Ziftomenib + Venetoclax + Azacitidine for Childhood Acute Leukemia

Overseen By David McCall, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, Antileukemic, Antivirals, others

Disqualifiers: Uncontrolled infection, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the highest safe dose of a new drug, ziftomenib, when combined with venetoclax and azacitidine. Researchers are testing these medications together to treat children and young adults with a type of acute leukemia characterized by specific genetic changes. The trial targets those whose leukemia has returned or did not respond to previous treatments. Participants should have leukemia with specific genetic changes and no recent severe heart or liver issues. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new drug combination.

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

The trial protocol does not specify if you must stop taking your current medications, but it does not allow other chemotherapeutic or anti-leukemic agents during the study, except for certain exceptions like intrathecal chemotherapy for CNS leukemia and hydroxyurea for rapidly proliferative disease. It's best to discuss your current medications with the study team.

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

Research shows that ziftomenib has promising safety results. In earlier studies, patients who took ziftomenib experienced manageable side effects, meaning the treatment didn't cause severe or uncontrollable problems. Other studies have tested ziftomenib with standard treatments for certain types of leukemia and found it well-tolerated, meaning most patients handled the treatment without major issues.

Venetoclax has FDA approval for treating certain types of leukemia, indicating a good safety record in humans. Similarly, azacitidine is another drug approved for leukemia, suggesting its safety is well-understood.

Overall, these treatments have been studied and found generally safe, though side effects can still occur. Participants considering joining this trial should discuss potential risks with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ziftomenib, Venetoclax, and Azacitidine for childhood acute leukemia because it takes a novel approach by integrating Ziftomenib, which targets a specific protein involved in cancer cell growth. While most existing treatments focus on general chemotherapy or inhibiting leukemia cell survival, Ziftomenib works uniquely by targeting the menin-MLL1 interaction, which is crucial for the growth of certain leukemia cells. This targeted approach has the potential to be more effective and less toxic, offering hope for improved outcomes in young patients with acute leukemia.

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

Studies have shown that ziftomenib yields promising results for patients with certain types of blood cancers. Specifically, it helped 23% of patients with relapsed or hard-to-treat acute myeloid leukemia (AML) with a specific mutation achieve complete remission, meaning their cancer completely disappeared for a while. Ziftomenib blocks a protein called menin, which aids cancer cell growth. Most patients tolerate it well, experiencing no severe side effects. In this trial, participants will receive ziftomenib in a dose-escalation and dose-expansion study to further evaluate its effectiveness and safety for treating acute leukemia with specific genetic changes. ^{1 5 6 7 8}

Who Is on the Research Team?

David McCall, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for children with acute leukemia that has come back or hasn't responded to treatment. They must have specific genetic mutations in their cancer cells. The exact criteria for who can join are not provided, but typically include age range and health status.

Inclusion Criteria

I agree to use birth control during and after the study for the required time.

I am currently receiving treatment for brain disease prevention or control.

It has been over 14 days since my last cancer treatment, or 5 half-lives of the medication.

Exclusion Criteria

I am not pregnant or breastfeeding.

I do not have active hepatitis B or C, nor uncontrolled HIV/AIDS.

I am not using other cancer drugs during this study, except for allowed exceptions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation

Participants receive escalating doses of ziftomenib to determine the maximum tolerated dose

Varies based on dose escalation protocol

Dose-expansion

Participants receive the recommended Phase II dose of ziftomenib in combination with venetoclax and azacitidine

Until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Venetoclax
• Ziftomenib

Trial Overview The study aims to find the safest high dose of a drug called Ziftomenib when used with Venetoclax and Azacitidine in kids with certain types of acute leukemia. It's an early-phase trial focused on dosage safety.

How Is the Trial Designed?

Group I: Dose-escalation + Dose-expansion of Ziftomenib Experimental Treatment 3 Interventions

The first group of 3 participants will receive the starting dose of ziftomenib. If no intolerable side effects are seen, the rest of the study participants will receive a higher dose of ziftomenib. If intolerable side effects were seen at the starting dose, the next group of 3 participants will receive a lower total dose given for a shorter time period. If needed for safety, an even lower total dose schedule can be assigned to the next group of participants.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Kura Oncology, Inc.

Industry Sponsor

Trials

19

Recruited

1,700+

Published Research Related to This Trial

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

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]

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]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., 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]

Citations

1. 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04067336

NCT04067336 | First in Human Study of Ziftomenib ... In this trial, ziftomenib, a menin-MLL(KMT2A) inhibitor, will be tested in patients for the first time. The trial includes a Main Study and four sub-studies ...

3. onclive.com onclive.com/view/ziftomenib-yields-complete-responses-regardless-of-prior-therapy-in-nmp1-mutant-aml

Ziftomenib Yields Complete Responses Regardless of ... Ziftomenib achieved a 23% complete remission rate in relapsed/refractory NPM1-mutant AML patients, with a median response duration of 4.6 months ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10881917/

Small Molecule Menin Inhibitors: Novel Therapeutic Agents ... The first clinical trials with the menin inhibitors SNDX-5613 (revumenib) and KO-539 (ziftomenib) demonstrated encouraging efficacy with ...

5. 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 Results showed that ziftomenib was well tolerated with manageable differentiation syndrome, lack of clinically significant QTc prolongation, and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06001788

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

7. kuraoncology.com kuraoncology.com/wp-content/uploads/falkenstein-ASH-2022-ziftomenib-ALL-poster-11.14.22-FINAL.pdf

Preclinical In Vivo Activity of the Menin Inhibitor Ziftomenib ... • Based upon early clinical safety and tolerability data for ziftomenib in adult patients and our pediatric-specific data described here, a phase 1 clinical ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12294120/

Therapeutic Implications of Menin Inhibitors in the ... On 15 November 2024, revumenib received the FDA approval for R/R acute leukemia (AL) with KMT2Ar in adult and pediatric patients 1 year and ...