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

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm.

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.

What data supports the effectiveness of the drug combination Azacitidine, Venetoclax, and Gilteritinib for leukemia?

Research shows that the combination of Venetoclax and Azacitidine improves remission rates and survival in older or unfit patients with acute myeloid leukemia compared to Azacitidine alone. Additionally, the combination significantly prolonged overall survival in patients ineligible for intensive chemotherapy. ^{1 2 3 4 5}

Is the combination of Azacitidine, Venetoclax, and Gilteritinib safe for humans?

Venetoclax has an acceptable safety profile for patients with certain types of leukemia, and Gilteritinib is a standard therapy for specific leukemia mutations. The combination of these drugs has been studied in patients with acute myeloid leukemia, showing potential safety and response, although specific safety data for the exact combination with Azacitidine is limited. ^{1 6 7 8 9}

What makes the drug combination of Azacitidine, Venetoclax, and Gilteritinib unique for treating leukemia?

This drug combination is unique because it combines three different agents: Azacitidine, which is a hypomethylating agent, Venetoclax, a B-cell lymphoma-2 inhibitor, and Gilteritinib, a FLT3 inhibitor, potentially offering a more comprehensive approach to treating acute myeloid leukemia, especially in patients who are older or have other health issues that make them ineligible for standard chemotherapy. ^{1 2 3 5 10}

Research Team

Nicholas Short

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

My leukemia has FLT3 mutations.

Signed informed consent

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

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

TP53 or Not TP53: That Is the Question. [2023]

3. 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]

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

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

5. 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]

6. New Zealand 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. [2022]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

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

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. [2018]

10. United States 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. [2023]