Acalabrutinib + Venetoclax/Obinutuzumab for Chronic Lymphocytic Leukemia

Overseen By Megan Nussbaum

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ohio State University Comprehensive Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: High-risk disease, CNS involvement, cardiovascular disease, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 30

Duration: 18 cycles (approximately 18 months)

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests whether acalabrutinib in combination with venetoclax or obinutuzumab works to shrink tumors in patients with treatment-naive chronic lymphocytic leukemia . Acalabrutinib is also an inhibitor that works in the body to block the activation of certain cells that lead to the growth of cancerous B cells. 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. Obinutuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib in combination with venetoclax or obinutuzumab may help ease symptoms, decrease the amount of cancer suggestive of improvement, prolonged disease-free remission and/or survival, and increased knowledge about cancer treatment in patients with chronic lymphocytic leukemia. Patients will be treated with acalabrutinib for 12 cycles, and then randomized to receive 6 cycles of acalabrutinib plus obinutuzumab or acalabrutinib plus venetoclax.

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

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs that affect liver enzymes (CYP3A inhibitors or inducers) within 7 days 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 Acalabrutinib, Venetoclax, and Obinutuzumab for treating chronic lymphocytic leukemia?

Research shows that the combination of Venetoclax and Obinutuzumab is effective for treating chronic lymphocytic leukemia, leading to longer periods without disease progression and higher response rates compared to other treatments. Additionally, using Acalabrutinib with Venetoclax and Obinutuzumab may result in deep and lasting remissions. ^{1 2 3 4 5}

Is the combination of Acalabrutinib, Venetoclax, and Obinutuzumab safe for treating chronic lymphocytic leukemia?

The combination of Venetoclax and Obinutuzumab has been shown to be generally safe for treating chronic lymphocytic leukemia, with manageable side effects like neutropenia (a low level of white blood cells). Acalabrutinib, when used with Venetoclax and Obinutuzumab, is also considered safe, but patients should be aware of potential side effects and discuss them with their doctor. ^{1 2 3 4 5}

What makes the drug combination of Acalabrutinib, Venetoclax, and Obinutuzumab unique for treating chronic lymphocytic leukemia?

This drug combination is unique because it combines continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax and obinutuzumab, aiming for deep and durable remissions by targeting minimal residual disease (MRD). This approach is different from traditional chemoimmunotherapy, offering a chemotherapy-free option that can lead to more patients achieving undetectable MRD. ^{1 2 3 4 6}

Research Team

Kerry A. Rogers, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

Adults diagnosed with chronic lymphocytic leukemia who haven't had previous cancer treatments, except for certain conditions like autoimmune diseases or symptom control. They must show specific symptoms or blood abnormalities as per iwCLL guidelines, have adequate organ function, and women of childbearing age must use effective contraception.

Inclusion Criteria

I am 18 years old or older.

Woman of childbearing potential must use contraception

Willing and able to participate in all required evaluations and procedures in this study protocol

Exclusion Criteria

Hepatitis B or C serologic status

I have uncontrolled autoimmune blood disorders.

I am on blood thinners like warfarin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive acalabrutinib for 12 cycles, followed by randomization to receive 6 cycles of acalabrutinib plus either obinutuzumab or venetoclax

18 cycles (approximately 18 months)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Follow-up at 30 days and every 6 months

Treatment Details

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing acalabrutinib combined with either venetoclax or obinutuzumab to see if they can shrink tumors in patients with untreated chronic lymphocytic leukemia. Patients will first receive acalabrutinib alone, then be randomly assigned to add one of the other drugs for further treatment cycles.

Participant Groups

Group I: Arm II (acalabrutinib, venetoclax) Experimental Treatment 2 Interventions

Patients receive acalabrutinib PO BID on days 1-28. Patients also receive venetoclax PO QD on days 1-28 days of cycles 13-18. Treatment repeats every 28 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (acalabrutinib, obinutuzumab) Experimental Treatment 2 Interventions

Patients receive acalabrutinib PO BID on days 1-28. Patients also receive obinutuzumab IV on days 1, 2, 8, and 15 of cycle 13 and day 1 of cycles 14-18. Treatment repeats every 28 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Findings from Research

In a phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

In a phase 2 study involving 37 patients with chronic lymphocytic leukaemia, the combination therapy of acalabrutinib, venetoclax, and obinutuzumab achieved a complete remission with undetectable minimal residual disease (MRD) in 38% of participants by cycle 16, indicating promising efficacy.

The treatment was generally well tolerated, with the most common serious adverse event being neutropenia, affecting 43% of patients, and no deaths reported during the study, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Davids, MS., Lampson, BL., Tyekucheva, S., et al.[2021]

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

Venetoclax, an oral BCL-2 inhibitor, combined with obinutuzumab, has demonstrated superior efficacy compared to traditional chemoimmunotherapy in both treatment-naive and relapsed/refractory chronic lymphocytic leukemia (CLL) patients.

Obinutuzumab, a novel anti-CD20 monoclonal antibody, has been safely used with other targeted therapies like venetoclax, showing better outcomes than the older drug rituximab when paired with chlorambucil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. Salvaris, R., Opat, S.[2021]

References

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

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. [2020]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]

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

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]

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

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. [2022]

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

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]

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

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. [2021]