Acalabrutinib for CNS Lymphoma

Not currently recruiting at 4 trial locations

Overseen By Rose Hall

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Anticoagulants, Proton pump inhibitors

Disqualifiers: Pregnancy, Severe hepatic insufficiency, HIV, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether acalabrutinib can safely and effectively control relapsed central nervous system (CNS) lymphoma, a cancer affecting the brain and spinal cord. Currently, no FDA-approved treatments exist specifically for relapsed CNS lymphoma. Acalabrutinib targets the cancer similarly to ibrutinib, which showed promising results in past studies. The trial includes individuals who have tried at least one chemotherapy treatment for CNS lymphoma and have no signs of cancer outside the CNS. Participants must be able to swallow pills and have a confirmed diagnosis of CNS lymphoma. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to potential advancements in CNS lymphoma treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but certain medications are prohibited. You cannot take anticoagulants like warfarin or direct oral anticoagulants close to the start of the study, and you must avoid proton pump inhibitors unless switched to alternatives. Check with the study team for specific guidance on your medications.

Is there any evidence suggesting that acalabrutinib is likely to be safe for humans?

Research has shown that acalabrutinib has been tested for safety in people with central nervous system (CNS) lymphoma. Early results suggest that most people tolerate this treatment well. In other studies, the FDA approved acalabrutinib for treating mantle cell lymphoma, indicating its general safety. This drug works similarly to ibrutinib, which has shown promise in treating CNS lymphomas. Although acalabrutinib still requires direct approval for relapsed CNS lymphoma, these findings offer some reassurance about its potential safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CNS lymphoma?

Acalabrutinib is unique because it specifically targets Bruton's tyrosine kinase (BTK), a key enzyme involved in the growth and survival of lymphoma cells. Unlike traditional chemotherapy, which can affect both cancerous and healthy cells, acalabrutinib zeroes in on this enzyme, potentially leading to fewer side effects. Researchers are excited about acalabrutinib because it offers a more targeted approach, which could be especially beneficial for relapsed central nervous system lymphomas where existing treatments often struggle to penetrate the blood-brain barrier effectively.

What evidence suggests that acalabrutinib might be an effective treatment for CNS lymphoma?

Research has shown that acalabrutinib, a drug approved for treating mantle cell lymphoma, might also help with CNS lymphoma. Acalabrutinib functions similarly to ibrutinib, another drug that has shown promise in treating CNS lymphomas. Both drugs target a specific protein that aids cancer cell growth. Acalabrutinib may target this protein more effectively than ibrutinib. Some studies suggest that acalabrutinib can shrink cancer cells in relapsed CNS lymphoma. While this is encouraging, further research is needed to confirm its effectiveness for CNS lymphoma. Participants in this trial will receive acalabrutinib to investigate its antitumor effects in subjects with relapsed primary central nervous system lymphoma (PCNSL) and relapsed secondary CNS lymphoma (SCNSL). ^{1 2 4 5 6}

Who Is on the Research Team?

Christopher E. Dittus

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with relapsed CNS lymphoma who've had at least one prior chemotherapy treatment can join this trial. They must not be pregnant, breastfeeding, or have severe liver issues. Participants need to use effective contraception and should not have a history of certain heart diseases or infections like HIV.

Inclusion Criteria

I have B-cell Non-Hodgkin Lymphoma.

My blood counts, kidney, liver, and clotting functions are within safe ranges.

I have another cancer type, but it won't affect this cancer treatment's safety or results.

Exclusion Criteria

I have been tested for hepatitis C and my PCR results are negative.

I have been treated with a BTK inhibitor before.

Subject has a known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or isavuconazole.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib at the dose of 100 mg every 12 hours

2 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Isavuconazole

Trial Overview The study is testing acalabrutinib's safety and effectiveness for controlling relapsed CNS lymphoma. There are no FDA-approved treatments for this condition yet. Acalabrutinib targets cancer cells similarly to an approved drug for another lymphoma type. Isavuconazole is also given to prevent fungal infections during the trial.

How Is the Trial Designed?

Group I: Open-label, single-arm Experimental Treatment 1 Intervention

A multicenter open-label, single-arm, phase 2 study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed primary central nervous system lymphoma (PCNSL), and relapsed secondary CNS lymphoma (SCNSL) with no evidence of current systemic disease. Subjects will receive acalabrutinib at the dose of 100 mg every 12 hours.

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?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

The ACCEPT trial is investigating the safety and efficacy of adding acalabrutinib, a second-generation Btk inhibitor, to the standard R-CHOP regimen in patients with untreated Diffuse Large B-cell Lymphoma (DLBCL), with a focus on establishing the recommended dose and assessing overall response rates.

This open-label trial includes up to 39 participants and aims to provide preliminary evidence on the combination's effectiveness and safety, potentially paving the way for larger Phase II/III trials in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial. Davies, A., Barrans, S., Burton, C., et al.[2021]

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, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

In a phase 2 trial involving 124 patients with relapsed or refractory mantle cell lymphoma, acalabrutinib was associated with common treatment-related adverse events (AEs) like headache and diarrhea, but these did not lead to any treatment discontinuations.

Effective management strategies, including patient education and the use of over-the-counter medications for mild AEs, helped maintain treatment adherence and allowed for better tracking and management of nonadherence issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. Badillo, M., Nava, D., Rosa, M., et al.[2022]

Acalabrutinib, a Bruton tyrosine kinase inhibitor, showed a 53% overall response rate in patients with relapsed/refractory marginal zone lymphoma, indicating its efficacy in this patient population.

The treatment was generally well tolerated, with a median progression-free survival of 27.4 months and a low incidence of severe adverse events, suggesting improved safety compared to other treatments like ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. Strati, P., Coleman, M., Champion, R., et al.[2022]

Acalabrutinib, a selective Bruton's tyrosine kinase inhibitor, was found to increase the risk of any-grade cardiac events in patients with chronic lymphocytic leukemia, with a risk ratio of 1.75.

There was a notable trend indicating a higher risk of any-grade atrial fibrillation associated with acalabrutinib, with a risk ratio of 2.56, although no significant increase in hypertension or high-grade cardiac events was observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials. Htut, TW., Han, MM., Thein, KZ.[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]

The combination of intra-arterial nimustine (ACNU) and whole brain radiotherapy resulted in a high complete response rate of 75% in 63 patients with primary central nervous system lymphoma, with median overall survival of 39 months.

While the treatment showed promising efficacy, it also led to significant side effects, particularly myelosuppression in 60% of patients and late neurotoxicity in 34% of older patients (over 60 years), highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy. Sonoda, Y., Matsumoto, K., Kakuto, Y., et al.[2013]

In a pivotal phase 3 study with 310 patients, acalabrutinib significantly improved progression-free survival (PFS) compared to standard treatments (Idelalisib plus rituximab or bendamustine plus rituximab), with a median PFS not reached for acalabrutinib versus 16.8 months for IdR/BR.

After approximately 4 years of follow-up, acalabrutinib demonstrated a favorable safety profile, with lower rates of treatment discontinuation due to adverse events compared to IdR/BR, while maintaining similar rates of serious infections and other significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Ghia, P., Pluta, A., Wach, M., et al.[2022]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/985/530401/Phase-I-Results-of-Acalabrutinib-in-Combination

Phase I Results of Acalabrutinib in Combination with ... Here we present the results of the phase I portion of the combination of acalabrutinib and durvalumab in R/R CNS lymphoma, as well as data ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04906902

Study Details | NCT04906902 | Acalabrutinib in CNSL This research study is a Phase 1/2 clinical trial testing the safety, tolerance and efficacy of the drug Acalabrutinib for people with recurrent or refractory ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124037327

Phase I Results of Acalabrutinib in Combination with ... Durvalumab 1500mg IV (day 1) and acalabrutinib 100 mg twice daily (days 1-28) of a 28-day cycle demonstrates clinical activity in pts with R/R PCNSL with ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04462328

NCT04462328 | Acalabrutinib and Durvalumab in Primary ... BTK inhibition and checkpoint blockade are promising classes of therapy for central nervous system (CNS) lymphoma and have demonstrated efficacy with ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12126982/

Novel Therapies in Primary Central Nervous System Lymphoma Currently, there is no published data available on acalabrutinib BBB penetration and activity of acalabrutinib in CNS lymphoma. Several ongoing ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265024015416

ABCL-607 Trial in Progress: Phase 1 Study With Dose ... Patients with secondary CNS lymphoma or primary vitreoretinal lymphoma will be excluded. The phase 1 portion will have a 3+3 design studying the combination of ...