Venetoclax + CLAG-M for Acute Myeloid Leukemia

Overseen By Mary-Beth M. Percival

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Washington

Must not be taking: CYP3A inhibitors, Steroids

Disqualifiers: CNS involvement, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

62 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial finds the best dose, side effects and how well giving venetoclax in combination with cladribine, cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in treating patients with acute myeloid leukemia and high-grade myeloid neoplasms. Venetoclax 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 mitoxantrone, 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 CLAG-M may kill more cancer cells.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications, such as CYP3A inhibitors (except voriconazole) and steroid therapy for cancer treatment, before starting the trial. Additionally, you should avoid grapefruit, Seville oranges, and star fruit three days before the first dose of venetoclax.

What data supports the effectiveness of the drug Venetoclax + CLAG-M for Acute Myeloid Leukemia?

Research shows that venetoclax, when combined with other drugs like cytarabine, has led to improved response and survival rates in patients with acute myeloid leukemia (AML). Additionally, venetoclax-based treatments have shown promising results in older and unfit patients with AML, suggesting potential benefits for broader patient groups. ^{1 2 3 4 5}

Is the combination of Venetoclax and CLAG-M safe for treating acute myeloid leukemia?

Venetoclax combined with other treatments has shown a generally favorable safety profile in elderly and unfit patients with acute myeloid leukemia, with a low rate of early treatment-related deaths. However, in some studies, there were frequent severe blood-related side effects and infections, especially in patients with relapsed or refractory conditions, indicating the need for careful monitoring. ^{2 3 4 5 6}

How is the drug Venetoclax + CLAG-M unique for treating acute myeloid leukemia?

The drug Venetoclax + CLAG-M is unique for treating acute myeloid leukemia because it combines venetoclax, which targets cancer cell survival, with a regimen of cladribine, cytarabine, and mitoxantrone, offering a novel approach that may improve outcomes, especially in older or unfit patients who cannot undergo intensive chemotherapy. ^{1 3 5 6 7}

Research Team

Mary-Beth M. Percival

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

Adults with acute myeloid leukemia or high-grade myeloid neoplasms, including those with biphenotypic leukemia. Participants must have adequate kidney and liver function, an ECOG score of 2 or less (meaning they can perform light activities), and a heart ejection fraction of at least 45%. They should understand the trial and consent to it. Pregnant women are excluded, as well as those with certain blood counts or who need intense treatment.

Inclusion Criteria

Your AST and ALT levels in your blood are not more than 3 times the upper limit of normal.

My kidneys work well enough, with a creatinine clearance of 30 mL/min or more.

Ability to understand and the willingness to sign a written informed consent document

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Patients receive induction treatment with granulocyte colony-stimulating factor, cladribine, cytarabine, mitoxantrone, and venetoclax. Treatment repeats every 28-35 days for up to 2 cycles.

4-10 weeks

Consolidation Treatment

Patients receive consolidation treatment with granulocyte colony-stimulating factor, cladribine, cytarabine, and venetoclax without mitoxantrone. Treatment repeats every 28-35 days for up to 4 cycles.

16-20 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 3 months for 12 months.

12 months

Treatment Details

Interventions

• Cladribine
• Cytarabine
• Mitoxantrone
• Recombinant Granulocyte Colony-Stimulating Factor
• Venetoclax

Trial Overview The trial is testing the combination of venetoclax with CLAG-M chemotherapy regimen for treating specific types of leukemia. Venetoclax targets proteins that cancer cells need to survive while CLAG-M includes various drugs that kill or stop cancer cells from growing.

Participant Groups

Group I: Treatment (CLAG-M, venetoclax) Experimental Treatment 8 Interventions

Patients will receive induction with granulocyte colony-stimulating factor on days 0-5 (if peripheral white blood cell count is less than 20,000/uL), cladribine on days 1-5, cytarabine on 1-5, and mitoxantrone on days 1-3. Patients also receive venetoclax orally (PO) on days 1-14. Treatment repeats every 28-35 days for up to 2 induction cycles including mitoxantrone, and up to 4 consolidation cycles without mitoxantrone in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and/or aspiration, and blood sample collection throughout the study.

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?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

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

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[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]

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 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]

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 of 31 patients with acute myeloid leukemia evolving from myeloproliferative neoplasms, venetoclax showed some efficacy in newly diagnosed patients, achieving complete remission in 6 patients with a median overall survival of 7 months, but no formal responses in relapsed/refractory patients with a median survival of only 3 months.

The treatment was associated with significant hematologic toxicities, with 83% of patients experiencing severe infections and 14 patients suffering from severe hemorrhagic complications, highlighting the need for safer and more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. Masarova, L., DiNardo, CD., Bose, P., 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]

References

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

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid 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. United States pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

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

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. [2021]

7. 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]