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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining acalabrutinib with either venetoclax or obinutuzumab can shrink tumors in people with chronic lymphocytic leukemia (CLL) who have never received treatment. Acalabrutinib blocks certain cells that aid cancer growth. Venetoclax inhibits a protein essential for cancer cell survival, while obinutuzumab is an antibody that may prevent cancer cell growth. The trial seeks participants with CLL symptoms such as enlarged lymph nodes or spleen, significant fatigue, or weight loss without infection. Participants will first take acalabrutinib and then be randomly assigned to receive either venetoclax or obinutuzumab. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that using acalabrutinib with venetoclax is safe and promising. Studies found that this combination reduced the risk of disease progression or death by 58% compared to standard treatments, indicating good patient tolerance.

For the acalabrutinib and obinutuzumab combination, studies indicate it is generally safe and effective. Trials with Japanese patients reported no major safety concerns, and the treatment was well-received.

Both combinations aim to treat chronic lymphocytic leukemia and have demonstrated a favorable safety profile in previous studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Chronic Lymphocytic Leukemia because they combine innovative drugs that target cancer cells in unique ways. Unlike traditional chemotherapy, which broadly attacks fast-growing cells, acalabrutinib is a targeted therapy that blocks a protein called BTK, crucial for cancer cell survival. Venetoclax is another standout, as it inhibits a protein called BCL-2, which helps cancer cells evade death. In a different approach, obinutuzumab is an antibody that directly targets and marks cancer cells for destruction by the immune system. These combinations aim to strike at the cancer's weaknesses more precisely, potentially leading to better outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

This trial will compare two treatment combinations for chronic lymphocytic leukemia (CLL). Studies have shown that acalabrutinib with venetoclax, which participants in one arm of this trial may receive, is highly effective against CLL. Specifically, this combination reduced the risk of disease progression or death by 58% compared to standard treatments, with 77% of patients not experiencing disease progression for three years. Additionally, research indicates that acalabrutinib with obinutuzumab, which participants in another arm of this trial may receive, improves survival rates. This pairing led to better outcomes in preventing disease progression compared to acalabrutinib alone, with significant reductions in residual cancer cells after treatment. Both combinations show promise for managing CLL, especially for newly diagnosed patients. ^{3 6 7 8 9}

Who Is on the Research Team?

Kerry A. Rogers, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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

Woman of childbearing potential must use contraception

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

Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

Exclusion Criteria

Hepatitis B or C serologic status

I have uncontrolled autoimmune blood disorders.

I am on blood thinners like warfarin.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40198878/

Acalabrutinib-obinutuzumab improves survival vs ... Acalabrutinib-obinutuzumab resulted in improved PFS vs acalabrutinib monotherapy (hazard ratio [HR]: 0.58, P = .0229).

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2409804

Fixed-Duration Acalabrutinib Combinations in Untreated ... Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib–venetoclax, 83.1% with ...

3. ashpublications.org ashpublications.org/blood/article/146/11/1276/536611/Acalabrutinib-obinutuzumab-improves-survival-vs

Acalabrutinib-obinutuzumab improves survival vs ... Patients with CLL who achieved CR/CRi in the acalabrutinib-obinutuzumab arm achieved higher rates of undetectable MRD in peripheral blood samples than patients ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04505254?term=r7159&viewType=Table&checkSpell=&rank=10

Acalabrutinib and Obinutuzumab for the Treatment of ... This phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating patients with chronic lymphocytic leukemia (CLL).

5. onclive.com onclive.com/view/acalabrutinib-plus-venetoclax-and-obinutuzumab-displays-high-level-of-activity-in-first-line-high-risk-cll

Acalabrutinib Plus Venetoclax and Obinutuzumab Displays ... Acalabrutinib, venetoclax, and obinutuzumab showed efficacy in high-risk CLL with TP53 aberrations, achieving 42% CR with BM-uMRD by cycle 16.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05517265

Study Details | NCT05517265 | Acalabrutinib in Patients ... The goal of CICERO is to investigate the clinical outcome with a particular focus on prospective data on safety using acalabrutinib (+/- obinutuzumab) in CLL ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38952054/

Safety and efficacy of acalabrutinib and obinutuzumab in ... Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12432023/

Real-world efficacy and safety outcomes of acalabrutinib in ... The ELEVATE-TN and ASCEND phase III trials have shown superior efficacy and a favourable safety profile compared to standard chemo-immunotherapy ...

9. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5151/503709/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... Real-world effectiveness and safety outcomes of Acalabrutinib treatment by line of therapy in patients with chronic lymphocytic leukemia and/or small ...