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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of acalabrutinib (Calquence), with or without obinutuzumab, for treating early-stage chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Acalabrutinib blocks certain enzymes to stop cancer cell growth, while obinutuzumab, an immunotherapy, helps the immune system attack cancer cells. Participants will receive either acalabrutinib alone, acalabrutinib with obinutuzumab, or be under observation. The trial seeks individuals diagnosed with CLL or SLL who have not received prior treatments for these conditions. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that acalabrutinib is generally well-tolerated by patients with chronic lymphocytic leukemia (CLL). One study identified common side effects such as anemia (a low red blood cell count) and upper respiratory infections, affecting less than one-third of patients. Another study found acalabrutinib to be safer than traditional chemotherapy, particularly concerning heart-related side effects.

When combined with obinutuzumab, studies indicate that acalabrutinib remains generally safe, with side effects similar to those of acalabrutinib alone. Research also suggests that this combination helps patients live longer compared to traditional treatments.

Overall, both treatments have undergone testing in several studies and are considered safe for many patients. However, like all treatments, there is a chance of side effects. Always discuss potential risks and benefits with a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments acalabrutinib and obinutuzumab for chronic lymphocytic leukemia (CLL) because they offer new approaches compared to standard chemotherapy and targeted therapies like ibrutinib. Acalabrutinib is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, which targets the BTK enzyme that helps CLL cells survive and multiply. This makes it potentially more selective and with fewer side effects than current BTK inhibitors. Obinutuzumab, on the other hand, is a monoclonal antibody that enhances the immune system's ability to attack cancer cells. Together, these treatments could offer a more effective and potentially less toxic option for patients with CLL.

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

Research has shown that acalabrutinib effectively treats chronic lymphocytic leukemia (CLL). In this trial, participants in Arm A will receive acalabrutinib alone. One study found that 83% of patients taking acalabrutinib did not experience cancer growth or spread. Participants in Arm B will receive a combination of acalabrutinib and obinutuzumab. Another study found that this combination allowed patients to live longer without their disease worsening and resulted in higher rates of undetectable minimal residual disease, meaning cancer cells were nearly gone, compared to using acalabrutinib alone. Additionally, after 48 months, 87% of patients on the combination treatment showed no disease progression, indicating its promise in controlling the disease. ^{2 3 6 7 8}

Who Is on the Research Team?

Sameer Parikh, MD

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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 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]

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]

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]

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]

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, 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40736551/

Real-world efficacy and safety outcomes of acalabrutinib in ... NAOS, a real-world study, complements these trials with real-world (rw) acalabrutinib data generated from clinical practice.

2. 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 ...

3. calquence.com calquence.com/why-calquence/how-effective-calquence-cll.html

How Effective Is CALQUENCE® (acalabrutinib)? | CLL 83% (128 of 155) of people on CALQUENCE had no cancer growth or spread compared to 56% (87 of 155) of people taking an alternative combination treatment.§.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1509981

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic ... At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39463596/

Assessment of the Efficacy and Safety of Acalabrutinib in ... Acalabrutinib is an active drug in treating CLL that induces significant clinical benefits concerning response rates and PFS.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/216387Orig2s000Correctedlbl.pdf

CALQUENCE® (acalabrutinib) tablets, for oral use In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04008706

NCT04008706 | Acalabrutinib Safety Study in Untreated ... To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.

8. hematologyadvisor.com hematologyadvisor.com/news/chronic-leukemia-cll-safety-profile-acalabrutinib-superior-chemoimmunotherapy/

Safety Profile of Acalabrutinib Superior to ... The cardiovascular safety profile of acalabrutinib is superior to that of chemoimmunotherapy in treating patients with chronic lymphocytic leukemia (CLL).