Acalabrutinib + Obinutuzumab for Chronic Lymphocytic Leukemia

Overseen By Jan A Burger, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Vitamin K antagonists

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, 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: 1

Duration: 24 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining acalabrutinib and obinutuzumab to treat individuals with chronic lymphocytic leukemia (CLL) who have not yet received treatment. Acalabrutinib blocks certain enzymes that promote cancer cell growth, while obinutuzumab, an immunotherapy, may enhance the immune system's ability to fight cancer. The study aims to determine if this combination can slow or halt the progression of CLL. Eligible participants have CLL that requires treatment and have not been previously treated for it. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take warfarin (a blood thinner) and must switch to a different type of blood thinner if needed. Also, you cannot use strong CYP3A4 inhibitors/inducers (types of drugs that affect how your body processes medications).

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

Research has shown that the combination of acalabrutinib and obinutuzumab is generally safe for patients. Studies have found this treatment to be safer than standard treatments for chronic lymphocytic leukemia (CLL). In these studies, patients did not experience severe side effects more frequently than those on other treatments.

The most common side effects were mild to moderate, such as headaches, which can often be managed with over-the-counter pain relievers, and mild infections, which are usually treatable. More serious side effects were less common. This suggests that, for many patients, the benefits of the treatment may outweigh the risks.

Prospective trial participants should consult a healthcare provider to understand how this treatment might align with their health needs. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about acalabrutinib combined with obinutuzumab for chronic lymphocytic leukemia (CLL) because this combo targets the cancer in a fresh way. Acalabrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which means it blocks a protein that helps cancer cells grow and survive. Obinutuzumab is a monoclonal antibody that specifically attacks cancer cells, helping to mark them for destruction by the immune system. This dual approach could offer more precise targeting of cancer cells compared to standard treatments, potentially leading to better outcomes for patients.

What evidence suggests that acalabrutinib and obinutuzumab might be effective for chronic lymphocytic leukemia?

Research has shown that using acalabrutinib and obinutuzumab together, as studied in this trial, may help treat chronic lymphocytic leukemia (CLL). Studies have found that this combination helps patients live longer without disease progression. In one study, 87% of patients experienced no disease progression after 48 months. Additionally, more patients achieved very low levels of cancer cells in their blood, known as undetectable minimal residual disease (MRD). Overall, these results suggest that acalabrutinib and obinutuzumab may effectively manage CLL. ^{1 2 4 6 7}

Who Is on the Research Team?

Jan A. Burger

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with chronic lymphocytic leukemia (CLL) who haven't been treated before. They should have a creatinine clearance over 30 mL/min, normal liver function tests, and no prior malignancies within the last 2 years except certain skin cancers or 'in situ' carcinomas. Participants must be willing to use effective birth control and not be pregnant or breastfeeding. People with previous CLL treatments, significant infections, uncontrolled heart conditions, recent strokes or surgeries are excluded.

Inclusion Criteria

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) except for patients with bilirubin elevation due to Gilbert's disease who will be allowed to participate

I have been diagnosed with CLL/SLL and have not received any treatment.

I am able to care for myself and perform daily activities.

Exclusion Criteria

I have not had major surgery or a serious injury in the last 28 days.

I need treatment with a strong medication that affects liver enzymes.

I can't swallow pills or have a stomach condition affecting medication absorption.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib orally twice a day and obinutuzumab intravenously, with treatment repeating every 28 days for up to 24 cycles

24 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 years

1 visit at 30 days post-treatment, then every 3 months

Optional Extension

Participants who do not achieve a complete response may receive additional cycles of acalabrutinib and obinutuzumab

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab

Trial Overview The trial is testing how well acalabrutinib combined with obinutuzumab works in treating CLL. Acalabrutinib blocks enzymes needed for tumor growth while obinutuzumab may help the immune system interfere with tumor cell growth and spread. The goal is to see if this combination can better manage disease progression in untreated CLL patients.

How Is the Trial Designed?

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

Patients receive acalabrutinib PO BID every 12 hours starting on day 1 of cycle 1, and obinutuzumab IV over 4-6 hours on days 1 and 2 of cycle 3, and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at the discretion of their treating physician. Patients who are in partial response or who have stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV. Treatment repeats every 28 days for up to 24 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Obinutuzumab combined with chlorambucil shows better treatment outcomes for patients with untreated chronic lymphocytic leukemia compared to rituximab plus chlorambucil, while maintaining a similar safety profile.

Infusion-related reactions (IRRs) are more common with obinutuzumab, particularly during the first infusion, but these reactions are generally manageable with proper monitoring and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. Dawson, K., Moran, M., Guindon, K., et al.[2017]

In a phase Ib/II study involving 45 patients with chronic lymphocytic leukemia (CLL), the combination of acalabrutinib and obinutuzumab resulted in high overall response rates of 95% for treatment-naïve patients and 92% for relapsed/refractory patients, demonstrating strong efficacy.

The treatment was well tolerated, with 94% of treatment-naïve and 88% of relapsed/refractory patients remaining progression-free at 36 months, indicating that this combination therapy could provide durable responses in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia. Woyach, JA., Blachly, JS., Rogers, KA., et al.[2022]

In a multinational phase III study, obinutuzumab combined with chlorambucil significantly improved progression-free survival and event-free survival in adults with previously untreated chronic lymphocytic leukaemia (CLL) compared to chlorambucil alone and rituximab plus chlorambucil.

Obinutuzumab plus chlorambucil had a manageable safety profile, with neutropenia and infusion-related reactions being the most common serious side effects, primarily occurring during the first infusion and generally manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. Hoy, SM.[2018]

In a phase 3 study involving 535 patients with treatment-naive chronic lymphocytic leukaemia, acalabrutinib combined with obinutuzumab or as a monotherapy significantly improved progression-free survival compared to the standard treatment of obinutuzumab with chlorambucil, with median survival not reached for the acalabrutinib groups versus 22.6 months for the chlorambucil group.

The safety profile of acalabrutinib was favorable, with fewer infusion reactions and a lower incidence of grade 3 or higher adverse events compared to the obinutuzumab-chlorambucil group, indicating it is a viable chemotherapy-free treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Sharman, JP., Egyed, M., Jurczak, W., et al.[2021]

In a phase III study involving 310 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared to investigator's choice treatments, with a median PFS not reached for acalabrutinib versus 16.5 months for the comparator group.

Acalabrutinib demonstrated a favorable safety profile, with serious adverse events occurring in 29% of patients, compared to 56% for idelalisib plus rituximab and 26% for bendamustine plus rituximab, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Ghia, P., Pluta, A., Wach, M., et al.[2021]

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., et al.[2021]

Obinutuzumab, in combination with chlorambucil, significantly improved progression-free survival (PFS) in patients with previously untreated chronic lymphocytic leukemia (CLL), with a median PFS of 23.0 months compared to 11.1 months for chlorambucil alone.

The treatment also resulted in a higher overall response rate (ORR) of 75.9% for the obinutuzumab group versus 32.1% for the chlorambucil group, indicating its efficacy in treating CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia. Lee, HZ., Miller, BW., Kwitkowski, VE., et al.[2022]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

Citations

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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 ...

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

Real-world efficacy and safety outcomes of acalabrutinib in ... The estimated 48-month progression-free survival (PFS) rates after 4 years of follow-up were 87.0% for acalabrutinib-obinutuzumab, 77.9% for ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04505254

NCT04505254 | Acalabrutinib and Obinutuzumab for the ... This phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating patients with chronic lymphocytic leukemia (CLL).

5. 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).

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. 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 ...