Acalabrutinib + Rituximab for B-Cell Lymphoma

(ACRUE Trial)

Recruiting at 72 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must not be taking: Warfarin

Disqualifiers: HIV, Hepatitis B/C, Stroke, 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: Unknown

Duration: 104 weeks

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination using acalabrutinib (a targeted therapy) and rituximab (a monoclonal antibody therapy) for individuals with diffuse large B-cell lymphoma, a type of blood cancer. The researchers aim to determine the safety and effectiveness of this combination for patients who have not received prior treatment and cannot undergo the usual chemoimmunotherapy. The trial seeks participants who are 65 or older, have been diagnosed with this type of lymphoma, and have no previous treatment history for it. As a Phase 2 trial, the research focuses on measuring 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, but it does exclude those who require anticoagulation with warfarin or similar medications. It's best to discuss your specific medications with the trial team.

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

A previous study found that acalabrutinib was generally well-tolerated by patients with certain types of lymphoma. Common side effects included low red blood cell count (anemia), low white blood cell count (neutropenia), and upper respiratory infections, occurring in more than 30% of patients.

Rituximab has been used for many years to treat different types of lymphoma. It often causes mild side effects like fever, chills, and nausea, especially during the first treatment. Serious side effects are rare but can include severe skin reactions and issues with B-cell lymphocytes, a type of white blood cell.

Both acalabrutinib and rituximab have safety records that support their use in treating lymphoma. However, potential trial participants should discuss any concerns with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of acalabrutinib and rituximab for treating B-cell lymphoma because it targets the disease in a unique way. Unlike standard treatments that often focus on chemotherapy, acalabrutinib works as a targeted therapy by inhibiting Bruton's tyrosine kinase (BTK), which plays a crucial role in the growth and survival of cancer cells. Rituximab, on the other hand, is a monoclonal antibody that targets the CD20 protein on the surface of B-cells, marking them for destruction by the immune system. This combination not only tackles the cancer cells from two different angles but also potentially reduces the side effects associated with traditional chemotherapy.

What evidence suggests that acalabrutinib and rituximab could be effective for diffuse large B-cell lymphoma?

Research has shown that combining acalabrutinib and rituximab holds promise for treating certain types of lymphoma, a kind of blood cancer. In this trial, participants will receive both acalabrutinib and rituximab. One study found this combination effective and safe as a first treatment, especially in older patients with mantle cell lymphoma. Another study demonstrated that using acalabrutinib with rituximab provided significant benefits with manageable side effects. These findings suggest this treatment could also be effective for diffuse large B-cell lymphoma, particularly for patients unable to tolerate standard treatments. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for elderly or frail patients who have not been treated for diffuse large B-cell lymphoma (DLBCL) and are unsuitable for standard treatments. Participants must be over 65 years old, with a performance status of 0-2, meaning they can perform daily activities with varying degrees of assistance. They should also have at least one measurable lesion and adequate organ/marrow function.

Inclusion Criteria

I am between 65 and 79 years old and not eligible for chemoimmunotherapy.

My physical ability hasn't worsened in the last 2 weeks, except for symptoms from my lymphoma.

I have a tumor that is at least 10 mm large and can be measured by scans.

Exclusion Criteria

I have been diagnosed with or currently have Progressive Multifocal Leukoencephalopathy.

I have not had a stroke or brain bleed in the last 6 months.

I do not have a severe illness or organ problem scored 4 or a total illness score over 6.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive acalabrutinib orally and rituximab intravenously/subcutaneously for up to 28 cycles

104 weeks

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Rituximab

Trial Overview The study tests the combination of Acalabrutinib and Rituximab in untreated elderly/frail patients with DLBCL to assess safety, tolerability, and effectiveness. It's designed for those who cannot undergo standard chemoimmunotherapy due to their age or frailty.

How Is the Trial Designed?

Group I: Acalabrutinib and Rituximab Experimental Treatment 2 Interventions

Patients will receive Dose A of acalabrutinib orally in X dosing schedule beginning on Cycle 1 Day 1 for a maximum of 28 cycles or until 2014 Lugano Classification for Non-Hodgkin's Lymphoma (NHL)-defined disease progression or another discontinuation criterion is met. Patients will also receive an intravenous (IV) infusion of Dose B rituximab on Cycle 1 Day 15 and Dose C of rituximab as an subcutaneous (SC) injection on Day 1 of Cycle 2 through Cycle 8.

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?

AstraZeneca

Lead 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

Rituximab, an anti-CD20 monoclonal antibody, significantly improves treatment outcomes for patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) when used in combination with chemotherapy, leading to better tumor remission and patient survival compared to chemotherapy alone.

Rituximab maintenance therapy prolongs tumor remission and is generally well tolerated, making it a valuable option for both first- and second-line treatments in advanced-stage B-cell NHL and CLL, and it is included in current treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Cvetković, RS., Perry, CM.[2018]

Rituximab is a genetically engineered monoclonal antibody that effectively targets CD20-positive B-cell malignancies, making it a key treatment for conditions like non-Hodgkin lymphoma and chronic lymphocytic leukemia.

While rituximab is effective for various B-cell related diseases, it carries significant risks, including severe infusion reactions and other serious side effects, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of rituximab in cutaneous medicine. Scheinfeld, N.[2020]

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]

Acalabrutinib, a selective BTK inhibitor, has shown improved progression-free survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) compared to standard treatments, indicating its efficacy as a treatment option.

The safety profile of acalabrutinib is favorable, with most side effects being mild (grade 1/2), such as headache and diarrhea, and a low rate of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies. Abbas, HA., Wierda, WG.[2023]

In a study of 34 patients with relapsed/refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), maintenance therapy with lenalidomide after bendamustine and rituximab (BR) did not significantly improve progression-free survival (PFS), which was 18.3 months compared to 15.2 months without maintenance.

The study highlighted challenges with lenalidomide maintenance due to hematological and infectious toxicities, as only 6 out of 19 patients completed the intended 12 cycles, suggesting that lenalidomide may be more effective in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study. Chang, JE., Havighurst, T., Kim, K., et al.[2018]

Rituximab plus bendamustine (R-B) is less toxic and achieves similar complete remission rates compared to R-CHOP in patients with follicular lymphoma grade 3A, with 97% vs. 96% complete remissions respectively.

Patients treated with R-B experienced significantly lower relapse rates (16% vs. 41%) and longer progression-free survival (15 years vs. 11.7 years) compared to those treated with R-CHOP, making R-B a more effective first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine plus Rituximab Versus R-CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study. Mondello, P., Steiner, N., Willenbacher, W., et al.[2019]

Rituximab is primarily indicated for refractory immune thrombocytopenic purpura and is considered the best treatment for cold agglutinin disease, but its long-term benefit-to-risk ratio remains uncertain, especially in relation to splenectomy.

While rituximab shows promise in treating various autoimmune diseases, including Wegener granulomatosis and HCV-associated cryoglobulinemia, there are significant risks of adverse events, particularly infections and severe reactions in certain patient populations, highlighting the need for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab off label use for difficult-to-treat auto-immune diseases: reappraisal of benefits and risks. Sailler, L.[2022]

Rituximab-treated patients with B cell non-Hodgkin lymphoma (NHL) showed significant humoral immunodeficiency, with only 20% responding to diphtheria and pneumococcal vaccinations, despite having relatively normal IgG levels.

Subcutaneous immunoglobulin (subq Ig) therapy was well-tolerated and significantly increased serum IgG levels, leading to a reduction in nonneutropenic infections, indicating its efficacy as a supportive treatment for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of 20% Subcutaneous Immunoglobulin Replacement Therapy in Patients With B Cell Non-Hodgkin Lymphoma With Humoral Immune Dysfunction After Treatment With Rituximab. Mustafa, SS., Jamshed, S., Vadamalai, K., et al.[2021]

In a study of Thai patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab and CHOP chemotherapy, the distribution of FcγRIIIa polymorphisms showed no significant correlation with clinical outcomes, indicating that genetic variations at this position do not affect treatment response.

The majority of patients had a complete response to treatment regardless of their FcγRIIIa genotype, with response rates of 84.62% for homozygous V/V, 88.24% for heterozygous V/F, and 80.00% for homozygous F/F, suggesting that rituximab's efficacy is consistent across different genetic backgrounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation of FcγRIIIa Polymorphisms to the Response of Rituximab in Thai Patients with Diffuse Large B-Cell Lymphoma. Angsirisak, N., Wittayalertpanya, S., Limpanasithikul, W., et al.[2018]

In a study involving four patients with primary refractory or early relapsed T cell rich B cell lymphomas (TCRBCL), the combination of rituximab with chemotherapy (vinorelbine and gemcitabine) resulted in three complete responses and one partial response, demonstrating significant efficacy.

The treatment was well-tolerated, with no significant adverse effects reported, suggesting that rituximab combined with chemotherapy could be a promising option for treating TCRBCL and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in combination with vinorelbine/gemcitabine chemotherapy in patients with primary refractory or early relapsed T cell rich B cell lymphoma. A pilot study. Xiros, N., Economopoulos, T., Valsami, S., 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 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 alone or in combination with rituximab for ... In this open-label, parallel-group study, patients with relapsed/refractory (R/R) follicular lymphoma (FL) were randomised to either acalabrutinib monotherapy ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03571568

NCT03571568 | A Study of BI-1206 in Combination With ... Evaluate the effect of BI-1206 administered IV or SC in combination with rituximab or rituximab and acalabrutinib measuring B Lymphocytes CD19+ (absolute value) ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00690

Acalabrutinib Plus Bendamustine-Rituximab in Untreated ... Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity. Introduction. Mantle cell lymphoma (MCL) is ...

4. ashpublications.org ashpublications.org/bloodadvances/article/8/17/4539/516190/Acalabrutinib-plus-venetoclax-and-rituximab-in

Acalabrutinib plus venetoclax and rituximab in treatment-naive ... This phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL).

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124057902

Acalabrutinib with Rituximab Is Highly Effective First Line ... Chemotherapy-free frontline therapy with AR is highly effective, safe, induces deep MRD negative responses and alters immune landscape in older pts with MCL.

6. ema.europa.eu ema.europa.eu/en/documents/variation-report/calquence-h-c-005299-ii-0026-epar-assessment-report-extention-indication_en.pdf

Calquence; INN-acalabrutinib - EMA MCL is a rare subtype of B-cell non-Hodgkin lymphoma (NHL) that accounts for approximately 7% of adult NHLs in the United States (US) and Europe ...

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/7744/528340/Real-World-Effectiveness-and-Safety-Outcomes-of

Real-World Effectiveness and Safety Outcomes of ... Real-world effectiveness and safety outcomes of Acalabrutinib treatment in patients with relapsed/refractory mantle cell lymphoma.

8. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/calquence-acalabrutinib-plus-chemoimmunotherapy-approved-in-the-us-for-patients-with-previously-untreated-mantle-cell-lymphoma.html

CALQUENCE® (acalabrutinib) plus chemoimmunotherapy ... Based on ECHO Phase III trial results which showed more than 16 months of progression-free survival improvement vs. chemoimmunotherapy alone.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/216387s004lbl.pdf

Clinical Trials - accessdata.fda.gov In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, ...

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Acalabrutinib (ACP-196), a Btk Inhibitor, for Treatment of de ... To characterize the safety profile of acalabrutinib in subjects with relapsed or refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell ...