Venetoclax Combination Therapy for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: OHSU Knight Cancer Institute

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: CNS involvement, Active malignancy, 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

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax works in treating patients with newly diagnosed monocytic acute myeloid leukemia (AML) and active signaling mutated AML. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as cladribine, cytarabine and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with cladribine and cytarabine alternating with azacitidine and venetoclax may kill more cancer cells in patients with newly diagnosed monocytic AML and active signaling mutated AML.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use drugs that strongly interact with the study drugs, particularly strong or moderate CYP3A4 inducers or inhibitors, within 2 days or 3 half-lives before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination therapy for acute myeloid leukemia?

Research shows that venetoclax combined with low-dose cytarabine improves response rates and overall survival in patients with acute myeloid leukemia who cannot undergo intensive chemotherapy. Additionally, venetoclax with azacitidine and cladribine has shown short-term effectiveness in children with relapsed or resistant acute myeloid leukemia. ^{1 2 3 4 5}

Is Venetoclax combination therapy generally safe for humans?

Venetoclax combined with other treatments like low-dose cytarabine or azacitidine has shown a favorable safety profile in patients with acute myeloid leukemia, including elderly and frail individuals. The treatment has a low rate of early treatment-related deaths, indicating it is generally safe for use in humans. ^{1 2 3 4 6}

How is the venetoclax combination drug unique for treating acute myeloid leukemia?

The venetoclax combination drug is unique because it combines venetoclax with nucleoside analogs like cladribine and cytarabine, which have different mechanisms of action, leading to improved response and survival rates in patients with acute myeloid leukemia who are not eligible for intensive chemotherapy. ^{1 3 4 5 7}

Research Team

Curtis A Lachowiez

Principal Investigator

OHSU Knight Cancer Institute

Eligibility Criteria

This trial is for patients with newly diagnosed monocytic AML or active signaling mutated AML. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be required to have a particular type of cancer.

Inclusion Criteria

I understand this study is experimental and I can give my consent.

I am willing to receive care for side effects related to blood issues, infections, and immediate aftereffects.

Negative urine pregnancy test at screening and within 24 hours of cycle 1 day 1 for persons of childbearing potential

Exclusion Criteria

My AML has spread to my brain or spinal cord and is causing symptoms.

I have not had another cancer in the last 5 years.

Investigational therapy within 28 days of C1D1

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive cladribine, cytarabine, and venetoclax to induce remission

4 weeks

Multiple visits for drug administration

Re-Induction

Patients with > 5% blasts after cycle 1 receive additional treatment to achieve remission

4 weeks

Multiple visits for drug administration

Remission After Induction

Patients achieving remission receive further treatment to consolidate response

4 weeks

Multiple visits for drug administration

Continuing Therapy

Patients receive alternating cycles of venetoclax and azacitidine or cladribine and cytarabine

Up to 18 cycles (each cycle is 4 weeks)

Regular visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Periodic visits for monitoring

Treatment Details

Interventions

• Azacitidine
• Cladribine
• Cytarabine
• Venetoclax

Trial Overview The trial tests venetoclax combined with cladribine and cytarabine, alternating with azacitidine plus venetoclax. It's a phase II study to see if this regimen can effectively kill more cancer cells in the specified patient group.

Participant Groups

Group I: Treatment (venetoclax, cladribine, cytarabine, azacitidine) Experimental Treatment 11 Interventions

See Detailed Description

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

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

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

Findings from Research

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]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., et al.[2023]

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 comparison of two combination therapies for acute myeloid leukemia—glasdegib+low-dose cytarabine (LDAC) and venetoclax+LDAC—no statistically significant differences in overall survival or complete remission rates were found, suggesting similar efficacy.

When choosing between these treatments, factors like safety profiles, ease of administration, and patient preferences will be important since both therapies appear equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. Tremblay, G., Daniele, P., Bell, T., et al.[2021]

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]

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]

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]

References

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

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

2. China pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. [2023]

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

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

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

Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia. [2021]

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

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

7. 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]