Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 79 trial locations

Overseen By Michel Zwaan

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: LLS PedAL Initiative, LLC

Must not be taking: CYP3A inducers

Disqualifiers: Down syndrome, APL, JMML, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

98 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether adding venetoclax to standard chemotherapy can help young patients with relapsed AML. Venetoclax works by blocking a protein that helps cancer cells survive, making it easier for the chemotherapy to kill them. The study aims to find better treatment options for these patients who have limited choices. Venetoclax has been shown to improve overall survival in older and unfit patients with newly diagnosed acute myeloid leukemia when combined with lower intensity therapies.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. Specifically, you must not have taken strong and moderate CYP3A inducers like rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of starting the study treatment. Additionally, you should avoid grapefruit, Seville oranges, and starfruit within 3 days of starting the study treatment.

What data supports the effectiveness of the drug Venetoclax for treating acute myeloid leukemia?

Venetoclax has shown promising results when combined with other therapies for older and unfit patients with acute myeloid leukemia, and it is effective in both newly diagnosed and relapsed cases. It has also been effective in treating chronic lymphocytic leukemia, achieving high response rates. ^{1 2 3 4 5}

Is Venetoclax safe for use in humans?

Venetoclax has been shown to have an acceptable safety profile in patients with chronic lymphocytic leukemia and acute myeloid leukemia, with common side effects including nausea, diarrhea, and low blood cell counts. Serious side effects are rare, and the drug is generally well-tolerated, though there is a risk of tumor lysis syndrome, a condition where cancer cells break down rapidly. ^{3 4 6 7 8}

How is the drug Venetoclax unique for treating acute myeloid leukemia?

Venetoclax is unique because it targets a specific protein called BCL-2, which helps cancer cells survive, and it is taken orally, making it more convenient than some other treatments. It is particularly effective for older patients or those who cannot undergo aggressive therapies, and it can be combined with other drugs to improve outcomes. ^{1 3 4 6 9}

Research Team

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults aged up to 21 with relapsed Acute Myeloid Leukemia (AML) who can't receive more anthracyclines or are in their second relapse. They should be generally fit, have recovered from previous cancer treatments, not have certain conditions like Down syndrome or active infections, and must not be on medications that could interfere with the study drugs.

Inclusion Criteria

I have not had a stem cell infusion before starting the treatment.

It has been over 21 days since I last received interleukins, interferons, or cytokines treatment.

My kidney function tests are normal for my age and sex.

Exclusion Criteria

I do not have HIV.

Participants who are pregnant or breast-feeding.

Participants of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per clinical trials facilitation group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive up to two cycles of induction chemotherapy with fludarabine, cytarabine, and gemtuzumab ozogamicin, with or without venetoclax

12 weeks

Multiple visits (in-person)

Maintenance Treatment

Participants receive maintenance therapy with azacitidine, with or without venetoclax, for a maximum of 24 cycles

Maximum of 24 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Venetoclax

Trial Overview The trial tests if adding venetoclax to a chemo mix of fludarabine/cytarabine/gemtuzumab ozogamicin improves survival in young AML patients at first or second relapse. It's randomized, meaning participants are put into groups by chance to compare different treatment combinations.

Participant Groups

Group I: Arm B: Experimental Arm with Venetoclax Experimental Treatment 5 Interventions

During Cycle 1 (42-day-cycles), participants will receive 300 mg adult dose equivalent of venetoclax once on Day 1 followed by 600 mg adult dose equivalent of venetoclax on Days 2-21. Participants will also receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 8-12. Gemtuzumab 3 mg/m\^2 will be given on Day 13 (only for participants with CD33 expression on leukemia blasts). During Cycle 2, participants will receive 600 mg adult dose equivalent of venetoclax on Days 1-21. Participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. After Cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy in combination with venetoclax.

Group II: Arm A: Control Arm without Venetoclax Active Control 4 Interventions

During Cycle 1 (42-day-cycles), participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. Gemtuzumab 3 mg/m\^2 will be given on Day 6 (only for participants with CD33 expression on leukemia blasts). During Cycle 2 participants will receive 30 mg/m\^2 of fludarabine followed by 2 g/m\^2 of cytarabine on Days 1-5. After Cycle 2 participants are assessed for HSCT or azacitidine maintenance therapy.

Venetoclax is already approved in United States, European Union for the following indications:

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

LLS PedAL Initiative, LLC

Lead Sponsor

Trials

4

Recruited

1,100+

EuPAL

Collaborator

Trials

1

Recruited

100+

Roche-Genentech

Industry Sponsor

Trials

27

Recruited

3,800+

Princess Maxima Center for Pediatric Oncology (European Sponsor)

Collaborator

Trials

1

Recruited

100+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Findings from Research

Venetoclax combined with hypomethylators and low-dose cytarabine has shown high response rates and improved overall survival in older, untreated patients with acute myeloid leukemia, based on preliminary data from small, uncontrolled studies.

The efficacy of venetoclax appears to stem from its ability to target leukemia stem cells by altering the metabolic environment, which is particularly effective in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? Pollyea, DA., Jordan, CT.[2020]

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 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 a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

Venetoclax has significantly improved treatment outcomes for elderly and unfit patients with acute myeloid leukemia, but resistance to the drug remains a significant challenge.

The study by Bhatt et al. identifies a general mechanism for the development of resistance to venetoclax and suggests potential treatment strategies for managing venetoclax-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondria in Their Prime Drive Venetoclax Response in Acute Myeloid Leukemia. Kriegbaum, MC., Wennerberg, K.[2021]

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]

The combination of venetoclax and alvocidib was found to be safe and tolerable in patients with relapsed/refractory Acute Myeloid Leukemia (AML), with no maximum tolerated dose reached, although significant gastrointestinal side effects were common.

The overall response rate to this treatment was modest, with only 11.4% achieving complete or incomplete remission, indicating that while the combination is safe, it may not significantly enhance efficacy compared to using each drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. Jonas, BA., Hou, JZ., Roboz, GJ., et al.[2023]

Venetoclax is an effective and well-tolerated treatment for advanced hematological malignancies, particularly in patients with chronic lymphocytic leukemia, showing a satisfactory overall event rate of 73%.

The most common adverse events associated with venetoclax include nausea, diarrhea, and thrombocytopenia, but these are generally mild and manageable, with few cases of severe complications like tumor lysis syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials. Li, Q., Cheng, L., Shen, K., et al.[2020]

Venetoclax, a BCL-2 inhibitor, shows promise in combination therapies for newly diagnosed or relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), achieving high remission rates and deep molecular responses.

Despite these encouraging results, there are concerns about side effects such as incomplete blood count recovery and increased infection rates, particularly when used with chemotherapy, and more research is needed to understand the long-term effectiveness and durability of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. Shimony, S., Stone, RM., Stahl, M.[2023]

References

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

Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? [2020]

2. 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]

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

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

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

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

Mitochondria in Their Prime Drive Venetoclax Response in Acute Myeloid Leukemia. [2021]

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

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

7. England pubmed.ncbi.nlm.nih.gov

A phase 1b study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Bcl-2 Inhibitor Venetoclax in Hematological Malignancy: A Systematic Review and Meta-Analysis of Clinical Trials. [2020]

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

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023]