Navtemadlin + Decitabine for Acute Myeloid Leukemia

Not currently recruiting at 14 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inducers, QT prolonging

Disqualifiers: Acute promyelocytic leukemia, GI disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—navtemadlin, decitabine, and venetoclax—to determine the best dose and understand side effects for patients with acute myeloid leukemia (AML) that may have returned after treatment or not responded to other treatments. Navtemadlin (also known as KRT-232) aims to stop cancer cell growth, while decitabine and venetoclax work to kill cancer cells in different ways. The trial seeks participants with AML that either returned after treatment or didn't respond, showing at least 20% cancer cells in their bone marrow. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that certain medications, like those causing QT interval prolongation, should be avoided unless approved by the principal investigator. It's important to discuss your current medications with the trial team to ensure there are no interactions.

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

Studies have shown that decitabine is generally well-tolerated in patients with acute myeloid leukemia (AML), though some serious side effects have occurred. About 30% of patients experienced severe side effects, which is common for chemotherapy drugs.

Navtemadlin, also known as KRT-232, has been tested on patients with various types of cancer. Research suggests it is usually well-tolerated, with most side effects being mild. Some studies reported no serious side effects or deaths.

Venetoclax, another drug used in this trial, is often combined with other treatments for AML. It is generally considered safe, but patients may experience side effects like nausea or low blood cell counts.

While these drugs can cause side effects, medical supervision often manages them. This trial is in its early phase and primarily aims to determine the safety and optimal dosages for these treatments when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for Acute Myeloid Leukemia (AML), which typically involves chemotherapy drugs like cytarabine and daunorubicin, the combination of navtemadlin, decitabine, and venetoclax offers a fresh approach. Researchers are excited about navtemadlin because it targets the MDM2 protein, which plays a role in cancer cell survival, potentially enhancing the effectiveness of the treatment. Additionally, decitabine is a hypomethylating agent that can reactivate genes that suppress tumors, and venetoclax is known for targeting the BCL-2 protein, which is involved in preventing cell death. This multi-pronged strategy could lead to better outcomes by attacking leukemia cells from different angles.

What evidence suggests that this treatment might be an effective treatment for acute myeloid leukemia?

Research has shown that using navtemadlin with other treatments might help treat acute myeloid leukemia (AML). Navtemadlin blocks a protein interaction that usually aids cancer cell growth, potentially helping the body fight tumors naturally. In this trial, participants will receive a combination of navtemadlin, venetoclax, and decitabine. Studies have found that navtemadlin can enhance the effectiveness of venetoclax, especially in some types of leukemia. Decitabine, another drug in this combination, has improved outcomes in older AML patients, with about 36% responding well in some studies. Using these three drugs together might be more effective than using decitabine alone, offering hope for patients with recurring or hard-to-treat AML. ^{1 3 4 6 7}

Who Is on the Research Team?

Kevin R. Kelly

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

Adults (18+) with acute myeloid leukemia that's either newly diagnosed, not responding to treatment, or has returned. They must have a specific type of gene (wild-type p53), be able to undergo certain tests, and have an acceptable level of organ function. People can't join if they're on blood thinners, have certain heart conditions or infections, are taking drugs that affect liver enzymes strongly, or if their cancer is a specific subtype (acute promyelocytic leukemia).

Inclusion Criteria

Patient must be willing to submit the blood sampling and bone marrow sampling for the PK and PD analyses and exploratory biomarkers

White blood count =< 25 x 10^9/L

My leukemia shows more than 20% blasts in my bone marrow or outside of it.

Exclusion Criteria

I am allergic to medications similar to KRT-232 or decitabine.

I do not have any severe illnesses or heart problems that my doctor has told me are uncontrolled.

I haven't taken any medications that affect heart rhythm recently, except for nausea.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive decitabine IV over 1 hour on days 1-10, navtemadlin PO QD on days 1-7, and venetoclax PO QD on days 1-21. Treatment repeats every 28 days for up to 4 cycles in patients with evidence of persistent AML.

16 weeks

Multiple visits for IV administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• KRT-232
• Navtemadlin

Trial Overview The trial is testing the safety and optimal dose of KRT-232 when combined with decitabine and venetoclax in patients with acute myeloid leukemia. KRT-232 aims to block enzymes needed for cancer cell growth while the chemotherapy agents work by killing or stopping the spread of cancer cells.

How Is the Trial Designed?

Group I: Treatment (decitabine, navtemadlin, venetoclax) Experimental Treatment 6 Interventions

Patients receive decitabine IV over 1 hour on days 1-10, navtemadlin PO QD on days 1-7, and venetoclax PO QD on days 1-21. Treatment repeats every 28 days for up to 4 cycles in patients with evidence of persistent AML. Starting cycle 2, patients with no morphologic evidence of AML receive decitabine IV over 1 hour on days 1-5, navtemadlin PO QD on days 1-7, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy, and blood sample collection throughout the trial.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

Decitabine is a DNA methyltransferase inhibitor with a long history of antileukemic efficacy, particularly effective in treating acute myeloid leukemia in older patients or those unable to undergo intensive therapy.

The current dosing regimen of decitabine (20 mg/m² for 5 days) has been refined to minimize nonhematologic toxicity, making it a promising option for patients who may not tolerate more aggressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. Marks, PW.[2018]

Decitabine has been approved for treating older patients (65 years and older) with newly diagnosed acute myeloid leukemia (AML) who cannot undergo standard chemotherapy, showing a median overall survival of 7.7 months compared to 5.0 months for those receiving low-dose cytarabine or supportive care.

The treatment demonstrated improved response rates and progression-free survival, with a manageable safety profile, making it a valuable option for older patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. Nieto, M., Demolis, P., Béhanzin, E., et al.[2018]

Decitabine, administered at a dose of 20 mg/m² for 5 consecutive days, has been approved for older patients (≥65 years) with acute myeloid leukaemia (AML) who cannot undergo standard treatment, showing clinically meaningful improvements in overall survival after extended follow-up.

In a pivotal phase III trial, decitabine demonstrated significantly higher complete remission rates compared to standard treatment options like cytarabine, with a safety profile similar to cytarabine, including common side effects like fever and low blood cell counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine: a review of its use in older patients with acute myeloid leukaemia. Curran, MP.[2021]

A new low-intensity treatment regimen combining cladribine and low-dose cytarabine alternating with decitabine showed promising results in elderly or unfit patients with acute myeloid leukaemia (AML), with a median disease-free survival of 10.8 months and a median overall survival of 13.8 months based on a study of 118 patients.

The regimen was well tolerated, with only 1% of patients experiencing early death within the first 4 weeks, indicating a favorable safety profile compared to traditional therapies, which often have higher toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Kadia, TM., Cortes, J., Ravandi, F., et al.[2019]

The D-CAG regimen, which combines decitabine with a modified chemotherapy approach, achieved a complete remission (CR) rate of 69.4% in 59 elderly patients (≥70 years) with newly diagnosed acute myeloid leukemia (AML), indicating its efficacy in this age group.

The treatment was found to be safe, with major adverse reactions including grade 3-4 myelosuppression and infections, but it significantly improved overall survival (OS) and event-free survival (EFS) for patients who achieved CR, with median OS of 19.8 months compared to 6.4 months for those who did not respond.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia]. Cao, L., Jiang, ZQ., Liu, WJ., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5522197/

Efficacy and safety of decitabine in treatment of elderly ... A multicenter, randomized phase III trial indicated that decitabine achieved a higher response rate and a trend toward improved OS compared with low-dose ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212621000254

Efficacy of 10-day decitabine in acute myeloid leukemia Highlights · Real world outcomes using the 10 day decitabine regimen in AML are lacking. · 10-day decitabine had an ORR of 36.1% in AML in the upfront setting.

3. ashpublications.org ashpublications.org/blood/article/144/5/541/516035/Decitabine-in-older-patients-with-AML-quality-of

Decitabine in older patients with AML: quality of life results of ... A systematic review of patient reported outcomes in phase II or III clinical trials of myelodysplastic syndromes and acute myeloid leukemia.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4478207/

Decitabine Improves Outcomes in Older Patients with ... Decitabine improves outcomes in older patients with acute myeloid leukemia (AML) and higher blast counts.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01149408

Decitabine Maintenance in Elderly Acute Myeloid ... Despite modest improvements in outcomes for younger patients with AML, adults over 55 years of age (the majority of patients with AML) continue to do poorly ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4912358/

The European Medicines Agency Review of Decitabine ... Thirty percent of AML patients treated with decitabine and 25% of patients treated with the comparator had adverse events with an outcome of death during ...

7. nature.com nature.com/articles/s41598-024-80496-x

Efficacy and safety of the combination of decitabine ... Decitabine priming followed by CHAG regimen is effective and tolerated in patients with r/r AML, and can be used as a salvage treatment for patients with r/r ...