Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 94 trial locations

Overseen By Michel Zwaan

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: PedAL BCU, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding venetoclax to a standard chemotherapy regimen can improve survival for children, teens, and young adults with acute myeloid leukemia (AML) facing a difficult relapse. Participants will receive either standard chemotherapy or the same regimen with added venetoclax, a drug that helps kill cancer cells. This trial suits those with AML who have relapsed and cannot tolerate more of a certain type of chemotherapy. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that venetoclax, when combined with chemotherapy, is generally well-tolerated. Studies have found it can be safely paired with other treatments like azacitidine for acute myeloid leukemia (AML). In one study, patients experienced some side effects, but these were often manageable. Common side effects included low blood cell counts, which can increase infection risk, and nausea. However, most patients continued treatment without major issues.

Venetoclax is already approved for treating certain types of leukemia, indicating that health authorities consider its safety profile acceptable. While every treatment can have side effects, existing evidence supports the use of venetoclax with chemotherapy as reasonably safe for patients with AML. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute myeloid leukemia?

Researchers are excited about venetoclax for Acute Myeloid Leukemia (AML) because it targets cancer cells in a unique way. Unlike traditional chemotherapy that attacks all rapidly dividing cells, venetoclax specifically inhibits a protein called BCL-2, which helps cancer cells survive. This targeted approach could potentially lead to more effective treatment with fewer side effects. Additionally, when combined with chemotherapy, venetoclax might enhance the overall effectiveness of the treatment, offering new hope for patients with AML.

What evidence suggests that venetoclax combined with chemotherapy could be an effective treatment for acute myeloid leukemia?

This trial will compare the effectiveness of chemotherapy with and without venetoclax for treating acute myeloid leukemia (AML). Research has shown that adding venetoclax to chemotherapy may aid in treating AML. In previous studies, venetoclax, when combined with other treatments, helped 30% to 40% of young AML patients achieve long-term remission. Another study found that venetoclax led to significant positive responses, with some patients showing no signs of the disease. These results suggest that venetoclax can enhance chemotherapy outcomes for AML patients. ^{3 6 7 8 9}

Who Is on the Research Team?

Seth E. Karol, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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?

PedAL BCU, LLC

Lead Sponsor

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

Published Research Related to This Trial

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]

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 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 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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Results were dramatic–venetoclax plus rituximab achieved an 84.9% progression-free survival rate at 2 years, vs the bendamustine plus rituximab arm, which ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01994837

NCT01994837 | A Phase 2 Study of ABT-199 in Subjects ... This was a Phase 2, open-label, multicenter study evaluating the preliminary efficacy and safety of venetoclax (ABT-199) administered orally in participants ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12032727/

Meta-analysis on the effectiveness and safety of venetoclax ... This approach has yielded a long-term cure rate of 30% to 40% in young AML patients [1, 15–18]. Despite these advancements, the cure rate ...

4. news.abbvie.com news.abbvie.com/2014-12-07-AbbVie-Presents-Results-from-Phase-2-Study-of-Investigational-Compound-Venetoclax-ABT-199-GDC-0199-in-Acute-Myelogenous-Leukemia-at-the-56th-American-Society-of-Hematology-Annual-Meeting

Study Evaluated Preliminary Efficacy of Venetoclax in 32 ... In the study, the venetoclax group showed an overall response rate (ORR) of 15.5 percent, with one patient achieving a complete response and ...

5. abbvieclinicaltrials.com abbvieclinicaltrials.com/study/?id=M14-212

A Phase 2 Study of ABT-199 in Subjects With Acute ... This was a Phase 2, open-label, multicenter study evaluating the preliminary efficacy and safety of venetoclax (ABT-199) administered orally in participants ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02203773

NCT02203773 | Study of ABT-199 (GDC-0199) in ... This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered venetoclax (ABT-199) ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118473065

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in ... Elderly AML patients (pts) respond poorly to standard chemotherapy, with low overall survival and poor outcomes. Venetoclax (VEN) is a selective, potent, orally ...

9. abbvieclinicaltrials.com abbvieclinicaltrials.com/study/?id=M14-358

Study of ABT-199 (GDC-0199) in Combination With ... This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered venetoclax (ABT-199) ...