Ziftomenib + Quizartinib for Acute Myeloid Leukemia

Overseen By Ghayas Issa, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Menin inhibitors

Disqualifiers: Active infection, Uncontrolled hypertension, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

44 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, the use of other chemotherapeutic or anti-leukemic agents is not allowed during the study, except for certain cases like intrathecal chemotherapy for CNS leukemia or hydroxyurea for rapidly proliferative disease.

What data supports the effectiveness of the drug Quizartinib for treating acute myeloid leukemia?

Quizartinib has shown to improve survival in patients with a specific mutation (FLT3-ITD) in acute myeloid leukemia, especially when added to standard nonintensive chemotherapy, leading to better response rates and longer overall survival compared to chemotherapy alone. ^{1 2 3 4 5}

Is the combination of Ziftomenib and Quizartinib safe for treating acute myeloid leukemia?

Quizartinib has been studied for safety in patients with acute myeloid leukemia and other conditions. Some patients experienced changes in heart rhythm (QT interval prolongation), but the safety profile improved with adjusted dosing. No specific safety data for Ziftomenib in combination with Quizartinib is available from the provided research. ^{1 4 6 7 8}

How is the drug combination of Ziftomenib and Quizartinib unique for treating acute myeloid leukemia?

The combination of Ziftomenib and Quizartinib is unique because Quizartinib is a highly potent and selective oral drug that targets the FLT3 mutation, which is often associated with poor outcomes in acute myeloid leukemia. This combination could potentially offer a new approach by targeting specific genetic mutations in the cancer cells, which is different from traditional chemotherapy. ^{1 2 3 4 6}

What is the purpose of this trial?

The goal of this all-oral combination is to deliver safe and effective therapy for the largest portion of AML subtypes (NPM1mt, KMT2Ar, NUP98r \~ 40-45%).

Research Team

Ghayas Issa, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with Acute Myeloid Leukemia (AML) or related conditions, who haven't responded to previous treatments. They must have certain blood counts, organ functions within set limits, and no major heart issues in the past 6 months. Participants need to be able to take pills and agree to use contraception if they can have children.

Inclusion Criteria

My white blood cell count is below 25,000/μL.

Baseline ejection fraction must be > 40%

My liver is functioning within the required limits for the trial.

Exclusion Criteria

I am not on chemotherapy, except for specific allowed treatments.

I have been treated with a menin inhibitor before.

I have an active hepatitis B, hepatitis C, or HIV infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation and Expansion

Participants receive ziftomenib in combination with quizartinib to determine the recommended phase 2 dose and assess safety and maximum tolerated dose

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Quizartinib
• Ziftomenib

Trial Overview The trial is testing a combination of two oral drugs, Ziftomenib and Quizartinib, for AML treatment. It aims to provide an effective therapy option for about 40-45% of AML subtypes that share specific genetic changes.

Participant Groups

Group I: Ziftoenib + Quizartinib Q4W Experimental Treatment 2 Interventions

Participants will be randomized to study

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a study of 202 older patients with acute myeloid leukemia (AML) who were not suitable for intensive chemotherapy, the addition of quizartinib to low-dose ara-C (LDAC) did not improve overall survival for the entire group, but it significantly enhanced response rates in patients with the FLT3-ITD mutation.

For the 27 FLT3-ITD patients, those receiving quizartinib plus LDAC had a median overall survival of 13.7 months compared to 4.2 months for those on LDAC alone, indicating that quizartinib could be a promising option for improving outcomes in this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Dennis, M., Thomas, IF., Ariti, C., et al.[2022]

In a phase III trial, the FLT3 inhibitor quizartinib showed a survival benefit compared to traditional chemotherapy in patients with relapsed or refractory FLT3-mutant acute myeloid leukemia.

The promising results from quizartinib suggest it may become a first-line treatment option for this type of leukemia, pending outcomes from ongoing studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quizartinib Bests Chemo for FLT3-Mutant AML. [2019]

In a phase 3 trial involving 367 patients with relapsed or refractory FLT3-ITD-positive acute myeloid leukaemia, treatment with quizartinib resulted in a longer median overall survival of 6.2 months compared to 4.7 months for those receiving standard chemotherapy, indicating a significant survival benefit.

Quizartinib demonstrated a manageable safety profile, with common serious adverse events being similar to those seen in chemotherapy, suggesting it could be a new standard of care for patients with this aggressive form of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Cortes, JE., Khaled, S., Martinelli, G., et al.[2020]

In a study involving 93 healthy subjects, quizartinib showed a significant increase in plasma concentration when coadministered with the strong CYP3A inhibitor ketoconazole, indicating that dose adjustments may be necessary to avoid potential toxicity.

The study found that quizartinib had a low incidence of related adverse events (5.4%), with no serious adverse events or deaths reported, suggesting it is generally safe when administered alone or with moderate CYP3A inhibitors like fluconazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. Li, J., Kankam, M., Trone, D., et al.[2021]

Quizartinib, a selective FLT3 inhibitor, demonstrated significant efficacy in treating relapsed or refractory acute myeloid leukaemia, particularly in patients with FLT3-ITD mutations, with 56% of FLT3-ITD-positive patients in cohort 1 achieving composite complete remission.

The treatment was generally well tolerated, although serious adverse events occurred in a notable percentage of patients, including febrile neutropenia and QTc prolongation, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Cortes, J., Perl, AE., Döhner, H., et al.[2023]

References

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

Randomized evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. [2022]

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

Quizartinib Bests Chemo for FLT3-Mutant AML. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. [2021]

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

Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. [2023]

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

Safety and tolerability of quizartinib, a FLT3 inhibitor, in advanced solid tumors: a phase 1 dose-escalation trial. [2019]

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

Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. [2021]