Ziftomenib for Relapsed/Refractory Acute Myeloid Leukemia

Recruiting at52 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Kura Oncology, Inc.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing ziftomenib, a new drug, in patients with difficult-to-treat acute myeloid leukemia (AML). The drug works by blocking a protein interaction that cancer cells need to grow.

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.

What data supports the idea that Ziftomenib for Relapsed/Refractory Acute Myeloid Leukemia is an effective treatment?

The available research does not provide specific data on the effectiveness of Ziftomenib for Relapsed/Refractory Acute Myeloid Leukemia. However, it mentions that new drugs like tyrosine kinase inhibitors have shown promise in improving survival and reducing complications for patients with a similar condition, FLT3-positive AML. This suggests that novel treatments, including Ziftomenib, could potentially offer benefits, but specific data for Ziftomenib is not provided in the research. ^{1 2 3 4 5}

What safety data is available for Ziftomenib in treating AML?

The provided research does not contain specific safety data for Ziftomenib (also known as KO-539) in the treatment of acute myeloid leukemia (AML). The articles focus on other targeted therapies and their safety profiles, but do not mention Ziftomenib or its safety data. Further research or specific clinical trial results would be needed to find safety information on Ziftomenib. ^{1 6 7 8 9}

Is the drug Ziftomenib a promising treatment for relapsed/refractory acute myeloid leukemia?

Ziftomenib is considered a promising drug for relapsed/refractory acute myeloid leukemia because it represents a novel approach in a field where new treatments are needed. Current treatments have limited success, especially for patients who have relapsed or have not responded to other therapies. Ziftomenib offers hope for better outcomes in these challenging cases. ^{1 2 10 11 12}

Research Team

Eligibility Criteria

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 6 months after the study.

I agree to use effective birth control during and for 3 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.

Trial Timeline

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

Treatment Details

Interventions

• Ziftomenib (Menin-MLL(KMT2A) Inhibitor)

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.

Participant Groups

Group I: Phase 2 Experimental Treatment 1 Intervention

NPM1-m patients will receive the recommended phase 2 dose determined in Phase 1

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

Cohort 1: KMT2A-r / NPM1-m patients will receive a dose previously studied in Phase 1a Cohort 2: KMT2A-r / NPM1-m patients will receive a dose previously studied in Phase 1a

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

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]

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]

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) 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]

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]

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]

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]

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]

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]

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]

References

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

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

2. England 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). [2018]

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

Relapsed/refractory acute myeloid leukemia: any progress? [2017]

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

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

5. England 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. [2021]

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

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

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

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

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

A comparative safety review of targeted therapies for acute myeloid leukemia. [2023]

9. 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]

10. United States 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. [2020]

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

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia. [2021]