Phase 3 Randomized Study of Bendamustine, Rituximab, and Acalabrutinib in Untreated Mantle Cell Lymphoma
- Trial ID
- 2023-509354-58-00
- Protocol
- ACE-LY-308
- Sponsor
- Acerta Pharma B.V.
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** of acalabrutinib (ACP-196) in combination with bendamustine and rituximab (BR) compared with placebo in combination with BR. This evaluation is based on the Independent Review Committee (IRC) assessment of progression-free survival (PFS) according to the Lugano Classification for Non-Hodgkin Lymphoma (NHL) in subjects with previously untreated mantle cell lymphoma (MCL). The clinical relevance of this objective lies in determining whether the addition of acalabrutinib to the standard BR regimen can improve PFS, which is a critical endpoint in assessing the effectiveness of cancer therapies.
Secondary objectives include: - Evaluating acalabrutinib in combination with BR compared with placebo in combination with BR in terms of investigator-assessed PFS per the Lugano Classification for NHL. - Investigator-assessed overall response rate (ORR) per the Lugano Classification for NHL. - IRC-assessed ORR, defined as a subject achieving either a partial response (PR) or complete response (CR) per the Lugano Classification for NHL. - Overall survival (OS). - IRC-assessed duration of response (DOR) per the Lugano Classification for NHL. - IRC-assessed time to response (TTR) per the Lugano Classification for NHL. - IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007). - Patient-reported outcomes (PRO) by Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) scale score. - PRO by the EuroQol (EQ-5D-5L) index score.
Participants
The clinical trial involves a total of **438 participants** diagnosed with **Mantle Cell Lymphoma**. The study population includes both men and women aged **65 years and older**. Participants were selected based on specific criteria, including a pathologically confirmed diagnosis of Mantle Cell Lymphoma with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1. All participants have not received prior systemic anticancer therapies and require treatment. The trial excludes vulnerable populations and includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Participants are required to have radiologically measurable lymphadenopathy and/or extranodal lymphoid malignancy. Lifestyle considerations such as the ability to swallow capsules without difficulty and adherence to contraception guidelines for men are noted. The trial ensures that all participants are willing and able to participate in all required evaluations and procedures, and have provided informed consent in accordance with privacy regulations.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy of **acalabrutinib** in combination with **bendamustine** and **rituximab** (BR) compared to placebo with BR in subjects with previously untreated **mantle cell lymphoma**. The primary endpoint is progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) per the Lugano Classification for Non-Hodgkin Lymphoma. The trial is expected to run from March 16, 2017, to May 15, 2027, with participants involved for the duration of the treatment period and follow-up assessments.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and performance status. Following randomization, participants will receive either the investigational treatment or placebo, with study visits scheduled to monitor safety, efficacy, and compliance. These visits will include assessments such as imaging studies, laboratory tests, and physical examinations. The end-of-study visit will occur after the completion of the treatment phase and any necessary follow-up, ensuring comprehensive data collection for final analysis.
The expected length of participant involvement is determined by the treatment regimen and follow-up period, with conditions for early termination including adverse events, withdrawal of consent, or disease progression. Participants must adhere to study protocols, including the use of contraception and refraining from sperm donation, to remain eligible. The trial's design ensures rigorous evaluation of the investigational treatment's impact on PFS and other secondary endpoints, contributing valuable data to the understanding of treatment options for mantle cell lymphoma.
Treatment
The clinical trial involves the administration of several treatments to evaluate their efficacy in subjects with previously untreated **mantle cell lymphoma**. The experimental medication **acalabrutinib**, marketed as Calquence, is provided in the form of 100 mg hard capsules. It is administered orally, with a dosing schedule that aligns with the study protocol. The maximum treatment period is set at 999 days, and participant compliance is monitored throughout the trial. Acalabrutinib is a chemical substance, and its role in the trial is as a test medication.
**Rituximab** is another key component of the study, administered in combination with other treatments. It is provided in a pharmaceutical form coded as PHF00230MIG and is administered via intravenous use. The dosing is measured in milligrams per square meter (mg/m²), although specific daily and total dose amounts are not predetermined, allowing for flexibility based on individual patient needs. Rituximab is a protein-based substance and serves as a comparator in the trial.
**Bendamustine hydrochloride** is also utilized in the study, administered intravenously in a form similar to rituximab (PHF00230MIG). Like rituximab, its dosing is calculated in mg/m², with no fixed maximum daily or total dose amounts specified. Bendamustine hydrochloride is a chemical substance and acts as a comparator in the trial. The treatment period for bendamustine hydrochloride is also set at a maximum of 999 days.
A placebo, referred to as "Capsule, hard," is included in the study as a control measure. However, specific details regarding its composition, pharmaceutical form, and administration route are not provided. The placebo serves to ensure the double-blind nature of the trial, allowing for an unbiased assessment of the experimental treatment's efficacy.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, as evaluated by an Independent Review Committee (IRC) according to the Lugano Classification for Non-Hodgkin Lymphoma (NHL). The primary analysis will involve a comparison of PFS between two study arms: Arm 1, which includes acalabrutinib in combination with bendamustine and rituximab (BR), and Arm 2, which includes a placebo in combination with BR.
Secondary endpoints for efficacy assessment include investigator-assessed PFS, overall response rate (ORR) as determined by both investigators and IRC, overall survival (OS), duration of response (DOR), and time to response (TTR), all evaluated per the Lugano Classification for NHL. Additionally, ORR will be assessed by IRC using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patient-reported outcomes (PROs) will be measured by changes in scores from baseline using the FACT-Lym scale and the EQ-5D-5L index score.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men and women, ≥65 years of age.
- 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 (eg, CD5, CD19, CD20, PAX5).
- MCL requiring treatment and for which no prior systemic anticancer therapies have been received.
- Presence of radiologically measurable lymphadenopathy and/or extranodal lymphoid malignancy.
- 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 and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest.
- Men must agree to refrain from sperm donation during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest.
- Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules 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).
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/INR or aPTT (in the absence of a Lupus anticoagulant) > 2.0 x ULN. Exception: Subjects receiving warfarin 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 HIV.
- Ongoing immunosuppressive therapy, including systemic (eg, 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. During study participation, subjects may also receive systemic (eg, IV or oral) corticosteroids as needed for treatment emergent comorbid conditions.
- Known history of anaphylaxis or hypersensitivity to bendamustine, rituximab, or any of their components.
- Subjects for whom the goal of therapy is tumor debulking before stem cell transplant.
- Any history of CNS lymphoma or leptomeningeal disease.
- Uncontrolled AIHA or 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, or QTc > 480 msec (calculated using Friderica's formula: QT/RR0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
- 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 ULN; or AST or ALT > 2.5 x ULN.
- Estimated creatinine clearance of < 50 mL/min, calculated using the formula of Cockcroft and Gault [(140-age)•mass (kg)/(72•creatinine mg/dL)•multiply by 0.85 if female].
- Serologic status reflecting active hepatitis B or C infection.
- 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).
- 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 cytochrome P450 3A (CYP3A) inhibitor/inducer.
- Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
- Concurrent participation in another therapeutic clinical trial.
- Active cytomegalovirus (CMV) infection (active viremia as evidenced by positive polymerase chain reaction [PCR] result for CMV DNA).
- History of confirmed progressive multifocal leukoencephalopathy (PML).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 16 Mar 2017 | 3 |
 Czechia | Not Recruiting | 16 Mar 2017 | 53 |
 France | Not Recruiting | 16 Mar 2017 | 11 |
 Germany | Not Recruiting | 16 Mar 2017 | 11 |
 Greece | Not Recruiting | 16 Mar 2017 | 19 |
 Hungary | Not Recruiting | 16 Mar 2017 | 13 |
 Italy | Not Recruiting | 16 Mar 2017 | 21 |
 Poland | Not Recruiting | 16 Mar 2017 | 40 |
 Spain | Not Recruiting | 16 Mar 2017 | 27 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
RITUXIMAB | Comparator | PHF00230MIG | INTRAVENOUS USE | 0 | 999 | SCP24437829 |
Capsule, hard | Placebo | N/A | — | — | — | N/A |
Calquence 100 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 0 | 999 | PRD8485701 |
BENDAMUSTINE | Comparator | PHF00230MIG | INTRAVENOUS USE | 0 | 999 | SCP20211730 |