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

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 the standard chemotherapy drugs cytarabine and idarubicin in patients with acute myeloid leukemia. Navtemadlin may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Chemotherapy drugs, such as cytarabine and idarubicin, 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. Giving navtemadlin with cytarabine and idarubicin may stabilize cancer for longer when compared to giving usual treatments alone.

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.

What data supports the effectiveness of the drug combination used in the Navtemadlin + Chemotherapy trial for Acute Myeloid Leukemia?

Research shows that a combination of idarubicin and high-dose cytarabine, similar to the drugs used in the trial, has been effective in achieving complete remission in patients with acute myeloid leukemia, with one study reporting a 78.4% remission rate. This suggests that the combination of these drugs can be effective in treating this type of leukemia. ^{1 2 3 4 5}

What safety data exists for Navtemadlin + Chemotherapy for Acute Myeloid Leukemia?

The combination of idarubicin and cytarabine, which are part of the chemotherapy regimen, has been generally well-tolerated in patients with acute myeloid leukemia, with side effects like nausea, vomiting, and changes in liver and kidney function being reported. Treatment-related mortality was low, and the regimen was considered feasible and effective in non-high-risk patients. ^{1 6 7 8 9}

What makes the drug Navtemadlin combined with chemotherapy unique for treating acute myeloid leukemia?

Navtemadlin, when combined with chemotherapy drugs like cytarabine and idarubicin, offers a novel approach by potentially enhancing the effectiveness of traditional chemotherapy. This combination may provide a new option for patients who do not respond to standard treatments, as Navtemadlin (also known as AMG 232 or KRT-232) is being explored for its ability to target specific pathways in cancer cells, which could improve outcomes in acute myeloid leukemia. ^{1 10 11 12 13}

Research Team

Kevin R. Kelly

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Eligibility Criteria

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

I am eligible for intensive chemotherapy with cytarabine and idarubicin.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

References

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

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia. [2019]

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

Idarubicin is superior to daunorubicin in remission induction of de novo acute myeloid leukemia patients with high MDR1 expression. [2018]

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

Remission induction therapy of untreated acute myeloid leukemia using a non-cytarabine-containing regimen of idarubicin, etoposide, and carboplatin. [2015]

4. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety analysis of different dose idarubicin plus cytarabine regimen as induction chemotherapy for young patients with de-novo acute myeloid leukemia]. [2020]

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

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia. [2013]

6. Australia pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia. [2021]

8. England pubmed.ncbi.nlm.nih.gov

The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Acute myeloid leukemia with poor prognosis: treatment with oral 4-demethoxydaunorubicin (idarubicin) and low-dose cytarabine via subcutaneous route]. [2013]

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

Combination of cytarabine and topotecan in patients treated for acute myeloid leukemia with persistent disease after frontline induction. [2019]

11. Greece pubmed.ncbi.nlm.nih.gov

Induction of Acute Myeloid Leukemia with Idarubicin, Cytarabine and Cladribine. [2015]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Is there an optimal adjunct therapy to traditional cytotoxic induction? [2022]

13. China pubmed.ncbi.nlm.nih.gov

[Comparison of 10 mg/m² or 8 mg/m² idarubicin plus cytarabine regimen as induction chemotherapy for adult patients with newly diagnosed acute myeloid leukemia]. [2020]