Evaluation of Acalabrutinib Monotherapy and Combination with Rituximab in Relapsed/Refractory Marginal Zone Lymphoma: A Phase 1b/2 Open-label Study
- Trial ID
- 2023-509350-63-00
- Protocol
- ACE-LY-003
- Sponsor
- Acerta Pharma B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to characterize the activity of **acalabrutinib** alone or in combination with rituximab in subjects with relapsed/refractory marginal zone lymphoma (R/R MZL), as measured by the overall response rate (ORR). This is clinically relevant as it aims to determine the efficacy of the treatment regimen in inducing a measurable response in this patient population, which is crucial for guiding therapeutic decisions and improving patient outcomes.
Secondary objectives include:
- To characterize the safety of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL.
- To evaluate the activity of acalabrutinib alone or in combination with rituximab in subjects with R/R MZL, as measured by duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Participants
The clinical trial involves a total of **23 participants** diagnosed with **relapsed/refractory marginal zone lymphoma**. The study population includes both **men and women aged 18 years and older**. Participants were selected based on their histologically confirmed diagnosis of marginal zone lymphoma, which encompasses splenic, nodal, and extranodal sub-types. All participants have previously undergone at least one line of systemic therapy, including a CD20-directed regimen, with documented failure to achieve partial response or disease progression after the most recent treatment. The trial includes individuals with radiographically measurable lymphadenopathy or extranodal lymphoid malignancy, as assessed by CT scan, and an ECOG performance status of 2 or less. Participants are required to have the ability to understand the study's purpose and risks and provide informed consent. The trial population is not restricted by gender, and both male and female subjects are included. The study also considers vulnerable populations, ensuring comprehensive representation within the trial cohort.
Plans and Procedures
The clinical trial is designed as an open-label, Phase 1b/2 study to evaluate the efficacy of **acalabrutinib** alone or in combination with rituximab in subjects with relapsed/refractory marginal zone lymphoma (R/R MZL). The primary objective is to assess the overall response rate (ORR) as per the Lugano classification for non-Hodgkin lymphoma (NHL). The trial is expected to run from October 29, 2020, to March 31, 2028. Participants will be randomly assigned to receive either acalabrutinib alone or in combination with rituximab, with the investigational medicinal product provided in HDPE bottles, differing from the marketed blister packaging.
Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as age (≥18 years), histologically confirmed MZL, and previous therapy history. Participants must have measurable disease and an ECOG performance status of ≤2. Following the screening, participants will undergo regular follow-up visits to monitor efficacy and safety, including assessments of adverse events (AEs), serious adverse events (SAEs), hematology, serum chemistry, and immune cell counts. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes.
The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The trial will ensure rigorous monitoring to maintain participant safety and data integrity throughout the study period.
Treatment
The clinical trial involves the administration of **acalabrutinib**, an experimental medication, in two pharmaceutical forms: hard capsules and film-coated tablets. The hard capsules, marketed under the name Calquence 100 mg, are supplied in high-density polyethylene (HDPE) bottles for the trial, differing from the marketed product which is packaged in blisters. Each capsule contains 100 mg of acalabrutinib, a chemical substance, and is intended for **oral use**. The administration schedule involves a specific dosage and frequency, which is determined by the study protocol. Participant compliance is monitored through regular assessments and adherence checks.
The film-coated tablets, also containing 100 mg of acalabrutinib, are similarly provided in HDPE bottles for the trial, with manufacturing sites differing from those of the marketed product. These tablets are designed for oral administration, and the dosing schedule is aligned with the study's objectives to evaluate the efficacy of acalabrutinib alone or in combination with rituximab in subjects with relapsed/refractory marginal zone lymphoma (R/R MZL). Compliance with the dosing regimen is ensured through systematic monitoring and documentation throughout the trial period.
In addition to the experimental treatments, the study may involve the use of rituximab as a combination therapy. Rituximab is a standard-of-care therapy for certain types of B-cell non-Hodgkin lymphoma and is administered according to established medical guidelines. The combination therapy aims to assess the overall response rate (ORR) in subjects, providing a comprehensive evaluation of the treatment's activity. The trial protocol includes detailed instructions on the administration and monitoring of rituximab to ensure consistency and accuracy in the study outcomes.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the **Overall Response Rate (ORR)**, as evaluated by investigators according to the Lugano classification for Non-Hodgkin Lymphoma (NHL). This classification provides a standardized method for assessing response to treatment in lymphoma patients, ensuring consistency and reliability in the evaluation of therapeutic outcomes. The ORR will be determined by measuring the proportion of patients who achieve a complete or partial response to the treatment regimen.
Secondary efficacy endpoints include the assessment of Duration of Response (DOR), Progression-Free Survival (PFS), and Overall Survival (OS), also evaluated according to the Lugano classification for NHL. These parameters will provide additional insights into the long-term benefits of the treatment, capturing not only the initial response but also the sustainability and impact on patient survival.
Data collection for these efficacy endpoints will be conducted at specified intervals throughout the trial, with assessments performed by qualified investigators. The use of validated scales and classification systems ensures that the efficacy data is robust and can be reliably compared across different studies and treatment regimens.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men and women ≥18 years of age.
- Histologically confirmed MZL including splenic, nodal, and extranodal sub-types
- Previous therapy: a. Cohort 1: Previously received 1 or more lines of systemic therapy including at least 1 CD20-directed regimen (either as monotherapy or as chemoimmunotherapy for MZL) with documented failure to achieve at least PR, or documented disease progression after the most recent treatment regimen. b. Cohort 2: Previously received 1 or more lines of therapy including at least 1 prior systemic therapy for MZL or radiation therapy with documented failure to achieve at least PR, or document disease progression after the most recent treatment regimen.
- Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥1 lesion that measures ≥2.0 cm in the longest dimension and ≥1.0 cm in the longest perpendicular dimension as assessed by CT scan).
- ECOG performance status of ≤2.
- Ability to understand the purpose and risks of the study and provide signed and dated informed consent
Exclusion Criteria
- Prior malignancy (other than indolent B-cell NHL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ≥2 years.
- Known medically apparent CNS lymphoma or leptomeningeal disease.
- Known evidence of transformation to another aggressive lymphoma.
- A life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
- Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).
- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia formula (QTcF) >480 msec.
- Prior exposure to a BCR inhibitor (e.g., BTK, or SYK inhibitors).
- Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment or other conditions within 1 week before the first dose of study drug.
- 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.
- Serologic status reflecting active hepatitis B or C infection.
- History of allogeneic stem cell (or organ) transplantation.
- History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist (e.g., phenprocoumon) within 7 days of first dose of study drug.
- ANC <1.0 × 109/L or platelet count <100 × 109/L. For subjects with documented disease involvement in the bone marrow, ANC <0.50 × 109/L or platelet count <30 × 109/L.
- Creatinine >1.5 × institutional ULN; total bilirubin >1.5 × ULN; and AST or ALT >2.5 × ULN.
- Breastfeeding or pregnant.
- Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.
- History of or ongoing progressive multifocal leukoencephalopathy (PML).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 29 Oct 2020 | 2 |
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 |
|---|---|---|---|---|---|---|
Calquence 100 mg hard capsules | Test | HARD CAPSULES | ORAL USE | — | — | PRD8485704 |
Calquence 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | — | — | PRD10242587 |