Ziftomenib Combinations for Acute Myeloid Leukemia

Recruiting in Palo Alto (17 mi)

+24 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Kura Oncology, Inc.

Must not be taking: Immunosuppressive drugs

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, uncontrolled infection, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

The safety, tolerability, and antileukemic response of ziftomenib in combination with standard of care treatments for patients with relapsed/refractory acute myeloid leukemia will be examined with the following agents: FLAG-IDA, low-dose cytarabine, and gilteritinib.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you should not have received any anticancer therapy within 14 days before starting the study treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination including Ziftomenib for treating acute myeloid leukemia?

The combination of cytarabine with other drugs has been a standard treatment for acute myeloid leukemia (AML), showing response rates of up to 70% in younger patients. Additionally, the approval of novel drugs like Gemtuzumab Ozogamicin in combination with cytarabine has provided new treatment opportunities, suggesting that combining traditional and new agents can improve outcomes in AML. ^{1 2 3 4 5}

What safety data exists for Ziftomenib and its combinations in treating acute myeloid leukemia?

The safety profile of midostaurin, a drug used in combination with chemotherapy for acute myeloid leukemia, was found to be manageable with common side effects like fever, nausea, and diarrhea. No new safety concerns were identified in the study, suggesting a generally safe use in humans. ^{1 6 7 8 9}

What makes the drug Ziftomenib unique for treating acute myeloid leukemia?

Ziftomenib is unique because it is a menin inhibitor, which targets specific genetic mutations (KMT2A rearrangement or mutant NPM1) in acute myeloid leukemia, offering a novel approach compared to traditional treatments. ^{1 10 11 12 13}

Research Team

Clinical Development

Principal Investigator

Kura Oncology

Eligibility Criteria

This trial is for adults with relapsed/refractory acute myeloid leukemia (AML) who have specific genetic changes like NPM1 mutation or KMT2A rearrangement. Participants need to be in a stable physical condition, have good liver and kidney function, and agree to use contraception. It's not suitable for those with poor heart function.

Inclusion Criteria

My liver and kidney functions are within normal ranges.

Your ejection fraction is above the predetermined limit.

You (or your legal representative) must be able to comprehend and submit written consent before the initial screening process.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Treatment

Participants receive oral ziftomenib in combination with standard of care treatments in sequential cohorts to identify safety and tolerability

28 days per cycle

Multiple visits per cycle

Phase 1b Treatment

Following determination of maximum tolerated dose, participants receive oral ziftomenib in combination with standard of care treatments in dose validation/expansion cohorts

28 days per cycle

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for transfusion independence, overall survival, and remission rates

Up to 12 months

Treatment Details

Interventions

• Cytarabine (Anti-metabolites)
• Fludarabine (Anti-metabolites)
• Gilteritinib (Other)
• Granulocyte colony-stimulating factor (Other)
• Idarubicin (Anti-tumor antibiotic)
• Ziftomenib (Other)

Trial Overview The trial tests the safety and effectiveness of Ziftomenib combined with other AML treatments: FLAG-IDA regimen, low-dose Cytarabine, or Gilteritinib. The goal is to see how well patients respond to these combinations when their AML has come back or hasn't improved after treatment.

Participant Groups

Group I: Phase 1b Experimental Treatment 6 Interventions

Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)

Group II: Phase 1a Experimental Treatment 6 Interventions

Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts: A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC) A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)

Who Is Running the Clinical Trial?

Kura Oncology, Inc.

Lead Sponsor

Trials

19

Recruited

1,700+

Findings from Research

Acute myeloid leukemia (AML) remains a challenging disease with only about 60% 5-year survival for patients classified as favorable risk, highlighting the need for better treatment options, especially for the elderly.

Recent advancements include the use of clofarabine for relapsed disease and hypomethylating agents, but clinical trials for FLT3 inhibitors have not shown promising results, indicating a need for ongoing research into new therapies targeting leukemia stem cells and minimal residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia: focus on novel therapeutic strategies. Lin, TL., Levy, MY.[2022]

Acute myeloid leukemia (AML) treatment remains difficult, especially for older patients over 60, who experience high toxicity and low response rates, while younger patients can achieve a 70% response rate with standard therapies.

New targeted therapies, such as oral farnesyltransferase inhibitors, are showing promise in treating refractory AML and are currently in phase II testing, potentially offering better efficacy and safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute myeloid leukemia: state-of-the-art and future directions. Stone, RM.[2019]

Midostaurin, a multikinase inhibitor, was found to have a manageable safety profile in a study of 103 patients with FLT3 mutation-positive acute myeloid leukemia, with no new safety events reported during treatment.

The treatment showed promising outcomes, including high rates of transplant success and low relapse rates during maintenance therapy, indicating its efficacy when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Roboz, GJ., Strickland, SA., Litzow, MR., et al.[2021]

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]

New targeted therapies for acute myeloid leukemia (AML) have shown to be more effective than standard chemotherapy and have a good safety profile, with gemtuzumab ozogamicin or midostaurin combined with intensive chemotherapy now considered the standard of care for fit patients.

For unfit patients, azacitidine-venetoclax has become the frontline treatment, while ongoing research into combinations with other agents like magrolimab or ivosidenib aims to improve outcomes, especially for those with relapsed or refractory disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updates on the Management of Acute Myeloid Leukemia. Huerga-Domínguez, S., Villar, S., Prósper, F., et al.[2023]

Recent advancements in the treatment of acute myeloid leukemia (AML) have led to the FDA approval of four new targeted therapies that show improved responses and overall survival in specific patient populations, particularly those with certain genetic mutations.

These therapies include midostaurin for FLT3-mutated AML, gemtuzumab ozogamicin for CD33+ AML, CPX-351 for therapy-related AML, and enasidenib for IDH2-mutated AML, marking a significant shift in treatment options after decades of limited progress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and emerging therapies for acute myeloid leukaemia. Davis, JR., Benjamin, DJ., Jonas, BA.[2020]

Two investigational menin inhibitors, SNDX-5613 and KO-539, showed promising efficacy in treating relapsed and refractory acute myeloid leukemia (AML), with overall response rates of 53% and 40%, respectively, in patients with specific genetic mutations.

The combination of pivekimab sunirine with azacitidine and venetoclax achieved a 45% overall response rate in relapsed and refractory AML, which increased to 53% in patients who had not previously received venetoclax, highlighting the potential of novel treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting. DiNardo, KW., LeBlanc, TW., Chen, H.[2023]

A phase III study demonstrated that combining azacitidine with the IDH1 inhibitor ivosidenib significantly improves treatment outcomes for patients with acute myeloid leukemia who cannot undergo intensive chemotherapy.

The combination therapy tripled overall survival rates and enhanced complete remission and event-free survival compared to azacitidine alone, indicating a substantial efficacy boost from this drug pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

In a phase 1/2 study involving 95 patients with untreated acute myeloid leukemia (AML), the combination of tipifarnib with idarubicin and cytarabine resulted in a 64% complete remission rate, indicating its efficacy in treating this aggressive cancer.

The treatment was found to be safe, with the most common severe side effects being gastrointestinal issues, liver dysfunction, and skin rash, while also showing improved remission duration compared to historical data for idarubicin and cytarabine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. Jabbour, E., Kantarjian, H., Ravandi, F., et al.[2021]

A phase III trial is investigating the efficacy of gemtuzumab ozogamicin (GO) combined with intensive induction therapy and glasdegib for older patients with acute myeloid leukemia (AML), aiming to improve measurable residual disease (MRD) negativity and event-free survival (EFS).

The trial will involve 252 patients aged 60 and older, comparing different dosing schedules of GO and the addition of glasdegib versus placebo, with the goal of enhancing survival outcomes in a population with historically poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML. Jaramillo, S., Krisam, J., Le Cornet, L., et al.[2022]

References

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

Acute myeloid leukemia: focus on novel therapeutic strategies. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin. [2021]

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

Treatment of acute myeloid leukemia: state-of-the-art and future directions. [2019]

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

A personalized approach to acute myeloid leukemia therapy: current options. [2020]

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

Acute myeloid leukaemia: optimal management and recent developments. [2022]

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

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. [2021]

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

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

Updates on the Management of Acute Myeloid Leukemia. [2023]

9. England pubmed.ncbi.nlm.nih.gov

New and emerging therapies for acute myeloid leukaemia. [2020]

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

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting. [2023]

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

Ivosidenib Boosts OS with Azacitidine in AML. [2022]

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

A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML. [2022]