Navtemadlin + Decitabine for Acute Myeloid Leukemia

Recruiting at 13 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

58 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial studies the side effects and best dose of navtemadlin when given together with decitabine and venetoclax in treating patients with acute myeloid leukemia that has come back after a period of improvement (recurrent), does not respond to treatment (refractory), or is newly diagnosed. Navtemadlin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving navtemadlin, decitabine, and venetoclax together may work better than decitabine alone in treating patients with acute myeloid leukemia.

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.

What data supports the effectiveness of the drug Navtemadlin + Decitabine for Acute Myeloid Leukemia?

Decitabine has shown promise in treating older patients with acute myeloid leukemia (AML), especially those who cannot undergo more intensive treatments. It has been found to improve overall survival and complete remission rates compared to other treatments, making it a potentially effective option for AML. ^{1 2 3 4 5}

What safety data exists for Decitabine and Navtemadlin in humans?

Decitabine is generally well tolerated in older patients with acute myeloid leukemia, with common side effects including fever, low platelet count, and anemia. In a study involving Decitabine, some patients experienced prolonged low blood cell counts, but adjustments were made to manage this. There is no specific safety data for Navtemadlin in the provided research. ^{3 4 5 6 7}

What makes the drug Navtemadlin + Decitabine unique for treating acute myeloid leukemia?

Navtemadlin combined with Decitabine is unique because it involves a novel combination of drugs, where Navtemadlin (also known as KRT-232 or AMG 232) is a newer agent that may enhance the effectiveness of Decitabine, a well-established drug for older patients with acute myeloid leukemia who are not candidates for intensive therapy. This combination aims to improve outcomes by potentially offering a more effective treatment option with manageable side effects. ^{2 3 4 5 6}

Research Team

Kevin R. Kelly

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

References

1. China 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]. [2023]

2. England 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. [2019]

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

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

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

Decitabine for acute myeloid leukemia. [2018]

5. China 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]. [2019]

6. England 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. [2018]

7. Italy pubmed.ncbi.nlm.nih.gov

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485. [2020]