Venetoclax with Chemotherapy for AML and MDS

Recruiting in Palo Alto (17 mi)

Overseen by Jacqueline S. Garcia, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Jacqueline Garcia, MD

Must not be taking: Chemotherapy, Radiotherapy, Investigational therapy

Disqualifiers: Active heart disease, CNS involvement, others

No Placebo Group

Breakthrough Therapy

Trial Summary

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.

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}

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

Trial 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 (Anti-metabolites)
• Busulfan (Alkylating agents)
• Decitabine/cedazuridine (Anti-metabolites)
• Fludarabine (Anti-metabolites)
• Venetoclax (BCL-2 Inhibitor)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Dana-Farber Cancer Institute Boston, MA

Who Is Running the Clinical Trial?

Jacqueline Garcia, MD

Lead Sponsor

Trials

3

Patients Recruited

130+

National Institutes of Health (NIH)

Collaborator

Trials

2896

Patients Recruited

8,053,000+

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] The effectiveness of venetoclax (VEN) in relapsed or refractory acute myeloid leukemia (RR-AML) has not been well established. This retrospective, multicenter, observational database studied the effectiveness of VEN in a cohort of 51 RR-AML patients and evaluated for predictors of response and overall survival (OS). The median age was 68 years, most were at high risk, 61% received ≥2 therapies for AML, 49% had received hypomethylating agents, and ECOG was ≥2 in 52%. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi), was 12.4%. Additionally, 10.4% experienced partial response (PR). The CR/CRi was higher in combination with azacitidine (AZA; 17.9%) than with decitabine (DEC; 6.7%) and low-dose cytarabine (LDAC; 0%). Mutated NPM1 was associated with increased CR/CRi. Median OS was 104 days (95% CI: 56-151). For the combination with AZA, DEC, and LDAC, median OS was 120 days, 104 days, and 69 days, respectively; p = 0.875. Treatment response and ECOG 0 influenced OS in a multivariate model. A total of 28% of patients required interruption of VEN because of toxicity. Our real-life series describes a marginal probability of CR/CRi and poor OS after VEN-based salvage. Patients included had very poor-risk features and were heavily pretreated. The small percentage of responders did not reach the median OS.

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] The meta-analysis sought to evaluate the efficacy and safety of a combination of venetoclax (Ven) and azacitidine (AZA) in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

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

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023] Venetoclax is a treatment option in patients with acute myeloid leukemia (AML) in both the front-line and relapsed/refractory settings. Initiation of therapy has been previously restricted to the inpatient setting at some institutions due to a risk of tumor lysis syndrome (TLS) and limitations in medication access efficiency given the high cost of therapy.

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] Evidence that a venetoclax (VEN)-combined regimen is effective in relapsed/refractory acute myeloid leukemia (R/R AML) is emerging. However, it is unknown how VEN-combined low intensity treatment compares to intensive chemotherapy (IC) in medically fit patients with R/R AML.

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

Venetoclax is safe and efficacious in relapsed/refractory AML. [2021] Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.

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] To investigate the efficacy and safety of venetoclax (VEN) combined with demethylating agents (HMA) in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML).

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] Venetoclax is a selective B-cell lymphoma 2 (BCL2) inhibitor, which is approved to treat elderly patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in combination with either low-dose cytarabine (ARA-C) or hypomethylating agents. We aimed to collect and share data among the efficacy and safety of venetoclax both as a monotherapy or in combination with other drugs used to treat high-risk MDS or AML.

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

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? [2021] Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082-3. ©2016 AACR.See related article by Konopleva and colleagues, p. 1106.