Ziftomenib Combinations for Acute Myeloid Leukemia

Recruiting at 27 trial locations

Overseen By Clinical Operations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Kura Oncology, Inc.

Must not be taking: Live vaccines

Disqualifiers: Leukostasis, CNS involvement, active infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, multiple cycles

212 Participants Needed

Trial Summary

What is the purpose of this trial?

This Phase 1 study will assess the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with venetoclax and azacitidine (ven/aza), ven, and 7+3 for two different molecularly-defined arms, NPM1-m and KMT2A-r.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are in the relapsed/refractory cohort, you should not have received chemotherapy, immunotherapy, or investigational therapy within 14 days before starting the trial.

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

Research shows that combining venetoclax with azacitidine improves remission rates and survival in patients with acute myeloid leukemia, especially those who are older or not fit for intensive chemotherapy. This suggests that similar drug combinations, like those including Ziftomenib, may also be effective. ^{1 2 3 4 5}

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

The combination of venetoclax and azacitidine has been studied for safety in patients with acute myeloid leukemia, showing that while it can cause some serious side effects like low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia), these side effects are generally considered tolerable. ^{2 4 6 7 8}

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

The Ziftomenib combination drug is unique because it includes Ziftomenib, a novel component not commonly used in standard treatments for acute myeloid leukemia. This combination also incorporates venetoclax and azacitidine, which have shown improved remission rates and survival in older or unfit patients compared to azacitidine alone. ^{1 2 7 8 9}

Eligibility Criteria

This trial is for adults with a specific type of leukemia (AML) that's either new or has come back after treatment. They must have certain genetic changes (NPM1 mutation or KMT2A rearrangement), be in decent physical shape, and agree to use birth control. People can't join if they have other active cancers, uncontrolled infections, heart problems, CNS involvement by AML, high white blood cell counts without management options like hydroxyurea or leukapheresis, HIV/Hepatitis B/C infection, or if women are pregnant/breastfeeding.

Inclusion Criteria

I agree to use birth control or abstain from sex as required.

My liver, kidneys, and heart are working well.

My AML is either new or has returned, and tests show I have an NPM1 mutation or KMT2A rearrangement.

Exclusion Criteria

I have a known BCR-ABL gene change.

Mean corrected QT interval corrected for heart rate by Fredericia's formula (QTcF) >480 ms on triplicate ECGs

I have not received any live vaccines within the last 14 days and won't until my B-cell levels recover.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ziftomenib in combination with venetoclax/azacitidine, venetoclax, or 7+3 chemotherapy

28 days per cycle, multiple cycles

Regular visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Long-term follow-up

Participants are assessed for overall survival and other long-term outcomes

Up to 1 year following end of treatment

Treatment Details

Interventions

• Azacitidine
• Cytarabine
• Daunorubicin
• Venetoclax
• Ziftomenib

Trial Overview The study tests the safety and potential effectiveness of Ziftomenib combined with Venetoclax/Azacitidine ('ven/aza'), just Venetoclax ('ven'), or standard chemo ('7+3') in patients with Acute Myeloid Leukemia (AML). It focuses on those who have NPM1 mutations or KMT2A rearrangements.

Participant Groups

Group I: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Experimental Treatment 3 Interventions

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Group II: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Experimental Treatment 3 Interventions

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy

Group III: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L NPM1-m (A-4) Experimental Treatment 3 Interventions

Ziftomenib/Venetoclax/Azacitidine in newly diagnosed NPM1-m AML patients

Group IV: Dose Validation/Expansion: Ziftomenib/Venetoclax/Azacitidine in 1L KMT2A-r (B-3) Experimental Treatment 3 Interventions

Ziftomenib/Venetoclax/Azacitidine in newly diagnosed KMT2A-r AML patients

Group V: Dose Validation/Expansion: Ziftomenib/Venetoclax in R/R NPM1-m (A-3) Experimental Treatment 2 Interventions

Ziftomenib/Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Group VI: Dose Validation/Expansion: Ziftomenib/7+3 in 1L NPM1-m (A-2) Experimental Treatment 3 Interventions

Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease

Group VII: Dose Validation/Expansion: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Experimental Treatment 3 Interventions

Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy

Group VIII: Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R NPM1-m (A-1) Experimental Treatment 3 Interventions

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy

Group IX: Dose Escalation: Ziftomenib/Venetoclax/Azacitidine in R/R KMT2A-r (B-1) Experimental Treatment 3 Interventions

Ziftomenib/Venetoclax/Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy

Group X: Dose Escalation: Ziftomenib/7+3 in 1L NPM1-m (A-2) Experimental Treatment 3 Interventions

Ziftomenib/7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease

Group XI: Dose Escalation: Ziftomenib/7+3 in 1L KMT2A-r (B-2) Experimental Treatment 3 Interventions

Ziftomenib/7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy and meet the protocol definition of high-risk disease

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Kura Oncology, Inc.

Lead Sponsor

Trials

19

Recruited

1,700+

Findings from Research

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[2023]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

The VA regimen, combining venetoclax and azacitidine, demonstrated a high complete remission (cCR) rate of 78.8% after the first treatment cycle and 81.8% after prolonged treatment in 66 patients with newly diagnosed acute myeloid leukemia (AML) who were not suitable for conventional chemotherapy.

The treatment was generally safe, with manageable adverse effects, primarily neutropenia, thrombocytopenia, and anemia, and showed better outcomes in patients with specific gene mutations (IDH1/2 or NPM1) and those experiencing rebound thrombocytosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. Sun, L., Ye, SJ., Zhou, N., et al.[2023]

In a study of 86 patients with relapsed or refractory acute myeloid leukemia (RR-AML) treated with venetoclax combinations, the complete remission rate was 24%, and the overall response rate was 31%, indicating that venetoclax is an effective treatment option for this patient group.

Azacitidine combined with venetoclax showed significantly better outcomes than low-dose cytarabine with venetoclax, with median overall survival of 25 months compared to 3.9 months, highlighting the importance of treatment choice in improving survival in RR-AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Stahl, M., Menghrajani, K., Derkach, A., et al.[2021]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

In a phase 2 trial involving 33 adults with newly diagnosed acute myeloid leukaemia, the combination of venetoclax with daunorubicin and cytarabine (DAV regimen) achieved a remarkable composite complete remission rate of 91% after one cycle of treatment.

The treatment was found to be safe, with no treatment-related deaths reported, although all patients experienced grade 3 or worse adverse events, such as neutropenia and thrombocytopenia, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Wang, H., Mao, L., Yang, M., et al.[2022]

In a study of 50 adults with acute myeloid leukemia (AML) in Mexico and Peru, venetoclax-based therapy showed a high complete response rate of 78.6% in newly diagnosed patients and 45.5% in those with relapsed/refractory disease, indicating its efficacy in treating AML.

The median overall survival was 9.6 months for newly diagnosed patients and 8 months for relapsed/refractory patients, suggesting that venetoclax is a viable treatment option even in real-world settings, despite common hematologic toxicities and dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. Gómez-De León, A., Demichelis-Gómez, R., Pinedo-Rodríguez, A., et al.[2022]

References

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

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]

2. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. [2023]

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

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience]. [2023]

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

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. [2023]

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

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. [2022]

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

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America. [2022]