Phase II Study of Acalabrutinib with R-CHOP in Previously Untreated Mantle Cell Lymphoma in Spain

Trial ID: 2025-521152-34-00
Protocol: D8220L00087
Sponsor: Astrazeneca Farmaceutica Spain S.A.

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Diseases & Conditions

Mantle cell lymphoma

Objectives

The primary objective of this study is to assess the **efficacy** in terms of treatment response to **acalabrutinib**, in combination with the R-CHOP standard of care, in subjects with previously untreated **mantle cell lymphoma (MCL)**. This is clinically relevant as it aims to determine the potential of acalabrutinib to improve treatment outcomes in MCL, a type of non-Hodgkin lymphoma that is often aggressive and challenging to treat.

Secondary objectives include:

To further assess the efficacy of acalabrutinib, in combination with the R-CHOP standard of care, in subjects with previously untreated MCL.
To assess the safety and tolerability profile of acalabrutinib, in combination with the R-CHOP standard of care, in subjects with previously untreated MCL.

Participants

The clinical trial involves participants diagnosed with **mantle cell lymphoma (MCL)**, specifically those who have not received prior systemic anticancer therapies. The study population includes both male and female adults aged 18 years and older. Participants are required to have a pathologically confirmed diagnosis of MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The sponsor has not provided the total number of participants. Lifestyle considerations such as the ability to swallow tablets without difficulty and adherence to contraception guidelines are necessary for participation. The selection criteria ensure that participants are suitable for the study's objectives, focusing on the efficacy of acalabrutinib in combination with the R-CHOP standard of care.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **acalabrutinib** in combination with the R-CHOP standard of care for patients with previously untreated **mantle cell lymphoma** (MCL). This is a single-arm, open-label, multicenter, phase II study. The trial aims to assess the treatment response in terms of overall response rate (ORR) as per the Lugano Classification for non-Hodgkin lymphoma (NHL). The study is expected to conclude by December 31, 2028, with recruitment starting on June 30, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ability to swallow tablets, and a confirmed diagnosis of MCL. The trial will include follow-up visits to monitor treatment response and adverse events, with the primary endpoint being the best ORR within one year. Secondary endpoints include time to response (TTR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS), measured over a 30-month period. The end-of-study visit will assess the final treatment outcomes and any long-term effects.

The expected length of participant involvement is approximately 30 months, with conditions for early termination including significant adverse events or disease progression. Participants must adhere to contraceptive guidelines during and after the study to prevent pregnancy. The study will monitor the incidence of adverse events (AEs) and serious adverse events (SAEs), with particular attention to those leading to dose modification or discontinuation of acalabrutinib. The trial is not classified as low intervention and is conducted under the authorization of AstraZeneca AB, with the investigational product being Calquence 100 mg film-coated tablets, administered orally.

Treatment

The clinical trial involves the administration of **acalabrutinib**, marketed under the name Calquence, as the experimental medication. Calquence is provided in the form of **film-coated tablets**, each containing 100 mg of the active substance acalabrutinib. The tablets are administered **orally**. The maximum daily dose is 200 mg, with a total maximum dose of 180,000 mg over the course of the treatment. The treatment period is set for a maximum of 30 days. Acalabrutinib functions as a chemotherapeutic agent, specifically a Bruton tyrosine kinase inhibitor, and is chemically synthesized. The medication is produced by AstraZeneca AB and is not formulated for pediatric use.

In addition to the experimental treatment, the study incorporates the R-CHOP regimen as the standard-of-care therapy. R-CHOP is a combination chemotherapy regimen commonly used in the treatment of mantle cell lymphoma. It includes the following components: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. This regimen is administered according to standard clinical practice guidelines for the treatment of previously untreated mantle cell lymphoma. The combination of acalabrutinib with R-CHOP aims to evaluate the efficacy of this treatment approach in the study participants.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the treatment response to **acalabrutinib** in combination with the R-CHOP standard of care in subjects with previously untreated mantle cell lymphoma (MCL). The primary endpoint for efficacy assessment is the investigator-assessed best Overall Response Rate (ORR), which includes Complete Response (CR) and Partial Response (PR) as per the Lugano Classification for Non-Hodgkin Lymphoma (NHL). This will be measured over a timeframe of one year.

Secondary endpoints include several parameters: Time to Response (TTR), which is defined as the time from the start of acalabrutinib to the first investigator-assessed CR or PR; Duration of Response (DoR), defined as the time from the first documentation of CR or PR to disease progression or death; Progression-Free Survival (PFS), defined as the time from the start of acalabrutinib to disease progression or death; and Overall Survival (OS), defined as the time from the start of acalabrutinib to death from any cause. The measures of interest for DoR, PFS, and OS are set at 30 months.

Additionally, the trial will describe the number and percentage of patients experiencing adverse events (AEs) and serious adverse events (SAEs), coded by MedDRA and graded by CTCAE. The incidence of AEs of clinical interest for acalabrutinib, grade ≥3 AEs, and AEs leading to dose modification, temporary interruption, or permanent discontinuation of acalabrutinib will also be recorded. These assessments will provide a comprehensive evaluation of the efficacy and safety profile of the treatment regimen in the study population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adult (aged ≥18 years) men or women.
WOCBP who are sexually active must use highly effective methods of contraception during the study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is the longerst. NOTE: Female participants should be stable on the chosen method of contraception for a minimum of 3 months before entering a trial.
Male patients should use barrier contraception (ie, condoms) from the time of screening until 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib , whichever is longest. Male patients wishing to father children in the future should be advised to arrange for the freezing of sperm prior to the start of study treatment. NOTE: Female partners should be advised to use accepted contraception during their partner’s study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is longest.
Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers
MCL requiring treatment and for which no prior systemic anticancer therapies have been received
Presence of radiologically measurable lymphadenopathy, splenomegaly and/or extranodal lymphoid malignancy
Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is longest.
Men must agree to refrain from sperm donation during the study treatment and for 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is longest
Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing tablets without difficulty
Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).
Unsuitable for autologous stem cell transplantation

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Exclusion Criteria

History of prior malignancy except for the following: a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician. Note: Provided they meet other eligibility criteria, subjects who are receiving hormonal therapy alone are allowed to enroll on study. b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer. c. Adequately treated carcinoma in situ without current evidence of disease.
Prothrombin time/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of a lupus anticoagulant) >2.0 x ULN. Exception: Subjects receiving a vitamin K antagonist are excluded; however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the medical monitor
Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug.
Known history of infection with human immunodeficiency virus (HIV).
Ongoing immunosuppressive therapy, including systemic (e.g., IV or oral) corticosteroids within 2 weeks before the first dose of study drug. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤20 mg prednisone equivalent/day for ≤2 weeks) as a therapy for comorbid conditions and/or pre-phase treatment up to 100 mg/day or equivalent (for a maximum of 10 days prior to beginning study treatment) in participants with bulky disease, systemic symptoms, compressive disease, impaired liver function or cytopenias due to lymphoma, or rapidly progressing adenopathies. During study participation, subjects will receive corticosteroids as part of the R-CHOP regimen according to institution standards. Subjects may also receive systemic (e.g., IV or oral) corticosteroids as needed for treatment-emergent comorbid conditions.
Known history of anaphylaxis or hypersensitivity to any study drug, or any of their components.
Serologic status reflecting active hepatitis B or C infection. a. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result before the first dose of study drug. Those who are HbsAg positive or hepatitis B PCR positive will be excluded. b. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before the first dose of study drug. Those who are hepatitis C PCR positive will be excluded.
Received a live virus vaccination within 28 days of first dose of study drug.
History of stroke or intracranial hemorrhage within 6 months of first dose of study drug.
History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
Subjects for whom the goal of therapy is tumor debulking before stem cell transplant
Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.
Requires treatment with a strong CYP3A inhibitor/inducer
Concurrent participation in another therapeutic clinical trial.
Active cytomegalovirus (CMV) infection (active viremia as evidenced by positive PCR result for CMV DNA).
History of confirmed progressive multifocal leukoencephalopathy (PML).
Any history of central nervous system (CNS) lymphoma or leptomeningeal disease
Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
Major surgical procedure within 28 days before first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
Significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
Absolute neutrophil count (ANC) <1.0 x 109/L or platelet count <75 x 109/L; for subjects with disease involvement in the bone marrow, ANC <0.75 x 109/L or platelet count <50 x 109/L. Subjects will only be considered eligible if peripheral blood counts can be maintained independent of growth factors or transfusions during the screening period.
Total bilirubin >1.5 x upper limit normal (ULN) unless other reason known (e.g. Gilbert Syndrome, or due to lymphoma involvement); or aspartate aminotransferase (AST) or alanine transaminase (ALT) >2.5 x ULN.
Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault [(140-age) • mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female].
Subjects who are deemed by the treating physician to be unfit to tolerate the R-CHOP regimen.
Pregnant or breastfeeding women.