Azacitidine + Venetoclax + Gilteritinib for Leukemia

Overseen By Nicholas Short

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers

Disqualifiers: Active infection, Cardiac failure, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 cycles (approximately 2 years)

97 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs—azacitidine, venetoclax, and gilteritinib—to evaluate their effectiveness against certain blood cancers, such as acute myeloid leukemia (AML), especially in cases that have recurred or resisted previous treatments. The trial aims to determine the optimal dose and monitor side effects. Individuals with specific mutations in their leukemia cells, particularly FLT3 mutations, may be suitable candidates, especially if their condition has returned or not improved with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you should avoid certain drugs like carbamazepine, phenytoin, rifampin, and St. John's wort within 3 days of starting the study. It's best to discuss your current medications with the study team to ensure safety and compatibility.

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

Research has shown that azacitidine and venetoclax are generally well-tolerated by patients with acute myeloid leukemia (AML). These medications can cause side effects, such as low blood cell counts and nausea, but these are usually manageable.

Gilteritinib, another drug in this trial, has been used in other studies for AML treatment and has similar side effects, with low blood counts being the most common.

Since this trial is in the early stages (phase 1/2), it primarily focuses on safety and patient response to the treatment. These studies are crucial for understanding how these drugs work together and what side effects might occur. Doctors can adjust doses to help manage any side effects if needed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of azacitidine, venetoclax, and gilteritinib for treating leukemia because it targets cancer cells from multiple angles. Azacitidine works by reactivating genes that suppress tumor growth, while venetoclax disrupts the energy production of cancer cells, making them more susceptible to treatment. Gilteritinib is especially appealing as it specifically targets FLT3 mutations found in some leukemia cases, which are often aggressive and hard to treat. Together, these drugs offer a more comprehensive attack on leukemia cells compared to traditional therapies, potentially leading to better outcomes for patients.

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

Research has shown that combining azacitidine, venetoclax, and gilteritinib, as studied in this trial, may effectively treat certain blood cancers. Studies have found that this combination can lead to high response rates in patients with a specific type of acute myeloid leukemia (AML) that has a FLT3 mutation. Gilteritinib blocks enzymes that cancer cells need to grow, potentially leading to better results than using just azacitidine and venetoclax. Azacitidine stops cancer cells from dividing, while venetoclax targets a protein that helps cancer cells survive. These findings suggest that this combination could be more effective in fighting these challenging conditions. ^{5 6 7 8 9}

Who Is on the Research Team?

Nicholas Short

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with FLT3-mutated acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that's recurrent or refractory. Participants need a performance status of <=3 on the ECOG scale and adequate liver and kidney function. Exclusions include long QT syndrome, active central nervous system leukemia, HIV/hepatitis B/C infection, pregnancy/breastfeeding women, and those unwilling to use contraception.

Inclusion Criteria

Signed informed consent

My leukemia has FLT3 mutations.

I am an adult with newly diagnosed AML that has a FLT3 mutation.

Exclusion Criteria

I am HIV positive.

I can have had any number of previous treatments.

My leukemia has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azacitidine, venetoclax, and gilteritinib. Azacitidine is administered SC or IV on days 1-7, venetoclax PO on days 1-28 of cycle 1 and days 1-21 of subsequent cycles, and gilteritinib PO on days 1-28. Treatment repeats every 28 days for up to 24 cycles.

Up to 24 cycles (approximately 2 years)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days post-treatment and every 6 months thereafter.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Gilteritinib
• Venetoclax

Trial Overview The trial is testing how well gilteritinib works with azacitidine and venetoclax in treating certain blood cancers with FLT3 mutation. It aims to find the best dose of gilteritinib for effectiveness when combined with these chemotherapy drugs compared to using azacitidine and venetoclax alone.

How Is the Trial Designed?

Group I: Treatment (azacitidine, venetoclax, gilteritinib) Experimental Treatment 3 Interventions

Patients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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+

Published Research Related to This Trial

Venetoclax, when combined with azacitidine, has shown effectiveness in treating a 73-year-old patient with acute myeloid leukemia (AML) who was undergoing dialysis and ineligible for standard therapies.

The combination of venetoclax and azacitidine appears to be a safe and feasible treatment option for AML patients with comorbidities, such as those requiring dialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. Akagi, Y., Yamashita, Y., Kosako, H., et al.[2023]

The combination of venetoclax and hypomethylating agents (VEN+HMA) has shown promising efficacy in treating FLT3-mutated acute myeloid leukemia (AML), particularly in newly diagnosed and relapsed patients, but some patients with the FLT3-ITD mutation did not respond to this treatment.

This study is the first to explore the safety and effectiveness of combining gilteritinib, a targeted FLT3 inhibitor, with venetoclax in two AML patients who were unresponsive to the standard VEN+AZA therapy, suggesting a potential new treatment avenue for FLT3-ITD mutated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid and Efficient Response to Gilteritinib and Venetoclax-Based Therapy in Two AML Patients with FLT3-ITD Mutation Unresponsive to Venetoclax Plus Azacitidine. Zhang, LS., Wang, J., Xu, MZ., 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 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]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

The combination of venetoclax and gilteritinib showed a high modified composite complete response (mCRc) rate of 75% in patients with FLT3-mutated acute myeloid leukemia (AML), indicating strong efficacy regardless of prior FLT3 inhibitor treatment.

While the treatment was effective, it also led to significant side effects, particularly cytopenias, prompting dose interruptions in about half of the patients, highlighting the need for careful monitoring and management of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia. Daver, N., Perl, AE., Maly, J., et al.[2023]

In a study involving 272 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), higher concentrations of venetoclax led to a quicker reduction in lymphocyte counts and tumor size, resulting in a high objective response rate (ORR) of 84.8% at a daily dose of 400 mg.

Importantly, increasing the dose of venetoclax did not correlate with a higher risk of serious adverse events like neutropenia or infections, suggesting that the 400 mg daily regimen is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Freise, KJ., Jones, AK., Eckert, D., et al.[2018]

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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11095865/

Azacitidine, Venetoclax, and Gilteritinib in Newly ... The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML.

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6060/526383/Azacitidine-and-Venetoclax-Followed-By-Sequential

Azacitidine and Venetoclax Followed By Sequential Gilteritinib ... Azacitidine and Venetoclax Followed By Sequential Gilteritinib Is an Effective Alternative in Very Frail Patients with FLT3-Mutated Acute ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04140487

NCT04140487 | Azacitidine, Venetoclax, and Gilteritinib in ... Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, ...

4. cancernetwork.com cancernetwork.com/view/azacitidine-combo-shows-high-response-rates-in-flt3-mutated-aml

Azacitidine Combo Shows High Response Rates in FLT3 ... A phase 1/2 study found that using azacitidine, venetoclax, and gilteritinib for patients with FLT3-mutated acute myeloid leukemia yielded high rates of ...

5. clinicaltrials.astellas.com clinicaltrials.astellas.com/study/2215-CL-0203

A study of gilteritinib, venetoclax and azacitidine as ... Gilteritinib, given with venetoclax and azacitidine, is a potential new treatment for people with AML with the changed FLT3 gene.

6. link.springer.com link.springer.com/article/10.1007/s00277-025-06643-0

Efficacy and safety of venetoclax plus azacitidine based ... This meta-analysis aimed to evaluate the efficacy and safety of venetoclax plus azacitidine (VEN + AZA) regimens in patients with relapsed ...

7. researchgate.net researchgate.net/publication/396986199_Efficacy_and_safety_of_venetoclax_plus_azacitidine_based_regimens_in_the_treatment_of_relapsed_or_refractory_acute_myeloid_leukemia_a_systematic_review_and_meta-analysis

(PDF) Efficacy and safety of venetoclax plus azacitidine ... This meta-analysis aimed to evaluate the efficacy and safety of venetoclax plus azacitidine (VEN + AZA) regimens in patients with relapsed ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12135334/

Efficacy and safety of venetoclax and azacitidine for acute ... Venetoclax (VEN) and azacitidine (AZA) are used to treat patients with newly diagnosed acute myeloid leukaemia (AML) who are unfit for intensive ...

9. clinicaltrial.be clinicaltrial.be/en/details/13943?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

A Study to Assess Change in Disease State in Adult Partic... This study will evaluate how well venetoclax in combination with azacitidine works to treat AML in adult participants in Colombia. Venetoclax in ...