A Randomized, Open-label, Phase 3 Study of Acalabrutinib in Combination with Rituximab and Reduced Dose CHOP (R-miniCHOP) in Older Adults with Untreated Diffuse Large B-Cell Lymphoma (ARCHED/GLA 2022-1)
- Trial ID
- 2022-501187-18-00
- Protocol
- ARCHED/GLA 2022-1
- Sponsor
- University Of Saarland
Trial statistics
Objectives
The primary objective of this study is to evaluate if the addition of **acalabrutinib** to R-miniCHOP prolongs progression-free survival (PFS) compared to R-miniCHOP alone in patients over 80 years or over 60 years who are ineligible for full-dose R-CHOP with previously untreated diffuse large B-cell lymphoma (DLBCL), based on investigator-assessed response. This is clinically relevant as it aims to improve treatment outcomes in a population with limited therapeutic options due to age or treatment tolerance.
Secondary objectives include:
- Evaluating overall survival (OS) with acalabrutinib plus R-miniCHOP compared to R-miniCHOP alone.
- Assessing PFS based on blinded independent central review (BICR).
- Evaluating event-free survival (EFS) based on investigator assessment and BICR.
- Analyzing outcomes according to cell of origin (COO) and DLBCL molecular genotype.
- Comparing outcomes between age groups, gender, and serum albumin levels.
- Comparing complete, partial, and overall remission rates, as well as duration of response between treatment and molecular groups.
- Comparing progression, relapse, and central nervous system (CNS) relapse rates between treatment and molecular groups.
- Evaluating the safety and tolerability of acalabrutinib plus R-miniCHOP relative to R-miniCHOP alone.
- Assessing protocol adherence of acalabrutinib plus R-miniCHOP relative to R-miniCHOP alone.
Participants
The clinical trial involves a study population comprising both **male** and **female** participants aged over 80 years or between 60 to 80 years who are ineligible for full-dose R-CHOP therapy. The trial focuses on individuals with previously untreated **diffuse large B-cell lymphoma (DLBCL)**, including various subtypes such as primary cutaneous DLBCL leg type, intravascular large B-cell lymphoma, and others as classified by the 2017 WHO classification. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, with a score of 3 acceptable only if directly attributable to lymphoma. The study does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include the ability to understand the study's purpose and risks, compliance with informed consent requirements, and meeting specific laboratory parameters. Lifestyle considerations such as diet and physical activity are not specified. The trial aims to evaluate the efficacy of adding acalabrutinib to R-miniCHOP in prolonging progression-free survival compared to R-miniCHOP alone.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **acalabrutinib** in combination with **rituximab** and a reduced dose of CHOP (R-miniCHOP) in older adults with untreated **diffuse large B-cell lymphoma** (DLBCL). The primary objective is to assess whether the addition of acalabrutinib prolongs progression-free survival (PFS) compared to R-miniCHOP alone. The trial is expected to run from April 2023 to April 2028, with participant involvement lasting up to 24 months, depending on individual treatment response and disease progression.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, disease stage, and laboratory parameters. Following randomization, participants will receive treatment and attend regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination due to disease progression, unacceptable toxicity, or withdrawal of consent.
The trial includes several key elements of research methodology, such as the use of a control group receiving R-miniCHOP alone, and the assessment of primary and secondary endpoints, including overall survival (OS) and event-free survival (EFS). Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The study aims to provide valuable insights into the treatment of DLBCL in older adults, potentially leading to improved therapeutic strategies.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Doxorubicin** is utilized as a **solution for injection** with a maximum daily dose of 25 mg/m² and a total dose of 150 mg/m² over a treatment period of 6 weeks. It is administered **intravenously** and classified as an antineoplastic agent. Participant compliance is monitored through regular assessments of dosing schedules and administration routes.
**Prednisone** is provided in **tablet form** with a maximum daily dose of 40 mg/m² and a total dose of 1200 mg/m² over a 30-day period. It can be administered both **orally and intravenously** and is categorized as a glycocorticoid. Compliance is ensured through scheduled dosing and monitoring.
**Cyclophosphamide** is administered as a **powder for solution for infusion** with a maximum daily dose of 400 mg/m² and a total dose of 2400 mg/m² over 6 weeks. The route of administration is **intravenous**, and it is classified as an antineoplastic agent. Dosing schedules are strictly adhered to, with compliance checks in place.
**Acalabrutinib** is available in two forms: **film-coated tablets** and **hard capsules**, both with a maximum daily dose of 200 mg and a total dose of 33600 mg over 24 weeks. It is administered **orally** and is classified as an antineoplastic agent. Participant adherence is monitored through regular assessments of dosing and administration.
**Rituximab** is used in two formulations: a **solution for injection** with a maximum daily dose of 1400 mg and a total dose of 8400 mg over 6 weeks, administered **subcutaneously**, and a **concentrate for solution for infusion** with a maximum daily dose of 375 mg/m² and a total dose of 2250 mg/m² over 6 weeks, administered **intravenously**. Both forms are classified as antineoplastic agents and monoclonal antibodies. Compliance is ensured through scheduled dosing and monitoring.
**Vincristine sulfate** is provided as an **injectable solution** with a maximum daily dose of 1 mg and a total dose of 6 mg over 6 weeks. It is administered **intravenously** and classified as an antineoplastic agent. Dosing schedules are strictly adhered to, with compliance checks in place.
**Prednisolone** is administered in **tablet form** with a maximum daily dose of 40 mg/m² and a total dose of 1200 mg/m² over a 30-day period. It can be administered both **orally and intravenously** and is categorized as a glycocorticoid. Compliance is ensured through scheduled dosing and monitoring.
**Pegfilgrastim** is provided as a **solution for injection** with a maximum daily dose of 6 mg and a total dose of 36 mg over 6 weeks. It is administered **subcutaneously** and classified as an immunostimulant and colony-stimulating factor. Participant adherence is monitored through regular assessments of dosing and administration.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**. PFS is defined as the time from randomization until disease progression, relapse after complete remission, or death from any cause, as per the Lugano Classification of 2014. Patients who have not experienced an event at the time of analysis will be censored at the most recent date of adequate disease assessment. Secondary endpoints include overall survival (OS), event-free survival (EFS), and various response rates such as complete remission (CR) and partial remission (PR). These endpoints will be measured from the day of randomization until the occurrence of specific events, with patients being censored at the last known date of survival or adequate disease assessment if no event has occurred.
Additional secondary endpoints include the overall response rate (ORR), duration of response (DoR), progression rate, relapse rate, and central nervous system (CNS) relapse rate. Safety and tolerability will also be evaluated through the incidence of adverse events (AEs), serious adverse events (SAEs), and treatment-related deaths. The trial will also assess the number and duration of therapy cycles, as well as the cumulative and relative doses of miniCHOP, rituximab, and acalabrutinib. These efficacy parameters will be collected and analyzed at predefined timepoints throughout the study, ensuring a comprehensive evaluation of the treatment's impact on patients with untreated diffuse large B-cell lymphoma (DLBCL).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Ability to understand the purpose and risks of the study and capable of giving signed informed consent which includes: a. Compliance with the requirements and restrictions listed in the informed consent form (ICF). b. Authorization to use protected health information/data [in accordance with the General Data Protection Regulation (GDPR)].
- Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
- Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty.
- Men and women >80 years of age or >60 up to 80 years of age and ineligible for full dose R-CHOP according to investigator assessment after standardized geriatric assessment
- Male patients who are sexually active with women of childbearing potential (definitions see section 17.8 of the protocol) must agree to use highly effective forms of contraception with the addition of a barrier method (condom) during the study (see section 17.8.1 of the protocol) as well as to the restrictions mentioned in section 9.13 of the protocol
- Female patients of childbearing potential (definitions see 17.8 in the protocol) who are sexually active must agree to use highly effective forms of contraception while on the study as well as to the restrictions mentioned in section 9.13. of the protocol
- Histologically proven, previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL) according to the 2017 WHO classification including: a. diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) b. primary cutaneous DLBCL leg type c. intravascular large B-cell lymphoma d. EBV+ DLBCL, NOS e. HHV8+DLBCL, NOS f. primary mediastinal (thymic) large B-cell lymphoma g. B-cell lymphoma, with intermediate features between DLBCL and classical Hodgkin lymphoma h. follicular lymphoma grade 3B i. high-grade B-cell lymphoma, NOS j. high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements k. T-cell/histiocyte-rich large B-cell lymphoma l. DLBCL associated with chronic inflammation m. ALK+ large B-cell lymphoma n. large B-cell lymphoma with IRF4 rearrangement Please note: patients in whom indolent lymphoma is diagnosed concurrently with the one of the above listed diagnoses can also be included
- Disease Stage I with bulk ≥7.5cm, II, III or IV according to Ann Arbor Classification
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. An ECOG Score of 3 is acceptable only if this is directly attributable to lymphoma
- Meet the following laboratory parameters: a. Absolut neutrophil count (ANC) ≥ 1500 cells/µl or platelet count ≥ 100.000/µl unless directly attributable to lymphoma. b. Serum AST and ALT ≤3 x upper limit of normal (ULN) unless directly attributable to lymphoma. c. Total bilirubin ≤1.5 x ULN, unless directly attributable to Gilbert’s syndrome or lymphoma. d. Estimated creatinine clearance of ≥30 mL/min, calculated by Cockcroft-Gault (using actual body weight) (if male, [140-Age] x Mass [kg] / [72 x serum creatinine mg/dL]; multiply by 0.85 if female), or serum creatinine ≤2.5 x ULN.
Exclusion Criteria
- Evidence of disease (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension and renal transplant) that, in the investigator’s opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol [e.g. a single score of 4 on one single category on the CIRS-G-Score (but not a cumulative score of 4)].
- Diagnosis of primary central nervous system lymphoma or secondary central nervous system or meningeal involvement by lymphoma
- Diagnosis of Richter’s Transformation/transformed CLL
- Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of randomization or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or LVEF < 40%. Patients with controlled, asymptomatic atrial fibrillation are allowed to enroll on study.
- Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists. Patients using therapeutic low molecule weight heparin, direct oral anticoagulants or low dose aspirin will be eligible. Switching from vitamin K antagonists to one of the allowed anticoagulants above prior to trial entry is permitted.
- Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. 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. See details in section 9.12.1 of the protocol
- Prior exposure to a BTK inhibitor.
- Prior anthracycline use >300 mg/m2 of doxorubicin equivalent.
- Already initiated lymphoma therapy except for steroid (max. total dose of 1500mg of prednisolone equivalent), vincristine (max. 1 mg once) and/or rituximab (max. total dose of 375mg/m2) prephase.
- Concurrent participation in another therapeutic clinical trial.
- Any active significant infection (e.g., bacterial, viral or fungal) as assessed by the investigator.
- Severe pulmonary dysfunction (CTCAE grade 3 or 4) unless associated with lymphoma.
- Severe psychiatric or neurologic disease that, in the investigator’s opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol.
- Persistent neuropathy CTCAE grade 3 or 4
- Refractory nausea and vomiting, inability to swallow acalabrutinib, or malabsorption syndrome; chronic severe gastrointestinal disease, gastric restrictions, or bariatric surgery such as gastric bypass; partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment.
- History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following: a. Curatively treated localised basal cell carcinoma or localised squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ / low risk carcinoma of the prostate requiring only observation, as well as untreated low grade lymphoma except chronic lymphocytic leukemia. b. Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥2 years (≥5 years for those treated with chemotherapy) without further treatment or which are not expected to limit survival to < 2 years.
- Received a live virus vaccination within 28 days of randomization.
- Known history of infection with HIV.
- History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
- Serologic status reflecting active hepatitis B or C infection. a. Patients who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Those who are HBsAg-positive or hepatitis B PCR positive will be excluded. b. Patients who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.
- History of stroke or intracranial hemorrhage within 6 months before randomization
- History of clinically relevant bleeding diathesis (e.g., hemophilia, von Willebrand disease).
- Major surgical procedure within 30 days before randomization. Note: If a patient had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
- Breastfeeding or pregnant women
- Current life-threatening illness, medical condition, organ system dysfunction, social, geographical or economic condition which, in the Investigator’s opinion, could compromise the patient’s safety or put the study at risk.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 15 Apr 2023 | 330 |
 Greece | Recruiting | 15 Apr 2023 | 30 |
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 |
|---|---|---|---|---|---|---|
CYCLOPHOSPHAMIDE | Other | — | INTRAVENOUS | 400 | 6 | SUB06859MIG |
PREDNISOLONE | Other | — | ORAL AND IV | 40 | 30 | SUB10018MIG |
RITUXIMAB | Other | — | INTRAVENOUS | 375 | 6 | SUB12570MIG |
PREDNISONE | Other | — | ORAL AND IV | 40 | 30 | SUB10020MIG |
VINCRISTINE SULFATE | Other | — | INTRAVENOUS | 1 | 6 | SUB05101MIG |
DOXORUBICIN | Other | — | INTRAVENOUS | 25 | 6 | SUB06391MIG |
RITUXIMAB | Other | — | SUBCUTANEOUS | 1400 | 6 | SUB12570MIG |
PEGFILGRASTIM | Other | — | SUBCUTANEOUS | 6 | 6 | SUB16451MIG |
Calquence 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 200 | 24 | PRD10242588 |
Calquence 100 mg hard capsules | Test | HARD CAPSULES | ORAL | 200 | 24 | PRD8485702 |