Venetoclax + Chemotherapy for Acute Myeloid Leukemia

(Venetoclax AML Trial)

Overseen By Ioannis Mantzaris, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Ioannis Mantzaris

Disqualifiers: Heart failure, Myocardial infarction, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

99 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1b, open-label study evaluating Venetoclax in combination with intensive induction and consolidation chemotherapy in previously untreated, adult patients with acute myeloid leukemia. In Part 1, the dose escalation phase, the safety and tolerability of the combination with Venetoclax at different doses and duration will inform the appropriate dose(s) and regimen(s) for Part 2. In Part 2, the dose expansion phase, a maximum of 28 additional patients will be randomized 1:1 to the MTD determined in Part 1 and the starting dose (assuming the MTD is not the starting dose), to further evaluate the safety and efficacy of the study drug combination.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

Research shows that combining Venetoclax with low-dose cytarabine or daunorubicin and cytarabine has improved response rates and overall survival in patients with acute myeloid leukemia, especially those who are older or unable to undergo intensive chemotherapy. These studies indicate that Venetoclax-based treatments can be effective, although there are concerns about side effects like prolonged myelosuppression (a decrease in blood cell production). ^{1 2 3 4 5}

Is the combination of Venetoclax and chemotherapy safe for treating acute myeloid leukemia?

The combination of Venetoclax with chemotherapy has shown a favorable safety profile, with a low rate of early treatment-related deaths, even in frail patients with acute myeloid leukemia. However, severe and prolonged myelosuppression (a decrease in bone marrow activity leading to fewer blood cells) is a concern. ^{1 2 3 4 5}

How is the drug combination of Venetoclax, Cytarabine, and Daunorubicin unique for treating acute myeloid leukemia?

This drug combination is unique because it includes Venetoclax, which targets a specific protein (BCL-2) that helps cancer cells survive, and is combined with chemotherapy drugs Cytarabine and Daunorubicin to improve treatment effectiveness, especially for patients who cannot undergo intensive chemotherapy. ^{1 2 3 4 6}

Research Team

Ioannis Mantzaris, MD

Principal Investigator

Montefiore Medical Center

Eligibility Criteria

Adults aged 18-75 with a new diagnosis of acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), who may have had prior treatments at the investigator's discretion. Participants must be in good physical condition (ECOG ≤2), have proper kidney and liver function, and agree to use contraception. Excluded are those with certain heart conditions, active CNS AML involvement, uncontrolled infections like HIV/Hepatitis B/C, gastrointestinal absorption issues, significant medical/psychiatric history affecting study participation, extremely high white cell count or women not using effective birth control.

Inclusion Criteria

I am between 18 and 75 years old.

Ability to understand and provide signed informed consent

I have been newly diagnosed with AML according to WHO standards.

Exclusion Criteria

My leukemia is of a specific type known as acute promyelocytic.

My acute myeloid leukemia has spread to my brain or spinal cord.

My white blood cell count is above 25 x 10⁹/L.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive Venetoclax in combination with daunorubicin and cytarabine to determine the maximum tolerated dose

Up to 6 weeks

Multiple visits for dose escalation and monitoring

Consolidation Treatment

Participants who achieve CRc proceed to consolidation therapy with high-dose cytarabine and Venetoclax

Up to 42 days per cycle, for up to 4 cycles

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

Treatment Details

Interventions

• Cytarabine
• Daunorubicin
• Venetoclax

Trial Overview The trial is testing Venetoclax combined with intensive chemotherapy drugs Daunorubicin and Cytarabine in untreated adults with AML/MDS. It has two parts: first determining the safest dose combination (dose escalation), then expanding to more patients to compare this optimal dose against the starting dose for safety and effectiveness (dose expansion).

Participant Groups

Group I: Venetoclax plus 7+3 Experimental Treatment 3 Interventions

see detailed description

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

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

Ioannis Mantzaris

Lead Sponsor

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

In a subgroup of 27 Japanese patients with newly diagnosed acute myeloid leukaemia, venetoclax combined with low-dose cytarabine showed a higher complete remission rate (44.4%) compared to placebo (11.1%), indicating potential efficacy in this population.

Despite the higher remission rate, the median overall survival was similar between the venetoclax (4.7 months) and placebo (8.1 months) groups, suggesting limited survival benefit, which may be influenced by small sample size and baseline health differences among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. Yamauchi, T., Yoshida, C., Usuki, K., et al.[2022]

In a phase 2 clinical trial involving 42 adults with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with daunorubicin and cytarabine (DA 2 + 6) achieved a high overall response rate of 92.9%, indicating strong efficacy in treating this condition.

The treatment demonstrated a shorter myelosuppressive period compared to previous regimens, with median recovery times for neutrophils and platelets of 13 and 12 days, respectively, while maintaining similar efficacy and safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax combined with daunorubicin and cytarabine (2 + 6) as induction treatment in adults with newly diagnosed acute myeloid leukemia: a phase 2, multicenter, single-arm trial. Suo, X., Zheng, F., Wang, D., et al.[2023]

In a Phase 3 clinical trial, venetoclax combined with low-dose cytarabine showed improved response rates and overall survival in patients with newly diagnosed acute myeloid leukemia who couldn't undergo intensive chemotherapy, supporting its efficacy.

In an expanded access study in Japan involving 14 patients, the safety profile of venetoclax was consistent with previous findings, with neutropenia being the most common serious side effect, indicating that careful management of adverse events is crucial in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. Asada, N., Ando, J., Takada, S., et al.[2023]

In a phase 2 trial involving 33 adults with newly diagnosed acute myeloid leukaemia, the combination of venetoclax with daunorubicin and cytarabine (DAV regimen) achieved a remarkable composite complete remission rate of 91% after one cycle of treatment.

The treatment was found to be safe, with no treatment-related deaths reported, although all patients experienced grade 3 or worse adverse events, such as neutropenia and thrombocytopenia, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. Wang, H., Mao, L., Yang, M., et al.[2022]

Venetoclax, when combined with hypomethylating agents or low-dose cytarabine, has shown remarkable effectiveness in treating newly diagnosed acute myeloid leukemia (AML) in elderly and unfit patients, with a favorable safety profile and low early treatment-related mortality.

Due to its success in older patients, venetoclax is now being explored as a frontline treatment for younger patients with AML and those with relapsed or refractory cases, indicating its potential to change AML treatment across different age groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax-containing regimens in acute myeloid leukemia. Aldoss, I., Pullarkat, V., Stein, AS.[2021]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Venetoclax combined with daunorubicin and cytarabine (2 + 6) as induction treatment in adults with newly diagnosed acute myeloid leukemia: a phase 2, multicenter, single-arm trial. [2023]

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

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Venetoclax-containing regimens in acute myeloid leukemia. [2021]

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

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. [2023]