What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML), particularly those involving Venetoclax (a BCL-2 inhibitor), often include combinations with hypomethylating agents (HMAs) like azacitidine or decitabine. Known side effects of these treatments include neutropenia, thrombocytopenia, infections, and tumor lysis syndrome (TLS). Other side effects can include gastrointestinal issues such as diarrhea, as well as hematologic adverse events like anemia and cytopenias. These side effects can vary in severity, with some patients experiencing grade 3 or higher toxicities.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myeloid Leukemia (AML), including hypomethylating agents (HMAs) such as azacitidine and decitabine. Venetoclax, a BCL-2 inhibitor, has been approved for use in combination with these HMAs for the treatment of newly diagnosed AML in adults who are 75 years or older or who have comorbidities precluding the use of intensive induction chemotherapy. This combination has shown promising results in clinical trials, providing a less intensive yet effective treatment option for certain AML patients.

What other types of research exist?

Promising novel alternatives to Venetoclax for AML patients include: 1) Gilteritinib, a FLT3 inhibitor, especially for patients with FLT3-ITD mutations. 2) Combination therapies such as Gilteritinib with Venetoclax for FLT3-mutated AML. 3) Immunotherapeutic approaches like Blinatumomab and Inotuzumab Ozogamicin for specific subtypes of AML. 4) Chimeric Antigen Receptor T cell (CAR-T) therapy for relapsed or refractory AML. These alternatives have shown encouraging results in clinical trials and may offer new hope for AML patients.

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B-cell lymphoma-2 (BCL-2) inhibitor

Venetoclax + Chemotherapy for Acute Myeloid Leukemia

Phase 3

Recruiting

Led By Seth Karol, MD

Research Sponsored by LLS PedAL Initiative, LLC

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

- Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoietic Growth Factors) before start of protocol treatment.

-- Normal serum creatinine based on age/sex

Must not have

No known human immunodeficiency virus (HIV) infection.

- to participants with CD33 negative leukemic blasts (determined at local lab)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Possible side effects include low blood counts leading to increased infection risk, bleeding problems, liver issues due to drug interactions, allergic reactions to medication components, and potential heart complications. The severity of side effects can vary among individuals.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Select...

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

Select...

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

Select...

It's been over 42 days since I had any cell therapy, like T cell or NK cell treatment.

Select...

I can take care of myself but might not be able to do heavy physical work.

Select...

I am not currently on medications like cyclosporine or tacrolimus for post-transplant care.

Select...

It's been over 14 days since my last long-acting growth factor dose or over 7 days for a short-acting one.

Select...

It has been more than 42 days since my last major bone marrow radiation.

Select...

I am fit enough for another intensive chemotherapy as this is my second relapse.

Select...

I have never needed treatment for heart failure.

Select...

My leukemia does not have the FLT3/ITD mutation.

Select...

I am between 29 days and 21 years old.

Select...

I do not have active symptoms of graft versus host disease.

Select...

I have never had severe liver blockage diseases or leukemia with CD33 negative cells.

Select...

I can take care of myself but might not be able to do heavy physical work.

Select...

I have been treated with venetoclax before.

Select...

I do not have heart failure symptoms at my cancer's return.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I do not have HIV.

Select...

My leukemia does not show CD33 on tests.

Select...

I should not receive gemtuzumab ozogamicin.

Select...

I have never had a severe case of VOD/SOS.

Select...

I do not have an active, uncontrolled infection.

Select...

I am a woman who has started menstruating and I have a positive pregnancy test.

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I cannot take medications by mouth due to a digestive condition.

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I have been diagnosed with APL or JMML.

Select...

My cancer has spread to my brain but is limited or causing symptoms.

Select...

I have a known congenital bone marrow failure syndrome.

Select...

I haven't taken strong medications like rifampin or St. John's wort in the last week.

Select...

I have had a severe liver condition after a transplant.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Side effects data

From 2022 Phase 3 trial • 389 Patients • NCT02005471

33%

Neutropenia

11%

SARS-CoV-2 test positive

11%

Sepsis

11%

Abdominal pain

11%

Pneumonia

11%

Rhinovirus infection

11%

COVID-19

11%

Gastroenteritis

11%

Pneumonia pseudomonal

11%

Electrocardiogram QT prolonged

11%

Anaemia

11%

Neutrophil count decreased

11%

Hypokalaemia

11%

Febrile neutropenia

11%

Supraventricular tachycardia

11%

Blood creatinine increased

11%

White blood cell count decreased

11%

Dermatitis

100%

80%

60%

40%

20%

Study treatment Arm

Bendamustine + Rituximab Crossover Substudy

Venetoclax + Rituximab Re-Treatment Substudy

Venetoclax + Rituximab Main Study

Bendamustine + Rituximab Main Study

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Arm B: Experimental Arm with VenetoclaxExperimental Treatment5 Interventions

During cycle 1 (each cycle is 42 days), 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 VenetoclaxActive Control4 Interventions

During cycle 1 (each cycle is 42 days), 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 hematopoietic stem cell transplantation (HSCT) or azacitidine maintenance therapy.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cytarabine

2016

Completed Phase 3

~3330

Venetoclax

2019

Completed Phase 3

~2240

Gemtuzumab Ozogamicin

2006

Completed Phase 4

~460

Fludarabine

2012

Completed Phase 4

~1860

Azacitidine

2012

Completed Phase 3

~1440

0 / 28Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Acute Myeloid Leukemia (AML) include Venetoclax, which inhibits the BCL-2 protein to promote apoptosis in cancer cells, and intensive combination chemotherapy, which targets rapidly dividing cells. Hypomethylating agents like azacitidine and decitabine interfere with DNA methylation to reactivate tumor suppressor genes. These treatments are vital for reducing leukemic cell burden, achieving remission, and improving survival rates in AML patients.

Synergistic effect of chidamide and venetoclax on apoptosis in acute myeloid leukemia cells and its mechanism.Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells.