Venetoclax with Chemotherapy for AML and MDS

Overseen By Jacqueline S. Garcia, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jacqueline Garcia, MD

Must not be taking: Chemotherapy, Radiotherapy, Investigational therapy

Disqualifiers: Active heart disease, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding Venetoclax, a study drug, to chemotherapy can help treat certain blood cancers. It focuses on individuals with conditions like Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) who are preparing for a bone marrow transplant. The trial aims to determine if Venetoclax can eliminate residual cancer before the transplant and help prevent its recurrence afterward. Individuals diagnosed with high-risk AML, MDS, or similar conditions and planning for a bone marrow transplant might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on venetoclax, you need a three-day break before starting the study. If you are on BCR-ABL, IDH, or FLT3 inhibitors, you can continue them until five days before the study starts.

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

Research has shown that venetoclax is usually well-tolerated, but it can cause side effects. Common issues include low blood cell counts, stomach problems, and infections, which might require a pause or change in dosage. Studies indicate that busulfan is safe when used with fludarabine, often resulting in long-lasting remission for patients with AML (a type of blood cancer) and MDS (a blood disorder). Fludarabine is known to be safe and is commonly used in these treatments. Azacitidine can help MDS patients live longer, though it may cause side effects like low blood cell counts and other reactions. Decitabine/cedazuridine is taken by mouth and is designed to be safe, but it can still lead to hospital stays or other issues. Overall, these treatments have safety data, but like all medications, they can have side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the venetoclax and chemotherapy combination for treating AML (Acute Myeloid Leukemia) and MDS (Myelodysplastic Syndromes) because it targets cancer cells in a novel way. Venetoclax is a BCL-2 inhibitor, which means it specifically works by promoting the death of cancer cells that rely on the BCL-2 protein for survival. This is different from standard chemotherapy, which generally targets rapidly dividing cells without such specificity. Additionally, integrating venetoclax with post-transplant therapies like azacitidine or decitabine/cedazuridine could enhance the effectiveness and potentially improve outcomes for patients. This approach offers a promising new avenue for managing these challenging blood cancers.

What evidence suggests that Venetoclax with chemotherapy could be effective for AML and MDS?

Research has shown that Venetoclax, one of the treatments in this trial, is promising for treating blood cancers when combined with azacitidine. In earlier studies, about 62% of patients responded to this treatment, and 27% achieved complete remission. Venetoclax blocks a protein called BCL-2, which helps cancer cells survive, thereby promoting their death. Azacitidine, another treatment option in this trial, is often used for certain bone marrow disorders and has been shown to extend patient survival. Studies also suggest that combining Venetoclax with azacitidine can enhance treatment effectiveness for acute myeloid leukemia (AML). Additionally, Venetoclax with decitabine/cedazuridine is being studied for its potential in treating AML and related disorders. ^{1 5 6 7 8}

Who Is on the Research Team?

Jacqueline S. Garcia, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults diagnosed with AML, MDS, CMML, or MDS/MPN who are suitable for a bone marrow transplant using reduced intensity conditioning. They must have an ECOG performance status ≤ 2 (which means they can do some activity), adequate blood counts without recent transfusions, no severe acute GVHD if on low-dose prednisone, normal liver and kidney function tests, agree to use contraception during the study and understand the consent form. Excluded are those with prior transplants, untreated brain involvement of disease, certain dietary restrictions before treatment starts (like grapefruit), malabsorption issues that affect oral drug intake, active heart disease in last 6 months or uncontrolled infections.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

My organs are functioning normally.

Agreement to use adequate contraception

Exclusion Criteria

I cannot take medicine by mouth due to a digestive condition.

Known active hepatitis B or C virus infection

Pregnancy, breastfeeding, or intention to become pregnant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Transplant Conditioning

Participants receive Venetoclax in combination with conditioning chemotherapy (FluBu2) prior to transplantation to eliminate leftover blood cancer cells.

1 week

Daily visits for chemotherapy administration

Transplantation

Participants undergo allogeneic hematopoietic stem cell transplantation.

1 week

Inpatient stay for transplantation

Post-Transplant Maintenance Therapy

Participants receive maintenance therapy with Venetoclax and either azacitidine or oral decitabine/cedazuridine to potentially reduce the chance of disease relapse.

8-12 months

Monthly visits for maintenance therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment.

12 months

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Busulfan
• Decitabine/cedazuridine
• Fludarabine
• Venetoclax

Trial Overview The trial is testing Venetoclax added to Fludarabine + Busulfan as pre-transplant conditioning therapy and combined with Azacitidine or Decitabine/Cedazuridine post-transplant as maintenance therapy. The aim is to see if these combinations can safely eliminate remaining leukemia cells before transplant and prevent recurrence after.

How Is the Trial Designed?

Group I: Venetoclax Experimental Treatment 5 Interventions

Part 1 dose escalation * Venetoclax: 6-7 total doses based on level assigned * Busulfan: given 2x daily for 4 days * Fludarabine: given 1x daily for 4 days Part 2 includes post-transplant therapy with azacitidine and venetoclax for 8-12 cycles per dose level. Part 3 includes post-transplant therapy with oral decitabine/cedazuridine and venetoclax for 8 cycles. Part 4 assesses PTCy/Tac/MMF GVHD regimen instead of Tac/Methotrexate -post transplant period includes therapy with azacitidine and venetoclax for 8 cycles.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

Jacqueline Garcia, MD

Lead Sponsor

Trials

3

Recruited

130+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In a study comparing treatment regimens for relapsed/refractory acute myeloid leukemia (R/R AML), the venetoclax (VEN) combination therapy showed a comparable overall response rate (59.3%) to intensive chemotherapy (IC) (44.0%), suggesting it is an effective alternative for patients who have failed previous treatments.

Patients receiving the VEN combination had a significantly higher percentage of successful stem cell transplants at blast clearance (86.5% vs. 62.3% for IC), indicating better disease control and potentially lower treatment-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective comparison of salvage intensive chemotherapy versus venetoclax-combined regimen in patients with relapsed/refractory acute myeloid leukemia (AML). Park, S., Kwag, D., Kim, TY., et al.[2022]

In a study of 26 adult patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of venetoclax (VEN) with demethylating agents (azacitidine or decitabine) resulted in a 57.7% overall response rate, including 13 complete responses, indicating its efficacy as a salvage therapy.

Patients who achieved minimal residual disease negativity had significantly better overall survival and event-free survival, highlighting the importance of this outcome in improving long-term prognosis for R/R AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. Wang, Y., Huang, SL., Zhang, XX., et al.[2023]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

Venetoclax is an oral medication with a favorable side-effect profile that shows promise in treating acute myeloid leukemia (AML), particularly for patients with refractory or relapsed cases.

This drug can serve as a bridge to hematopoietic cell transplant for curative treatment and may significantly extend survival for older patients who cannot tolerate more aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? Pullarkat, VA., Newman, EM.[2021]

In a study of 60 patients with high-risk MDS and AML, venetoclax demonstrated a 35% overall response rate, indicating its efficacy as a treatment option for these conditions.

However, the treatment was associated with significant hematologic toxicity, with 86.7% of patients experiencing grade 2 or higher side effects, and infections, particularly pneumonia, being the most common nonhematologic complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. Gemici, A., Ozkalemkas, F., Dogu, MH., et al.[2022]

In a study of 51 patients with relapsed or refractory acute myeloid leukemia (RR-AML), venetoclax (VEN) showed a low complete remission (CR) rate of 12.4%, indicating limited effectiveness in this heavily pretreated population.

The median overall survival (OS) for patients treated with VEN was only 104 days, with 28% of patients experiencing treatment interruptions due to toxicity, highlighting the challenges and risks associated with this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia: The PETHEMA Registry Experience. Labrador, J., Saiz-Rodríguez, M., de Miguel, D., et al.[2022]

In a retrospective study of 40 patients with relapsed/refractory acute myeloid leukemia (AML) treated with venetoclax, 76% of those who survived more than two cycles achieved neutrophil recovery, indicating a positive response to the treatment.

Venetoclax demonstrated safety and efficacy in advanced AML, with a median overall survival of 5.5 months for all patients and 6.5 months for those who survived beyond two months, suggesting it can be a viable option for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax is safe and efficacious in relapsed/refractory AML. Ganzel, C., Ram, R., Gural, A., et al.[2021]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine has been reported to prolong survival in MDS patients. Azacitidine has been studied in different dosing schedules and combination therapies with the ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2152265023021973

Real-world Effectiveness of Azacitidine in Treatment-Naive ... The real-world outcomes from AZA have been lower than expected with a registry of the Spanish cooperative group on MDS reporting a median OS of 13.4 months from ...

3. hematologyadvisor.com hematologyadvisor.com/news/combination-azacitidine-venetoclax-acute-myeloid-leukemia-aml-treatment-risk/

Combination Azacitidine, Venetoclax Effective in AML ... Analysis showed that the overall response rates in the azacitidine plus venetoclax, chemotherapy, and azacitidine monotherapy groups were 38.5%, ...

4. ashpublications.org ashpublications.org/hematology/article/2023/1/65/506420/Frontline-treatment-options-for-higher-risk-MDS

Frontline treatment options for higher-risk MDS: can we move ... Real-world data from numerous trials have shown similar results with a median overall survival of 14-18 months, a 40%-50% overall response rate, ...

5. mdpi.com mdpi.com/2072-6694/16/7/1333

Real-World Outcome and Prognostic Factors in MDS ... Azacitidine (AZA) is recognized as a vital drug used in the therapy of myelodysplastic syndromes (MDS) due to its beneficial effect on survival ...

6. hematologyadvisor.com hematologyadvisor.com/news/azacitidine-myelodysplastic-syndrome-mds-adverse-events-safety-concerns/

New Adverse Events Highlight Safety Concerns With ... An analysis of 2 pharmacovigilance databases revealed a high prevalence of azacitidine-related adverse events in patients with MDS or AML.

7. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... The AZA-001 phase 3 study demonstrated that azacitidine prolonged survival of patients with HR MDS ineligible for SCT to 24.5 vs 15 months with ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118587462

Efficacy and Safety of Azacitidine (AZA) in Combination ... Conclusions: To our knowledge, this is the first large randomized trial of AZA with or without ICP blockade in older unfit AML and HR-MDS pts reported to date.