Acalabrutinib +/- Obinutuzumab for Chronic Lymphocytic Leukemia

Recruiting at 2 trial locations

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Antiretrovirals, Anticoagulants, CYP3A inducers

Disqualifiers: CNS lymphoma, Active infection, 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: 6

Duration: 12 cycles (approximately 1 year)

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trials studies how well acalabrutinib with or without obinutuzumab works in treating patients with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving acalabrutinib with or without obinutuzumab will work better in treating patients with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on anticoagulation therapy with warfarin or similar drugs, or if you require treatment with a strong CYP3A inducer, you may need to stop these before starting the trial.

What data supports the effectiveness of the drug Acalabrutinib +/- Obinutuzumab for Chronic Lymphocytic Leukemia?

Research shows that Acalabrutinib, alone or with Obinutuzumab, significantly extends the time patients live without their disease getting worse compared to standard treatments for chronic lymphocytic leukemia. It has a favorable safety profile, meaning it generally causes fewer side effects compared to other targeted therapies. ^{1 2 3 4 5}

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

Acalabrutinib, used alone or with Obinutuzumab, generally has a favorable safety profile compared to other treatments for chronic lymphocytic leukemia, though it may increase the risk of low white blood cell counts (neutropenia and leukopenia). Obinutuzumab can cause infusion-related reactions, which are usually mild to moderate and manageable. ^{1 2 3 6 7}

How is the drug Acalabrutinib +/- Obinutuzumab unique for treating chronic lymphocytic leukemia?

Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor, which means it specifically targets a protein involved in the growth of cancer cells, and when combined with Obinutuzumab, an antibody that helps the immune system attack cancer cells, it offers a novel approach with improved safety and durable responses compared to some existing treatments for chronic lymphocytic leukemia. ^{1 2 4 5 8}

Research Team

Sameer Parikh, MD

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

Adults diagnosed with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma, who have not been treated before, can join this trial. They must be in good health overall and able to provide blood and saliva samples for research. Pregnant or nursing individuals, those with certain heart conditions, active infections like hepatitis B/C or HIV on treatment are excluded.

Inclusion Criteria

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

Provide written informed consent

Willing to provide blood and saliva samples for correlative research purposes

Exclusion Criteria

For high risk and very high risk CLL-IPI (Arms A and B) only: Persons of childbearing potential who are unwilling to employ highly effective contraception

Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

For high risk and very high risk CLL-IPI (Arms A and B) only: Pregnant persons

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive acalabrutinib with or without obinutuzumab for 12 cycles, with initial cycles of 28 days and subsequent cycles of 84 days

12 cycles (approximately 1 year)

Multiple visits per cycle, including in-person and IV administration visits

Observation

Patients in Arm C are observed every 6 months for up to 2 years

2 years

Biannual visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 6 months

Treatment Details

Interventions

• Acalabrutinib
• Obinutuzumab

Trial Overview The trial is testing the effectiveness of acalabrutinib alone versus combined with obinutuzumab in treating patients. Acalabrutinib blocks enzymes that cancer cells need to grow while obinutuzumab may help the immune system attack cancer.

Participant Groups

Group I: Arm B (acalabrutinib, obinutuzumab) Experimental Treatment 4 Interventions

Patients receive acalabrutinib PO BID on days 1-28 and obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1 and days 1 of subsequent cycles. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive acalabrutinib PO BID on days 1-84. Treatment repeats every 84 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment with acalabrutinib If MRD negative CR/CRi is not achieved after 12 cycles.

Group II: Arm A (acalabrutinib) Experimental Treatment 3 Interventions

Patients receive acalabrutinib PO BID on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive acalabrutinib PO BID on days 1-84. Treatment repeats every 84 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment with acalabrutinib If MRD negative CR/CRi is not achieved after 12 cycles.

Group III: Arm C (observation) Active Control 3 Interventions

Patients will be observed every 6 months for up to 2 years.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

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]

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 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 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]

References

1. United States 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. [2021]

2. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

3. United States 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. [2022]

4. England 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. [2021]

5. United States 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. [2021]

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

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab. [2017]

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

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

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

Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia. [2022]