Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 9 trial locations

Overseen By Jeffrey E. Rubnitz, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Down syndrome, Fanconi anemia, others

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

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

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding venetoclax (Venclexta) to standard chemotherapy is safe and effective for children and young adults newly diagnosed with acute myeloid leukemia (AML), a type of blood cancer. Researchers aim to determine if this combination clears cancer from the body and improves survival rates. The trial includes three different treatment plans based on the patient's risk level. Children and young adults with AML who have received minimal prior treatment might be suitable candidates for this study. As a Phase 2 trial, it focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important research that could enhance future AML treatments.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong or moderate CYP3A inducers and inhibitors, at least 3 days before enrolling. If you're on these medications, you may need to discuss alternatives with your doctor.

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

A previous study found that venetoclax was generally well-tolerated by patients with acute myeloid leukemia (AML). While patients experienced some side effects, most were not severe. Venetoclax was used either alone or with other treatments.

Research has shown that the FDA has approved venetoclax for treating some types of leukemia, indicating its safety for those conditions. However, when combined with chemotherapy, as in this study, it is still being tested for effectiveness and safety in younger patients with newly diagnosed AML.

This trial is in phase 2, focusing on assessing the treatment's safety and effectiveness. This phase usually indicates some early evidence of safety in humans, but it is not yet fully confirmed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about venetoclax for treating acute myeloid leukemia (AML) because it targets the BCL-2 protein, which plays a key role in cancer cell survival. Unlike standard chemotherapy treatments like cytarabine and daunorubicin, venetoclax specifically induces cancer cell death by disrupting this protein's function. This targeted approach can potentially make venetoclax more effective and less toxic than traditional chemotherapy options. Additionally, when combined with chemotherapy drugs, venetoclax may enhance the overall anti-leukemic effect, offering hope for improved outcomes in AML patients across different risk groups.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that venetoclax, when combined with chemotherapy, may help treat acute myeloid leukemia (AML). In one study, 68% of patients responded to the treatment, with 61% achieving full or nearly full remission in about a month. Another study found that patients treated with venetoclax lived for a median of 4.7 months. This trial will explore the effectiveness of venetoclax combined with various chemotherapy agents across different risk groups: low, intermediate, and high. These results suggest that venetoclax can be effective, especially when used early in treatment, by better targeting leukemia cells. ^{3 4 5 6 7}

Who Is on the Research Team?

Hiroto Inaba, MD, PhD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for pediatric patients aged over 28 days and under 22 years with newly diagnosed acute myeloid leukemia (AML), who haven't had prior treatment except possibly one dose of intrathecal therapy or specific low-dose chemotherapy. Participants must be able to tolerate the protocol therapy, not have certain infections or diseases that could affect safety or results, and agree to use effective contraception if applicable.

Inclusion Criteria

Written informed consent from the patient and/or parent/legal guardian

I agree to use effective birth control during and for 6 months after the study.

I am older than 28 days and younger than 22 years.

Exclusion Criteria

I haven't taken strong medications like ketoconazole within the last 3 days.

I haven't taken strong medications like rifampin in the last 3 days.

I do not have any severe infections or diseases that could affect my safety or participation in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction 1

Venetoclax and chemotherapy drugs are administered to patients based on risk category

4 weeks

Multiple visits for drug administration

Induction 2

Continuation of venetoclax and chemotherapy regimen with adjustments based on response

4 weeks

Multiple visits for drug administration

Intensification

Further chemotherapy courses with venetoclax, adjusted for patient risk and response

8-12 weeks

Multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Venetoclax

Trial Overview The study tests whether adding Venetoclax to standard chemotherapy is tolerable and effective in children with AML. It aims to see if this combination can reduce disease traces after one treatment course and improve rates of complete remission, event-free survival, and overall survival.

How Is the Trial Designed?

Group I: Low Risk Experimental Treatment 8 Interventions

All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Cytabrine, Danunorubicin Hydrochloride, Gemtuzumab Ozogamicin, Etoposide, Mitoxantrone Hydrochloride, Gilteritinib

Group II: Intermediate Risk Experimental Treatment 9 Interventions

All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Cytabrine, Danunorubicin Hydrochloride, Fludarabine Phosphate, Gemtuzumab Ozogamicin, Etoposide, Idarubin Hydrochloride, Mitoxantrone Hydrochloride, Gilteritinib

Group III: High Risk Experimental Treatment 9 Interventions

All eligible patients receive intervention according to the Detailed Description section with the following: Venetoclax, Azacitidine, Cytabrine, Danunorubicin Hydrochloride, Fludarabine Phosphate, Gemtuzumab Ozogamicin, Etoposide, Idarubin Hydrochloride, Gilteritinib

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

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 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]

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 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 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]

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, 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]

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]

Citations

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

Evaluating venetoclax and its potential in treatment-naïve ... Overall response rate was 68%; 61% achieved CR or CRi, with a median time to CR/CRi of 0.9–1.2 months, and median response duration of 11 months; OS at 12 ...

2. 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 ...

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

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in ... Nineteen of 22 pts completed C1 and were response evaluable. Overall response rate (CR/CR with incomplete marrow recovery/partial remission) using the intent-to ...

4. 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 ...

5. aacrjournals.org aacrjournals.org/cancerdiscovery/article/6/10/1106/5537/Efficacy-and-Biological-Correlates-of-Response-in

Efficacy and Biological Correlates of Response in a Phase II ... A and B, the median leukemia-free survival was 2.3 months (range, 1.0–2.7), and the median overall survival was 4.7 months (range, 2.3–6.0), in patients with ...

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5436271/

Efficacy and Biological Correlates of Response in a Phase 2 ... Venetoclax monotherapy demonstrated clinical activity in patients with relapsed/refractory AML or those unfit for intensive chemotherapy and had a tolerable ...