Ziftomenib for Relapsed/Refractory Acute Myeloid Leukemia

Recruiting at 52 trial locations

Overseen By Kura Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kura Oncology, Inc.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, 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

263 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ziftomenib, a new treatment for people with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) that hasn't responded to other treatments. Some sub-studies combine ziftomenib with other drugs to assess if the combination is more effective. Patients with specific genetic changes in their leukemia, such as certain mutations, may be suitable for this trial. The research aims to determine the safety and effectiveness of ziftomenib, both alone and with other medications. As a Phase 1 trial, it focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications. However, you cannot take drugs that are strong inhibitors or inducers of CYP3A4, except for essential antibiotics, antifungals, and antivirals. You also need to stop any investigational therapies at least 14 days before the trial.

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

Research has shown that ziftomenib, the treatment being tested, was safe in earlier studies. In patients with relapsed or hard-to-treat acute myeloid leukemia (AML), ziftomenib caused manageable side effects. While some side effects occurred, they were not severe enough to halt treatment in those studies.

Ziftomenib was also tested with other standard treatments and proved to be safe and tolerable. This suggests that patients could handle the treatment well, even when combined with other medications.

For those considering joining a trial, this information provides confidence about the safety of ziftomenib in humans based on past research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ziftomenib for relapsed/refractory acute myeloid leukemia (AML) because it offers a novel approach compared to the standard treatments like chemotherapy and targeted therapies such as FLT3 inhibitors. Ziftomenib is unique because it targets specific genetic mutations, particularly those linked to MEIS1 overexpression and KMT2A rearrangements, which are often resistant to current treatments. This targeted action could potentially improve outcomes for patients who have limited options due to the aggressive nature of their disease. By focusing on these genetic mutations, ziftomenib aims to provide a more effective and personalized treatment option for patients with relapsed or refractory AML.

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

Research has shown that ziftomenib holds promise for treating relapsed or hard-to-treat acute myeloid leukemia (AML). This trial includes several sub-studies where participants receive ziftomenib in different combinations or dosages. Studies have found that ziftomenib targets a protein called menin, which plays a role in leukemia, especially in patients with specific genetic changes known as NPM1 mutations. In one study, ziftomenib was particularly successful in patients with these genetic changes. The treatment aims to block the pathways that cancer cells use to grow, offering hope for those whose leukemia has returned or resisted other treatments. Early research also suggests that ziftomenib could effectively slow cancer cell growth in cases that depend on menin. This evidence suggests a potentially effective new option for people facing this challenging condition. ^{2 4 5 6 7}

Are You a Good Fit for This Trial?

Adults with relapsed or refractory acute myeloid leukemia (AML) who have failed standard treatments can join this trial. They must have controlled white blood cell counts, be in relatively good health, and agree to use effective contraception. People with active central nervous system leukemia, recent heart issues, uncontrolled infections, or those on certain drugs that affect liver enzymes are excluded.

Inclusion Criteria

My liver and kidneys are working well.

I agree to use effective birth control during and for 3 months after the study.

I agree to use effective birth control during and for 6 months after the study.

Exclusion Criteria

I have recovered from major side effects of previous treatments.

I am not taking strong drugs that affect liver enzyme CYP3A4, except for necessary antibiotics, antifungals, or antivirals.

I am on immunosuppressive therapy after a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a - Dose Escalation

Determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of ziftomenib

28 days (1 cycle)

Multiple visits for dose escalation and monitoring

Phase 1b - Dose-Validation Expansion

Determine the safety, tolerability, and minimal biologically effective dose of ziftomenib in dosing cohorts

Up to 12 months

Regular visits for safety and efficacy assessments

Phase 2

Assess the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with NPM1-m AML

Up to 12 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months following discontinuation of treatment

What Are the Treatments Tested in This Trial?

Interventions

• Ziftomenib

Trial Overview The study is testing Ziftomenib's safety and effectiveness for AML patients whose disease has returned or hasn't responded to treatment. It's a two-phase trial: the first phase adjusts doses; the second expands testing specifically to patients with an NPM1 mutation.

How Is the Trial Designed?

Group I: Sub-study 4 Experimental Treatment 1 Intervention

R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib

Group II: Sub-study 3 Experimental Treatment 1 Intervention

Part 1a: KMT2A-r R/R ALL patients will receive multiple ziftomenib doses Part 1b: KMT2A-r R/R ALL patients will receive ziftomenib

Group III: Sub-study 2 Experimental Treatment 2 Interventions

R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole

Group IV: Sub-study 1 Experimental Treatment 2 Interventions

R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam

Group V: Phase 2 Experimental Treatment 1 Intervention

NPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose

Group VI: Phase 1b - Dose-Validation Expansion Experimental Treatment 1 Intervention

Cohort 1: KMT2A-r / NPM1-m R/R AML patients will receive ziftomenib Cohort 2: KMT2A-r / NPM1-m R/R AML patients will receive ziftomenib

Group VII: Phase 1a - Dose Escalation Experimental Treatment 1 Intervention

AML patients will receive multiple doses of ziftomenib

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

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]

New prognostic molecular markers such as FLT3-ITD, mutated IDH1, and biallelic CEBPA mutations have been identified in patients with relapsed/refractory acute myeloid leukemia (r/r-AML), which can help guide treatment decisions.

Intensive combination chemotherapy, particularly with gemtuzumab ozogamicin, has shown effectiveness as a salvage therapy for refractory AML, and the timing of allogeneic hematopoietic cell transplantation (allo-HCT) should be based on the likelihood of achieving a response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapsed/refractory acute myeloid leukemia: any progress? Schlenk, RF., Müller-Tidow, C., Benner, A., et al.[2017]

Acute myeloid leukemia (AML) often shows resistance to standard chemotherapy agents like cytarabine and daunorubicin, particularly in elderly patients, where the failure to achieve complete remission can be as high as 40-60%.

Research is focusing on molecular targeted therapies and immunotherapy to improve treatment outcomes, especially for patients with specific mutations like DNMT3A and TP53, by addressing the mechanisms of resistance to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia. Gurnari, C., Pagliuca, S., Visconte, V.[2021]

In a phase 1b/2 trial involving 19 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of azacitidine and the anti-PD-L1 inhibitor avelumab was well tolerated but showed limited clinical activity, with an overall complete remission rate of only 10.5%.

Analysis of bone marrow blasts revealed significantly higher expression of PD-L2 compared to PD-L1, suggesting that PD-L2 may play a key role in the resistance to anti-PD-L1 therapy in AML, indicating a potential target for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia. Saxena, K., Herbrich, SM., Pemmaraju, N., et al.[2022]

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]

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]

In a trial involving 70 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of azacitidine and nivolumab resulted in an overall response rate of 33%, with particularly promising results in patients who had not previously received hypomethylating agents, achieving a response rate of 58%.

The treatment was generally safe, with only 11% of patients experiencing grade 3 to 4 immune-related adverse events, and pretherapy levels of CD3 and CD8 in bone marrow and blood were identified as potential biomarkers for predicting patient response to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Daver, N., Garcia-Manero, G., Basu, S., et al.[2020]

The study evaluated MK-8242 in 26 subjects with refractory/recurrent acute myeloid leukemia (AML), finding that a 7on/14off dosing regimen (210mg or 300mg BID) had a more favorable safety profile compared to the 7on/7off regimen, with no dose-limiting toxicities observed in the higher doses.

Efficacy was demonstrated with responses including one partial response and one complete response in patients, suggesting that MK-8242, an HDM2 inhibitor, warrants further investigation for treating AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Ravandi, F., Gojo, I., Patnaik, MM., et al.[2018]

In a study of 49 patients with relapsed or refractory acute myeloid leukemia (AML) who have the FLT3 mutation, treatment with tyrosine kinase inhibitors (TKIs) resulted in better overall survival compared to conventional chemotherapy.

Patients receiving TKIs experienced fewer and less severe adverse events, along with shorter hospital stays, highlighting the potential of TKIs to improve both survival and quality of life in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile and impact on survival of tyrosine kinase inhibitors versus conventional therapy in relapse or refractory FLT3 positive acute myeloid leukemia patients. Marconi, G., De Polo, S., Martinelli, G., et al.[2021]

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]

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]

Recent advancements in acute myeloid leukemia (AML) treatment have led to the approval of several new targeted therapies from 2017 to 2023, improving patient outcomes compared to traditional 7+3 chemotherapy.

These new agents have unique safety profiles and may cause different adverse events than standard chemotherapy, highlighting the importance of understanding each drug's safety concerns for effective patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative safety review of targeted therapies for acute myeloid leukemia. Dalgetty, M., Leurinda, C., Cortes, J.[2023]

Citations

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

Ziftomenib in relapsed or refractory acute myeloid ... Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models.

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

Ziftomenib in Relapsed or Refractory NPM1-Mutated AML Here, we present the primary clinical activity and safety results in 92 patients with relapsed/refractory NPM1-m AML from the registrational ...

3. 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 ...

4. 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 ...

5. kuraoncology.com kuraoncology.com/wp-content/uploads/ASH-2022_Ziftomenib_16-Nov-2022_FINAL.pdf

KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with ... KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with. Relapsed or Refractory Acute Myeloid Leukemia. Harry P. Erba1, Amir Fathi2, Ghayas Issa3, Jessica ...

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

Study Details | NCT06001788 | Safety and Tolerability of ... The safety, tolerability, and antileukemic response of ziftomenib in combination with standard of care treatments for patients with relapsed/refractory ...