subgroups can enhance outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy. Montalban-Bravo, G., Kanagal-Shamanna, R., Class, CA., et al.[2023]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04609826

NCT04609826 | A Study of JNJ-74856665 in Participants ...

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 ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12379018/

A phase 1, first‐in‐human, dose‐escalation study of JNJ‐ ...

To the Editor,. JNJ‐74856665 is an orally bioavailable, potent and selective dihydroorotate dehydrogenase inhibitor (DHODHi) designed to ...

3.

delta.larvol.com

delta.larvol.com/Products/?ProductId=03da8952-6eba-42bd-9029-f592e98d66d1

JNJ-6665 / J&J - Leukemia • Myelodysplastic Syndrome

A Study of JNJ-74856665 in Participants With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) (clinicaltrials.gov) - P1 | N=153 | Completed ...

4.

aacrjournals.org

aacrjournals.org/cancerres/article/81/13_Supplement/1256/667115/Abstract-1256-JNJ-74856665-a-novel-DHODH-inhibitor

JNJ-74856665, a novel DHODH inhibitor, mediates potent anti ...

The results described herein demonstrate that JNJ-74856665 exerts potent anti-leukemic activity in vitro and in vivo and warrant further investigation.

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40598790/

A phase 1, first-in-human, dose-escalation study of JNJ ...

A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS

6.

ctv.veeva.com

ctv.veeva.com/study/a-study-of-jnj-74856665-in-participants-with-acute-myeloid-leukemia-aml-or-myelodysplastic-syndrom

A Study of JNJ-74856665 in Participants With Acute Myeloid ...

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 ...