Evaluation of Acalabrutinib and Rituximab in Elderly Patients with Untreated Mantle Cell Lymphoma: A Clinical Trial Analysis

Trial ID: 2023-509864-96-00
Protocol: NLG-MCL8
Sponsor: Region Skane

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Diseases & Conditions

Mantle cell lymphoma

Objectives

The primary objective of this study is to evaluate **progression-free survival** in elderly patients with untreated **mantle cell lymphoma** (MCL) when treated with a combination of acalabrutinib and rituximab. This is compared to historical data from the NLG-MCL4 trial. Progression-free survival is a critical endpoint in oncology trials as it measures the length of time during and after treatment that a patient lives with the disease without it worsening, providing insights into the efficacy of the treatment regimen.

Secondary objectives include assessing the following outcomes:

Complete response rate
Molecular remission rate (MRR) by PCR
Overall response rate
Progression-free survival
Response duration
Duration of molecular remission
Overall survival
Safety
CR, MRR, and ORR in TP53-mutated MCL

These secondary objectives aim to provide a comprehensive evaluation of the treatment's impact on various clinical outcomes, including response rates, survival metrics, and safety profile, which are essential for understanding the broader clinical benefits and risks associated with the treatment regimen.

Participants

The clinical trial involves a total of **one** participant, focusing on individuals diagnosed with **Mantle Cell Lymphoma (MCL)**. The study population includes both male and female subjects, with an age range starting from 60 years and above. Participants are required to have a pathologically confirmed diagnosis of MCL, characterized by specific genetic markers such as chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1. The trial excludes individuals who have received prior treatment for MCL, except for localized radiotherapy or a short course of steroids for symptom control. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are fully active or capable of self-care. The trial does not include vulnerable populations, and participants must meet specific health criteria, including adequate blood counts and organ function, to ensure they are in a suitable health status for the study. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The sponsor has not provided additional information regarding the selection process or lifestyle considerations.

Plans and Procedures

The clinical trial is designed to evaluate the **progression-free survival** of patients with untreated **mantle cell lymphoma** (MCL) using a combination of acalabrutinib and rituximab. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to run from December 7, 2021, to December 31, 2028. Participants will be involved for a maximum treatment period of 36 months, with the primary endpoint being progression-free survival, defined as the time from informed consent to documented progression, relapse, or death from any cause.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit involves screening to confirm eligibility based on criteria such as age (≥60 years), confirmed MCL diagnosis, and specific laboratory values. Following the inclusion visit, participants will undergo regular follow-up visits to assess treatment efficacy and safety, including evaluations of complete response rate at 6 months, molecular remission rate, and overall response rate. The end-of-study visit will conclude the participant's involvement, with final assessments of progression-free survival and overall survival.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, withdraw consent, or if the investigator deems it necessary for safety reasons. The trial's design ensures rigorous adherence to ethical standards and scientific validity, with the primary objective of comparing outcomes to historical data from the NLG-MCL4 trial. The study will utilize oral administration of acalabrutinib, with a maximum daily dose of 200 mg, and will monitor safety in terms of all grade 3-5 adverse events.

Treatment

The clinical trial involves the administration of **acalabrutinib**, a **BTK inhibitor**, as the experimental medication. Acalabrutinib is provided in an oral pharmaceutical form, identified by the code PHF00006MIG. The active substance, acalabrutinib, is chemically derived and is also known by the synonyms ACP-196 and (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)-imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)-benzamide. The maximum daily dose of acalabrutinib is 200 mg, with a total maximum dose of 201,600 mg over the treatment period. The treatment duration is set for a maximum of 36 months. The administration route is oral, and the medication is not formulated for pediatric use.

In addition to acalabrutinib, the study includes the administration of **rituximab** as a non-experimental treatment. Rituximab is a standard-of-care therapy used in combination with acalabrutinib for the treatment of untreated mantle cell lymphoma in elderly patients. The trial aims to evaluate the progression-free survival of patients receiving this combination therapy compared to historical data from the NLG-MCL4 trial. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed treatment regimen.

Efficacy

The efficacy of the clinical trial involving acalabrutinib and rituximab in elderly patients with untreated mantle cell lymphoma will be assessed primarily through **progression-free survival**. This primary endpoint is defined as the interval between the date of obtaining informed consent and the date of documented progression, first relapse, or death from any cause. Patients will be censored at the last date they were known to be alive if none of these events occur.

Secondary endpoints include the complete response rate at 6 months, molecular remission rate (MRR) by PCR, overall response rate, median progression-free survival, median response duration, median duration of molecular remission, median overall survival, and the rates of complete response, MRR, and overall response in TP53-mutated mantle cell lymphoma. Additionally, safety will be evaluated in terms of all grade 3-5 adverse events. These parameters will be measured and analyzed at specified intervals throughout the trial to provide a comprehensive assessment of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥60 years
Pathologically confirmed MCL (according to the WHO 2016 classification), with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1
Stage II-IV, measurable by imaging and requiring treatment in the opinion of the treating clinician
No previous treatment for MCL (other than localised radiotherapy or 7-day pulse of steroids for symptom control)
ECOG performance status 0 – 2
Absolute neutrophil count (ANC) > 1.0 x 10^9 and platelet count > 100 x 10^9, unless related to lymphoma - in this situation, the threshold for inclusion is ANC >0.5 x 10^9 and platelet count > 50 x 10^9
Creatinine clearance >30 ml/min (Cockcroft-Gault)
AST and/or ALT <3x ULN and/or P-bilirubin <3x ULN
Able to give voluntary written informed consent
Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception (see appendix 2) during treatment and for 2 days after the last dose of acalabrutinib or for 12 months after last dose of rituximab, whichever is longer

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Exclusion Criteria

Patients considered fit enough to undergo autologous or allogeneic stem cell transplant for MCL
Major surgery within two weeks prior to day 1 of cycle 1
Patients who are unable to swallow capsules/tablets, or who have disease significantly affecting gastrointestinal function that would limit oral absorption of medication
Known serological positivity for HBV, HCV, HIV. Patients who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) result. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Patients who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded
Diagnosed with or treated for any other malignancy than MCL within 2 years prior to day 1 of cycle 1 (except basal cell carcinoma, cutaneous squamous cell carcinoma or any other in situ malignancy)
Active infection requiring treatment
Serious medical or psychiatric illness likely to interfere with participation in this clinical study
Concurrent treatment with another investigational agent outside of this protocol
Known history of drug-specific hypersensitivity or anaphylaxis to rituximab or acalabrutinib (including active product or excipient components)
Active bleeding, history of bleeding diathesis (eg, hemophilia or von Willebrand disease)
Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.
Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.
Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study
History of significant cerebrovascular disease or event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug
Breastfeeding or pregnant women
Concurrent participation in another therapeutic clinical trial
History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
Significant cardiovascular disease such as 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 at Screening. Note: Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study
Received a live virus vaccination within 28 days of first dose of study drug