JNJ-74856665 for AML and MDS

(DHODH Trial)

Recruiting at 34 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

153 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called JNJ-74856665, alone or with other drugs, in patients with specific blood cancers like AML, MDS, and CMML. The goal is to see if it can safely stop cancer cells from growing and make them die.

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.

What data supports the effectiveness of the drug JNJ-74856665 for AML and MDS?

Azacitidine (AZA), one of the drugs in the treatment, has been shown to improve survival in patients with higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is more effective than conventional care and has a good safety profile, making it a promising component of the treatment. ^{1 2 3 4 5}

Is JNJ-74856665 (AZA) safe for humans?

Azacitidine (AZA) has been studied in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), showing an acceptable safety profile. Common side effects include myelosuppression (reduced bone marrow activity) and infections, but it is generally considered safe for use in these conditions. ^{3 6 7 8 9}

What makes the drug JNJ-74856665 unique for treating AML and MDS?

JNJ-74856665 is unique because it is being studied in combination with azacitidine, which is an oral drug that can be more convenient for patients compared to traditional injections. This combination may offer a novel approach to treating AML and MDS by potentially enhancing the effects of azacitidine, which is already used for these conditions. ^{9 10 11 12 13}

Research Team

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Giacomo Salvadore

Janssen Research & Development, LLC

Chief Medical Officer since 2023

MD from the University of Rome, Tor Vergata

Ricardo Attar

Janssen Research & Development, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology from the University of Buenos Aires

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of advanced myelodysplastic syndrome with demethylating agents: azacitidine. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Azacitidine prolongs overall survival and reduces infections and hospitalizations in patients with WHO-defined acute myeloid leukaemia compared with conventional care regimens: an update. [2021]

3. Switzerland 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. [2021]

4. England pubmed.ncbi.nlm.nih.gov

A randomised phase II study of azacitidine (AZA) alone or with Lenalidomide (LEN), Valproic acid (VPA) or Idarubicin (IDA) in higher-Risk MDS or low blast AML: GFM's "pick a winner" trial, with the impact of somatic mutations. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Bridging-to-transplant with Azacitidine for Myelodysplastic Syndrome and Acute Myeloid Leukemia, Reduces the Incidence of Acute Graft-versus-host Disease. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. [2018]

7. United States 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. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Oral Azacitidine (CC-486) for the Treatment of Myeloid Malignancies. [2022]

9. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with CAG (Cytarabine, Aclarubicin, G-CSF) for Patients with Intermediate or High Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia: a Meta-Analysis]. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy. [2023]

13. New Zealand pubmed.ncbi.nlm.nih.gov

The Time Has Come for Targeted Therapies for AML: Lights and Shadows. [2020]