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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs to treat acute myeloid leukemia, a type of blood cancer, and other related high-grade blood disorders. The goal is to determine the best dose and understand the side effects of using venetoclax with a chemotherapy combination called CLAG-M. Venetoclax blocks a protein that helps cancer cells survive, while the other drugs aim to stop cancer cells from growing and spreading. People with newly diagnosed or relapsed acute myeloid leukemia who have certain high-risk features might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

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

Research has shown that the FDA approves venetoclax for treating chronic lymphocytic leukemia and acute myeloid leukemia (AML) due to its safety for these conditions. In AML patients, venetoclax is often combined with other treatments, but it can cause serious side effects such as febrile neutropenia (a fever with a low white blood cell count) and pneumonia in some cases.

Studies on the CLAG-M treatment, which includes cladribine, cytarabine, and mitoxantrone, have found it to be generally well tolerated by AML patients. These studies suggest that while the treatment can be intense, it is usually manageable for both younger and older adults with relapsed or difficult-to-treat AML.

Researchers are investigating the effectiveness and safety of combining venetoclax with the CLAG-M treatment for AML. While all treatments carry potential risks, previous research provides insight into their safety for individuals with this type of leukemia. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination treatment of Venetoclax with CLAG-M for Acute Myeloid Leukemia (AML) because it offers a new approach to tackling this aggressive cancer. Unlike traditional chemotherapy treatments, which typically target fast-dividing cells broadly, Venetoclax specifically inhibits the BCL-2 protein. This protein helps cancer cells survive, so blocking it can make them more vulnerable to chemotherapy. By combining Venetoclax with CLAG-M, which includes cladribine, cytarabine, and mitoxantrone, the treatment aims to increase the effectiveness and precision of attacking leukemia cells, potentially leading to better outcomes for patients with fewer side effects.

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

Research has shown that venetoclax combined with chemotherapy may be promising for treating acute myeloid leukemia (AML). Studies have demonstrated that combining venetoclax with a modified form of intensive chemotherapy led to remission in 75% of older, fit patients with AML. Additionally, venetoclax with hypomethylating agents has proven effective in treating AML. In this trial, participants will receive the CLAG-M treatment, which includes cladribine, cytarabine, and mitoxantrone, known to be effective for patients whose AML has returned or did not respond to initial treatment, with a success rate of 61%. The trial will also test venetoclax with CLAG-M, which might improve these results and target cancer cells more effectively. ^{3 6 7 8 9}

Who Is on the Research Team?

Mary-Beth M. Percival

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6442971/

Phase I/II trial of cladribine, high-dose cytarabine ... In summary, CLAG-M with mitoxantrone up to 16 mg/m2 appears safe and relatively well tolerated in fit younger and older adults with relapsed/refractory AML and ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0145212620300059

Efficacy of mitoxantrone-based salvage therapies in ... We compared CLAG-M and MEC in relapsed and refractory AML. Response rates were 61 % for CLAG-M and 56 % for MEC. No significant differences in overall survival ...

3. jhoponline.com jhoponline.com/issue-archive/2015-issues/march-vol-5-no-1/clag-clag-m-in-patients-with-relapsed-refractory-acute-myeloid-leukemia

CLAG/CLAG-M in Patients with Relapsed/Refractory Acute ... Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory ...

4. journals.lww.com journals.lww.com/md-journal/fulltext/2023/11030/cladribine,_cytarabine,_and_filgrastim_based.106.aspx

Cladribine, cytarabine, and filgrastim based regimen in... The CLAG-related regimen is an effective and safe therapy for R/R AML patients, CLAG seems to have more superiority than CLAG combined therapy.

5. haematologica.org haematologica.org/article/view/8865

Phase I/II trial of cladribine, high-dose cytarabine ... In summary, CLAG-M with mitoxantrone up to 16 mg/m appears safe and relatively well tolerated in fit younger and older adults with relapsed/ ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5935/501114/Outcomes-in-Patients-with-Acute-Myeloid-Leukemia

Outcomes in Patients with Acute Myeloid Leukemia Treated ... Similar number of pts received CLAG/Ven (47.5%) and CLAG-M/Ven (52.6%). Pts received on average 2.6 lines of treatment prior to CLAG(M)/Ven with ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123125341

Outcomes in Patients with Acute Myeloid Leukemia ... Eighty percent (4/5) had adverse risk disease and received CLAG-M/Ven. Forty percent (2/5) had TP53 mutation. Objective response rate (ORR) of ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39800921/

A Multicenter Retrospective Analysis This study aimed to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M versus midostaurin plus 7+3 in FLT3-mutated AML patients.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04797767

Study Details | NCT04797767 | Venetoclax and CLAG-M ... This phase I/II trial finds the best dose, side effects and how well giving venetoclax in combination with cladribine, cytarabine, ...