Ziftomenib Combinations for Acute Myeloid Leukemia

Recruiting at 46 trial locations

Overseen By Kura Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Kura Oncology, Inc.

Must not be taking: Immunosuppressive drugs

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

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

171 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment called ziftomenib for people with acute myeloid leukemia (AML) that hasn't responded to previous treatments or has returned. Researchers combine ziftomenib with standard treatments like FLAG-IDA, low-dose cytarabine (a chemotherapy drug), or gilteritinib to determine if these combinations are more effective. The trial seeks participants with relapsed or refractory AML who have specific genetic changes, such as NPM1 mutations or KMT2A rearrangements, and are in stable enough health to join. 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 treatment.

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.

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

Research shows that ziftomenib, when used alone, is promising and has manageable side effects for patients with acute myeloid leukemia (AML) who have tried other treatments. Studies indicate that ziftomenib is generally safe, even for patients with extensive treatment histories.

When combined with standard treatments like FLAG-IDA, low-dose cytarabine, or gilteritinib, ziftomenib's safety is still under careful observation. However, earlier studies suggest it is usually well-tolerated. Some side effects occur, but they can often be managed with proper care.

This trial is in its early stages, so researchers are still determining the safest doses. This phase is crucial for understanding patient tolerance and potential side effects. For those considering joining this trial, safety remains a top priority, and patients will receive close monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Ziftomenib is unique because it specifically targets genetic mutations in acute myeloid leukemia (AML), such as NPM1 mutations and KMT2A rearrangements. Unlike traditional chemotherapy regimens, which often affect both healthy and cancerous cells, ziftomenib works more precisely by focusing on these genetic abnormalities. Researchers are excited about ziftomenib because it offers a new mechanism of action, potentially improving outcomes for patients with these specific genetic profiles. This targeted approach could lead to more effective treatments with fewer side effects compared to conventional options like cytarabine and anthracyclines.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research shows that ziftomenib may help treat relapsed or hard-to-treat acute myeloid leukemia (AML), especially in patients with specific genetic changes like NPM1 and KMT2A. This trial will administer ziftomenib alongside other treatments, such as FLAG-IDA and low-dose cytarabine, to evaluate its effectiveness. Studies have found that these combinations can improve outcomes for patients with these genetic profiles. In earlier trials, some patients improved in as little as 1.9 months. Ziftomenib has shown manageable side effects and has been effective even in patients with extensive prior treatments. These findings suggest that ziftomenib could be a helpful option for AML patients with certain genetic profiles. ^{2 5 6 7 8}

Who Is on the Research Team?

Clinical Development

Principal Investigator

Kura Oncology

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Fludarabine
• Gilteritinib
• Granulocyte colony-stimulating factor
• Idarubicin
• Ziftomenib

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.

How Is the Trial Designed?

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)

Ziftomenib is already approved in United States for the following indications:

Approved in United States as Ziftomenib for:

• None - Investigational for Acute Myeloid Leukemia (AML)

Who Is Running the Clinical Trial?

Kura Oncology, Inc.

Lead Sponsor

Trials

19

Recruited

1,700+

Published Research Related to This Trial

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]

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]

Current treatments for acute myeloid leukaemia (AML) have low cure rates of 30-40%, prompting the exploration of new therapies to improve patient outcomes.

High doses of daunorubicin have shown better responses in younger patients and are well tolerated in older patients, while new agents like monoclonal antibodies and drugs targeting signaling pathways are being studied for their potential to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukaemia: optimal management and recent developments. Villela, L., Bolaños-Meade, J.[2022]

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]

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]

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]

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]

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]

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]

Recent advancements in genomic studies have revealed the genetic and molecular complexities of acute myeloid leukemia (AML), leading to the development of new targeted therapies.

The FDA has approved several novel drugs for AML treatment, including midostaurin and enasidenib, expanding the options available for clinicians beyond traditional therapies that have been used for decades.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A personalized approach to acute myeloid leukemia therapy: current options. Illangeswaran, RSS., Das, S., Paul, DZ., et al.[2020]

Gemtuzumab Ozogamicin (GO) has been approved for treating newly diagnosed CD33+ acute myeloid leukemia (AML) in combination with daunorubicin and cytarabine, offering new therapeutic options for patients.

Key biomarkers such as elevated CD33 expression and favorable cytogenetic profiles have been identified as predictors of a good response to GO, helping clinicians tailor treatments more effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin. Gottardi, M., Simonetti, G., Sperotto, A., et al.[2021]

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]

Citations

1. targetedonc.com targetedonc.com/view/final-trial-data-shows-success-for-ziftomenib-in-npm1-aml

Final Trial Data Show Success for Ziftomenib in NPM1 AML Ziftomenib shows promising results in treating relapsed/refractory acute myeloid leukemia with NPM1 mutations, offering hope for improved ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-01694

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML In this trial, the median time to response was 1.9 months, with some patients requiring up to 3.7 months of continuous therapy to achieve ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00386-3/abstract

Ziftomenib in relapsed or refractory acute myeloid ... Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10543165/

Menin inhibitor ziftomenib (KO-539) synergizes with drugs ... Zifomenib acts highly selective in MLL-r and NPM1mut acute myeloid leukemia and synergizes with a variety of targeted drugs in vitro. (A) Dose-response curve ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04067336

NCT04067336 | First in Human Study of Ziftomenib ... This first-in-human (FIH), open-label study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory (R/R) acute myeloid ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39362248/

Ziftomenib in relapsed or refractory acute myeloid ... Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06001788

NCT06001788 | Safety and Tolerability of Ziftomenib ... Safety and Tolerability of Ziftomenib Combinations in Patients With Relapsed/​Refractory Acute Myeloid Leukemia. ClinicalTrials.gov ID NCT06001788. Sponsor ...

8. ir.kuraoncology.com ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-provides-update-phase-1b-study-ko-539-acute

Kura Oncology Provides Update on Phase 1b Study of KO- ... The US Food and Drug Administration (FDA) has placed the KOMET-001 Phase 1b study of KO-539 in patients with relapsed or refractory acute myeloid leukemia (AML ...