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

102 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Venetoclax with chemotherapy for AML and MDS?

Research shows that combining Venetoclax with azacitidine can lead to complete remission in some patients with relapsed or refractory acute myeloid leukemia (AML), with a higher response rate compared to other combinations. Additionally, a study found that 52% of patients who survived more than two months achieved complete remission or remission with incomplete blood recovery. ^{1 2 3 4 5}

Is Venetoclax with chemotherapy safe for treating AML and MDS?

Venetoclax, when used with chemotherapy for treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), has been generally considered safe, though some patients may experience side effects that require stopping the treatment. There is a risk of tumor lysis syndrome (TLS), a condition where cancer cells break down too quickly, which is why careful monitoring is needed. ^{1 3 5 6 7}

What makes the drug Venetoclax with chemotherapy unique for treating AML and MDS?

Venetoclax is unique because it targets a specific protein in cancer cells, potentially making it more effective for certain patients with acute myeloid leukemia (AML), especially those who are not candidates for aggressive treatments. It can be used in combination with chemotherapy and has shown promise in improving survival for older patients or those with relapsed/refractory AML. ^{1 3 4 5 8}

What is the purpose of this trial?

This clinical trial involves individuals who have been diagnosed with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), or MDS/myeloproliferative neoplasm-unclassifiable (MDS/MPN-unclassifiable) and are planning to have an allogeneic hematopoietic stem cell transplant ("bone marrow transplant"). The goal of this research study is to (1) test the safety of adding the study drug, Venetoclax, to a standard of care conditioning regimen for bone marrow transplantation as a possible means of eliminating residual (left-over) disease prior to transplant, (2) to test the safety of combination Venetoclax and azacitidine as "maintenance therapy" after transplant to possibly prevent disease recurrence and (3) to test the safety of combination Venetoclax and oral decitabine/cedazuridine as "maintenance therapy" after transplant to possibly prevent disease recurrence. * The name of the study drug involved in this study is Venetoclax. * It is expected that about 102 people will take part in this research study.

Research Team

Jacqueline S. Garcia, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

Agreement to use adequate contraception

My organs are functioning normally.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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 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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Use of Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia: The PETHEMA Registry Experience. [2022]

2. England 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]

4. England 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). [2022]

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

Venetoclax is safe and efficacious in relapsed/refractory AML. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical Observation of Venetoclax Combined with Demethylating Agents on the Treatment of Relapsed/Refractory Acute Myeloid Leukemia]. [2023]

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

A Real-life Turkish Experience of Venetoclax Treatment in High-risk Myelodysplastic Syndrome and Acute Myeloid Leukemia. [2022]

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

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? [2021]