Quizartinib + Decitabine + Venetoclax for Acute Myeloid Leukemia

Overseen By Musa Yilmaz

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Uncontrolled CNS leukemia, Diabetes, Cardiovascular disease, 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

73 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—quizartinib (a type of targeted therapy), decitabine, and venetoclax—to evaluate their effectiveness in treating acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), particularly if the disease is untreated or has recurred. These drugs work in different ways to stop cancer cells from growing, dividing, or spreading. Suitable candidates for this trial include those with AML or MDS who cannot undergo more intensive chemotherapy or have experienced frequent relapses and possess specific genetic markers, such as the FLT3-ITD mutation. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain drugs that affect the heart's rhythm or strong CYP3A4 inhibitors (a type of enzyme that affects drug metabolism). It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research is investigating the safety of a combination of three drugs—quizartinib, decitabine, and venetoclax—for treating acute myeloid leukemia. In earlier studies, 78% of patients who received this treatment achieved a complete response, meaning their cancer showed no signs of returning. However, like many cancer treatments, some side effects occurred, such as low blood cell counts and infections. These studies aim to find the right balance between effectively treating the cancer and reducing these side effects. As this trial is in its early stages, researchers are still learning about the treatment's safety and patient tolerance. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of quizartinib, decitabine, and venetoclax for treating acute myeloid leukemia (AML) because this trio targets the cancer in a unique way. Unlike standard treatments that mainly focus on chemotherapy, this combination includes quizartinib, which specifically targets a mutation in the FLT3 gene, a common driver of AML. Venetoclax works by inhibiting a protein that helps cancer cells survive, potentially making the treatment more effective in killing leukemia cells. Additionally, decitabine helps to boost the effectiveness of these drugs by altering the cancer cell's DNA, making it easier to eliminate them. This multi-pronged approach aims to tackle the disease from different angles, offering hope for better outcomes.

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

Research has shown that a combination of three drugs—quizartinib, decitabine, and venetoclax—may help treat acute myeloid leukemia (AML). In studies with patients who had not previously used FLT3 inhibitors, 71% achieved a complete response, meaning no signs of cancer were found. Another study indicated that patients with a specific mutation called FLT3-ITD had a 78% complete response rate with this treatment. This suggests that the combination can effectively stop leukemia cells from growing. The average survival time for patients using this combination ranged from 7.6 to 10.3 months, highlighting its potential benefits. Participants in this trial will receive this combination treatment to further evaluate its effectiveness and safety. ^{1 2 3 4 6}

Who Is on the Research Team?

Musa Yilmaz

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with untreated or relapsed Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS). Eligible participants include those over 60 not fit for intensive therapy, under 60 with poor risk factors, and must have specific genetic mutations. They should be able to take oral medication and not have severe medical conditions or allergies related to the drugs tested.

Inclusion Criteria

I have not received chemotherapy for my condition.

I can take certain medications during the study.

I am generally healthy, can take pills, understand and agree to the study, not pregnant, and not on experimental drugs.

Exclusion Criteria

I have previously used quizartinib.

I do not have other severe illnesses or cancers.

Known allergy or hypersensitivity to specific components

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine intravenously over 1 hour on days 1-10, quizartinib orally every day beginning on day 1 of cycle 1, and venetoclax orally on days 1-14 (days 1-21 if persistent leukemia). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3-6 months for up to 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Quizartinib
• Venetoclax

Trial Overview The study tests a combination of quizartinib, decitabine, and venetoclax in patients with AML/MDS. Quizartinib targets enzymes that cancer cells need to grow while decitabine and venetoclax are chemotherapy drugs aimed at stopping cancer cell growth by various mechanisms.

How Is the Trial Designed?

Group I: Treatment (decitabine, quizartinib, venetoclax) Experimental Treatment 3 Interventions

Patients receive decitabine IV over 1 hour on days 1-10, quizartinib PO every day beginning on day 1 of cycle 1, and venetoclax PO on days 1-14 (days 1-21 if persistent leukemia). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen 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+

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

A case of early-relapsed high-risk T-cell acute lymphoblastic leukemia (T-ALL) with high BCL-2 expression was successfully treated with a combination of decitabine and venetoclax, leading to complete remission (CR).

The results suggest that decitabine and venetoclax may work synergistically in treating BCL-2 positive acute lymphoblastic leukemia, indicating a potential new therapeutic strategy for this high-risk group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Zappone, E., Cencini, E., Defina, M., et al.[2020]

In a study of 22 heavily pre-treated patients with relapsed or refractory acute myeloid leukaemia (RR-AML), the combination of venetoclax and decitabine resulted in a 45.5% overall response rate, with 40.9% achieving complete remission, demonstrating its efficacy in a real-world setting.

While the treatment was effective, it was associated with significant side effects, including grade IV neutropenia and thrombocytopenia in all patients, but no deaths were attributed to the treatment side effects, indicating that the adverse effects were manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. Tong, J., Zhao, N., Hu, X., et al.[2022]

In a study involving 145 older patients (median age 74) with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of venetoclax with decitabine or azacitidine resulted in a high complete remission (CR) rate of 67%, demonstrating its efficacy in this challenging population.

The treatment was well tolerated, with no cases of tumor lysis syndrome reported, and the median overall survival was 17.5 months, indicating that venetoclax combined with hypomethylating agents is a promising option for elderly patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. DiNardo, CD., Pratz, K., Pullarkat, V., et al.[2021]

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 phase 2 trial involving 168 patients with acute myeloid leukaemia (AML), the combination of venetoclax and a 10-day regimen of decitabine resulted in a high overall response rate of 74%, with particularly impressive results in newly diagnosed AML patients (89%).

The treatment demonstrated a manageable safety profile, with common adverse events including neutropenia and infections, and a 30-day mortality rate of only 3.6%, indicating that this combination therapy is both effective and relatively safe for older patients or those unfit for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. DiNardo, CD., Maiti, A., Rausch, CR., et al.[2021]

In a study of 118 patients with acute myeloid leukemia (AML), those with TP53 mutations had significantly worse outcomes when treated with a combination of decitabine and venetoclax, showing lower response rates (66% vs 89%) and higher 60-day mortality (26% vs 4%) compared to patients without TP53 mutations.

Patients with TP53-mutant AML had a median overall survival of only 5.2 months, compared to 19.4 months for those with wild-type TP53, indicating that TP53 mutations confer a poor prognosis even with current treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax. Kim, K., Maiti, A., Loghavi, S., et al.[2023]

In a study comparing older adults with newly diagnosed acute myeloid leukemia (AML), those treated with the combination of decitabine (DEC) and venetoclax (VEN) had a significantly longer median overall survival of 13.4 months compared to 8.3 months for those receiving DEC alone.

The combination therapy also resulted in a higher response rate of 70.3% versus 24.3% for DEC monotherapy, indicating that DEC+VEN is more effective in treating AML without increasing short-term mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax with decitabine versus decitabine monotherapy in elderly acute myeloid leukemia: a propensity score-matched analysis. Kwag, D., Cho, BS., Bang, SY., et al.[2022]

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 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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4263/533525/Phase-I-II-Study-of-Quizartinib-Venetoclax-and

Phase I/II Study of Quizartinib, Venetoclax, and Decitabine ... Among the seven prior FLT3 inhibitor naïve pts the CRc, CR+CRi, median OS and 1-year OS were 71%, 57%, 10.3 months and 28%. We enrolled 19 newly ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.7036

Quizartinib (QUIZ) with decitabine (DAC) and venetoclax ... DAC + VEN + QUIZ is active in R/R FLT3-ITD mutated AML pts, with CRc rates of 78% and the median OS of 7.6 months.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03661307

NCT03661307 | Quizartinib, Decitabine, and Venetoclax in ... This phase I/II trial studies how well quizartinib, decitabine, and venetoclax work in treating participants with acute myeloid leukemia or high risk ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124070216

Phase I/II Study of Quizartinib, Venetoclax, and Decitabine ... Results: A total of 66 pts were enrolled, including 47 R/R and 19 newly FLT3-ITD mutated AML pts. A detailed demographic data will be reported ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11572082/

Quizartinib: a new hope in acute myeloid leukemia, an applied ... The findings of this study indicated that using Quizartinib as a single treatment had a notable advantage in terms of patient survival compared with SC in ...

6. journals.lww.com journals.lww.com/hemasphere/fulltext/2022/06003/s127__quizartinib_with_decitabine_and_venetoclax.28.aspx

s127: quizartinib with decitabine and venetoclax (triplet) is ... Summary/Conclusion: DAC + VEN + QUIZ is active in R/R FLT3-ITD mutated AML pts, with CRc rates of 78% and the median OS of 7.6 months. The high response rate ...