Venetoclax + Azacitidine for Myeloproliferative Disorders

Overseen By Vikas Gupta, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Venetoclax, Azacytidine, HMAs, others

Disqualifiers: Active infection, Recent malignancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining two drugs, azacitidine and venetoclax, to treat myeloproliferative neoplasms, a type of blood cancer, particularly in its more aggressive stages. Participants will receive azacitidine (Vidaza) through skin injections and venetoclax as a daily pill in set cycles. Suitable candidates have BCR-ABL negative myeloproliferative neoplasms that have progressed to an accelerated or blast phase and have not undergone certain previous treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken certain drugs like venetoclax, azacitidine, or strong CYP3A inducers recently. It's best to discuss your current medications with the trial team.

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

Research has shown that the combination of venetoclax and azacitidine has been studied for safety. Results suggest that the safety profile of this combination aligns with what is known about each drug individually, indicating no unexpected safety issues when used together.

Venetoclax treats certain types of cancer, while azacitidine is a chemotherapy drug. Various studies have tested their combined use. Although side effects can occur, they typically resemble those seen when each drug is used separately. Common side effects include nausea or low blood cell counts, which are typical for such treatments.

In summary, previous research considers the combination of venetoclax and azacitidine safe. Participants in trials have demonstrated that the treatment's safety is predictable, with no surprises so far. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for myeloproliferative disorders?

Researchers are excited about combining Venetoclax with Azacitidine for treating myeloproliferative disorders because of its potential to enhance effectiveness over current treatments. Unlike existing therapies that may not target cancer cells directly, Venetoclax works by inhibiting the BCL-2 protein, which helps cancer cells survive. This mechanism can lead to the death of these cells, potentially offering a more targeted approach. Additionally, the use of Venetoclax in conjunction with Azacitidine could improve outcomes by attacking the cancer from multiple angles, potentially resulting in better responses and longer-lasting effects.

What evidence suggests that this treatment might be an effective treatment for myeloproliferative disorders?

Research has shown that combining venetoclax with azacitidine holds potential for treating certain advanced blood disorders. In one study, more patients experienced remission (a reduction in symptoms) with both drugs compared to azacitidine alone. Another study with a large patient group also supported these findings, showing positive results for those treated with the combination. Although some trials on different conditions did not always meet expectations, the combination has been notably successful in certain blood cancers. This trial will evaluate the effectiveness of the venetoclax and azacitidine combination for treating advanced stages of myeloproliferative disorders, but further studies are needed to confirm this. ^{2 5 6 7 8}

Who Is on the Research Team?

Vikas Gupta, M.D.

Principal Investigator

Princess Margaret Cancer Centre

Are You a Good Fit for This Trial?

This trial is for adults with advanced BCR-ABL negative myeloproliferative neoplasms who haven't had blast reduction therapy for their condition. They should be able to perform daily activities with ease to moderate difficulty (ECOG 0-2) and have good organ function. Participants must not be pregnant, breastfeeding, or have a recent history of other cancers or serious health conditions that could affect study participation.

Inclusion Criteria

My blood disorder diagnosis follows WHO 2016 criteria and is not caused by the BCR-ABL gene.

I am a woman who can have children and have a negative pregnancy test within the last 14 days.

My organs are working well.

Exclusion Criteria

I have had a stem cell transplant from a donor for my blood disorder.

I have had treatment to reduce blood cell precursors for myeloproliferative neoplasm.

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

Safety Run-In Period

7 participants will receive the study drugs to ensure that the combination is safe and tolerable

4 weeks

1 visit (in-person) per week

Stage 1

About 15 participants will receive the study drugs and will be evaluated to see whether they respond to the study drugs

4 weeks

1 visit (in-person) per week

Stage 2

An additional 25 participants will take part in the study to further see if participants respond to the study drugs

4 weeks

1 visit (in-person) per week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Venetoclax

Trial Overview The study tests the safety and effectiveness of combining two drugs, Venetoclax and Azacitidine, in treating accelerated or blast phase myeloproliferative neoplasms. It aims to understand how well these drugs work together for patients who haven't received prior treatment specifically aimed at reducing blasts in their blood.

How Is the Trial Designed?

Group I: Azacitidine and Venetoclax Experimental Treatment 2 Interventions

A treatment cycle is 28 days long. Azacitidine will be given by injection under the skin, once a day, for the first 6 days of every cycle. Venetoclax will be given orally, once a day, as follows at the discretion of their study doctors: Cycle 1: * Day 1 - 100 mg * Day 2 - 200 mg * Days 3 to 28 - 400 mg Cycle 2: * Participants with a response to the study drugs will continue taking 400 mg from Days 1 to 21, with no study drug from Days 22 to 28 during Cycle 2. * Participants who have not yet responded to the study drugs will continue taking 400 mg from Days 1 to 28 during Cycle 2. Cycle 3 and subsequent cycles: * Participants with a response to the study drugs will continue to take 400 mg from Days 1 to 21, with no study drug from Days 22 to 28. * Participants whose disease has not worsened will continue taking 400 mg from Days 1 to 28. * Participants have not responded to the study drugs will be withdrawn from the study.

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?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

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 1b study involving 44 patients with relapsed/refractory higher-risk myelodysplastic syndromes (MDS), the combination of venetoclax and azacitidine demonstrated significant activity, with a median overall survival of 12.6 months after prior treatment failure with hypomethylating agents.

The treatment resulted in hematological improvements, including complete remission in 7% of patients and transfusion independence in 36%, indicating that venetoclax plus azacitidine can provide meaningful clinical benefits for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Zeidan, AM., Borate, U., Pollyea, DA., et al.[2023]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

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]

In a study of 57 elderly patients (average age 69.9 years) with acute myeloid leukemia, the combination of venetoclax and azacitidine (VEN + AZA) showed a high overall response rate of 87.5% and a complete remission (CR) rate of 68.8%, indicating strong efficacy in this population.

The treatment was associated with a median overall survival (OS) of 11.5 months, and achieving minimal residual disease (MRD) negativity (<0.1%) was more common with VEN + AZA compared to traditional chemotherapy, although older patients (≥75 years) and those with higher ECOG scores faced more challenges in achieving MRD negativity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-institution experience of venetoclax combined with azacitidine in newly diagnosed acute myeloid leukemia patients. Yu, H., Wang, C., Lei, Y., 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]

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]

Citations

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Venetoclax with azacitidine or decitabine in blast‐phase ... The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast‐phase ...

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NCT04401748 | Study Of Venetoclax Tablet With ... The purpose of this study is to see how safe and effective venetoclax and azacitidine (AZA) combination are when compared to AZA and a placebo (contains no ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000177

Real-world outcomes of newly diagnosed AML treated with ... Here we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n=587) or LDAC (n=67).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10100228/

A phase 1b study of venetoclax and azacitidine ... In this phase‐1b study, we evaluated the safety of venetoclax either alone or in combination with azacitidine therapy after HMA failure. Due to the limited ...

7. ashpublications.org ashpublications.org/ashclinicalnews/news/8514/A-Study-Evaluating-Safety-and-Efficacy-of

A Study Evaluating Safety and Efficacy of Venetoclax in ... A study evaluating safety and efficacy of venetoclax in combination with azacitidine versus standard of care after allogeneic stem cell transplant.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04160052

Venetoclax and Azacitidine for the Treatment of High-Risk ... Safety data will be summarized by category, severity, and frequency. Up to 5 years. Secondary Outcome Measures. Outcome Measure, Measure Description, Time Frame ...