Navtemadlin + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 substrates, CYP2C8 substrates

Disqualifiers: P53 mutation, Uncontrolled illness, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of a new drug, navtemadlin, when combined with standard chemotherapy drugs for treating acute myeloid leukemia (AML). Navtemadlin may inhibit cancer growth by blocking a protein essential to cancer cells. The trial will assess whether combining navtemadlin with chemotherapy can control cancer more effectively than chemotherapy alone. It seeks participants with newly diagnosed AML who have not yet received standard chemotherapy treatment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications, such as those that are CYP3A4 or CYP2C8 substrates with a narrow therapeutic window, are not allowed within 14 days before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that navtemadlin, a new treatment under study, has been safe in earlier research. One study found it worked well for patients who had already tried many other treatments, indicating that navtemadlin is generally well-tolerated.

Cytarabine, another treatment in this trial, has been shown to be safe and effective for many patients with acute myeloid leukemia. Even at high doses, it is considered safe, though some side effects may occur.

Idarubicin, the third treatment in this trial, is also used for similar leukemia cases. Research has found it to be safe and effective, often comparing well to other drugs.

Overall, these treatments have been generally well-tolerated in past research. However, since this is an early trial, the main goal is to determine the best dose and monitor for any side effects. Participants should consider this when deciding to join the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute myeloid leukemia?

Researchers are excited about navtemadlin in combination with chemotherapy for acute myeloid leukemia (AML) because it introduces a new mechanism by targeting a protein called MDM2, which plays a role in cancer cell survival. Unlike traditional chemotherapy drugs like cytarabine and idarubicin, which primarily work by damaging the DNA of cancer cells, navtemadlin specifically inhibits MDM2, potentially restoring the function of the tumor suppressor protein p53. This could lead to improved outcomes by making cancer cells more susceptible to treatment and reducing the likelihood of resistance. This novel approach might offer a significant advantage over existing treatments by enhancing the effectiveness of standard chemotherapy.

What evidence suggests that navtemadlin combined with chemotherapy could be an effective treatment for acute myeloid leukemia?

Research has shown that navtemadlin is a promising treatment for acute myeloid leukemia (AML). It blocks a protein called MDM2, which aids cancer cell growth. By inhibiting MDM2, navtemadlin enables another protein, p53, to effectively kill cancer cells. In this trial, participants will receive navtemadlin alongside the chemotherapy drugs cytarabine and idarubicin. Studies suggest that navtemadlin may enhance the effectiveness of these chemotherapy drugs by preventing cancer cells from growing and spreading. Together, these treatments aim to control AML for longer periods. ^{6 7 8 9 10}

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?

This trial is for adults with newly diagnosed, untreated Acute Myeloid Leukemia (AML) that's not acute promyelocytic leukemia. They must have a specific protein (wild-type p53), be fit for intensive chemo, and have good heart function and organ health. People with HIV can join if their treatment is effective. Pregnant or breastfeeding women can't join, nor those unwilling to use contraception.

Inclusion Criteria

All my side effects from previous treatments, except hair loss, are mild now.

I am eligible for intensive chemotherapy with cytarabine and idarubicin.

My kidney function tests are within normal limits.

Exclusion Criteria

I am not taking any drugs that strongly affect other medications.

I have a history of unusual bleeding.

Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable hepatitis C virus ribonucleic acid (RNA) by a polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive navtemadlin orally once daily on days 1-7, cytarabine intravenously twice daily over 3 hours on days 1-7, and idarubicin intravenously over 10-15 minutes on days 1-3. Treatment repeats every 28 days for up to 2 cycles.

8 weeks

Daily visits during treatment days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days, then every 3 months for 2 years, and every 6 months thereafter.

2 years

Extension

Patients with residual disease may receive additional cycles of cytarabine and idarubicin, and those achieving a complete response may receive further cycles.

3-4 additional cycles of 28-35 days each

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Idarubicin Hydrochloride
• Navtemadlin

Trial Overview The trial tests Navtemadlin combined with standard chemotherapy drugs Cytarabine and Idarubicin in AML patients. It aims to find the best dose of Navtemadlin and see how well it works alongside these chemotherapies by blocking a growth-essential protein in cancer cells.

How Is the Trial Designed?

Group I: Treatment (navtemadlin, cytarabine, idarubicin) Experimental Treatment 3 Interventions

Patients receive navtemadlin PO QD on days 1-7, cytarabine IV BID over 3 hours on days 1-7, and idarubicin IV over 10-15 minutes on days 1-3. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with residual disease may receive cytarabine IV BID over 3 hours for 5 days and idarubicin IV over 10-15 minutes for 2 days starting between days 14-21 of cycle 1 or the second cycle of navtemadlin, cytarabine, and idarubicin. Patients who achieve a CR or a CRi in either cycle 1 or 2 may receive cytarabine IV BID over 3 hours on days 1, 3, and 5 for 3-4 additional 28 to 35-day cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic 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

The FLAG-IDA chemotherapy regimen was administered to seven children with refractory acute myeloid leukemia (AML), and while it was tolerable with no early deaths, the efficacy remains uncertain due to high relapse rates and limited patient numbers.

Hematological toxicity was common among patients, with one case of severe non-hematological toxicity (bacterial meningitis), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. Nakayama, H., Tomizawa, D., Tanaka, S., et al.[2018]

In a study of 24 patients with acute myeloid leukemia (AML) treated with a combination of idarubicin, cytarabine, and cladribine (ICC), 79.2% achieved complete remission (CR), indicating a high efficacy of this treatment regimen.

The study also reported a 33-month overall survival rate of 56% and a disease-free survival rate of 36%, suggesting that ICC can be an effective induction therapy, especially in high-risk AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Acute Myeloid Leukemia with Idarubicin, Cytarabine and Cladribine. Wiedower, E., Jamy, O., Martin, MG.[2015]

In a study of 52 patients under 55 with acute myeloid leukemia (AML), the chemotherapy regimen BF12 led to a high remission rate of 78.4%, demonstrating its efficacy in treating newly diagnosed AML.

The same regimen also showed effectiveness in relapsed acute leukemia, with 65% of patients achieving complete remission, although some patients experienced toxicity-related deaths, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia. Mehta, J., Powles, R., Singhal, S., et al.[2013]

In a study of 43 patients under 60 years old with untreated acute myeloid leukemia, the combination of idarubicin, etoposide, and carboplatin achieved a remission rate of 67% with a median leukemia-free survival of 15.4 months.

The treatment was associated with significant mucosal toxicity, including severe gastrointestinal side effects in a substantial number of patients, indicating that while effective, the regimen's tolerability may need improvement through adjustments in postremission therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. Bow, EJ., Gallant, G., Williams, GJ., et al.[2015]

In a study involving five patients with therapy-related acute myeloid leukemia, a combination of idarubicin, high-dose cytarabine, and etoposide achieved complete remission in all patients after just one course of treatment.

The treatment was well-tolerated, with low levels of toxicity and no deaths during the induction therapy, suggesting it is a promising option for inducing remission in secondary acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. Philpott, N., Mehta, J., Treleaven, J., et al.[2019]

In a study of 125 patients with de novo acute myeloid leukemia, idarubicin combined with cytarabine resulted in a significantly higher complete remission rate (82.1%) compared to daunorubicin (41.2%) in patients with high MDR1 expression.

Idarubicin also showed superior efficacy in high MDR1 expressers with favorable or intermediate risk, while no significant differences were observed between the two treatments in low MDR1 expressers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idarubicin is superior to daunorubicin in remission induction of de novo acute myeloid leukemia patients with high MDR1 expression. Shi, P., Zha, J., Guo, X., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03041688

Testing a New Chemotherapy Drug, KRT-232 (AMG- ... Giving navtemadlin, decitabine, and venetoclax together may work better than decitabine alone in treating patients with acute myeloid leukemia. Detailed ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9306949/

Pharmacokinetics and Macrophage Inhibitory Cytokine‐1 ... Navtemadlin (KRT‐232) is a potent, selective, orally available, small‐molecule MDM2 inhibitor that restores p53 activity to drive apoptosis of malignant cells.

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/2782/501687/Navtemadlin-a-Novel-MDM2-Inhibitor-Potentiated

Navtemadlin, a Novel MDM2 Inhibitor, Potentiated Venetoclax ... Conclusions: Nvtm, a potent second-generation MDM2 inhibitor, rapidly restored p53 function, induced apoptosis in p53 WT AML MOLM-13 by impeding ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9506

Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 ... Conclusions: Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/ ...

5. onclive.com onclive.com/view/dr-rampal-on-the-potential-utilization-of-navtemadlin-in-relapsed-refractory-aml-and-mpns

Dr. Rampal on the Potential Utilization of Navtemadlin in ... This actively accruing trial is examining the safety and efficacy of navtemadlin, a novel oral small molecule MDM2 inhibitor in patients with ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40348597/

The Clinical Safety and Efficacy of Cytarabine ... Results: CPX-351 exhibited an adverse event profile that was comparable to that of conventional chemotherapy. It resulted in complete remission rates of 18%-41% ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12330780/

Outpatient cytarabine consolidation in acute myeloid leukemia ... Outpatient cytarabine consolidation for select patients is safe and cost‐effective without an increased risk of major treatment complications.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18535

Real-world outcomes of cytarabine consolidation in older ... Conclusions: Cytarabine consolidation in patients ≥60 years with AML is safe and feasible. Neurotoxicity was rare, especially at reduced dose.

9. sciencedirect.com sciencedirect.com/science/article/pii/S253113792300161X

Toxicity and outcome of adults with acute myeloid leukemia ... In conclusion, our data suggest that high-dose of cytarabine (18 g/m2) is a safe option after induction of AML. Conflicts of interest. None. Recommended ...

10. ashpublications.org ashpublications.org/blood/article/145/17/1870/535523/Venetoclax-plus-daunorubicin-and-cytarabine-for

Venetoclax plus daunorubicin and cytarabine for newly ... In a phase 1b study, we assessed the safety and efficacy of Ven with daunorubicin and cytarabine in patients with newly diagnosed AML. A total ...