Phase 3 Study of Acalabrutinib with R-CHOP in Patients Aged ≤75 with Untreated Non-Germinal Center Diffuse Large B-Cell Lymphoma

The primary objective of this study is to evaluate if the addition of **acalabrutinib** to the R-CHOP regimen prolongs progression-free survival (PFS) compared to placebo plus R-CHOP in subjects aged 75 years or younger with previously untreated non-germinal center diffuse large B-cell lymphoma (non-GCB DLBCL), specifically the activated B-cell (ABC) subtype or unclassified, as selected by gene expression profiling (GEP). This is clinically relevant as improving PFS can potentially lead to better long-term outcomes and quality of life for patients with this aggressive form of lymphoma.

Secondary objectives include:

• Evaluating event-free survival (EFS) with acalabrutinib plus R-CHOP compared to placebo plus R-CHOP in the same patient population, as assessed by the investigator.
• Assessing the complete response (CR) rate with acalabrutinib plus R-CHOP compared to placebo plus R-CHOP, evaluated by Blinded Independent Central Review (BICR).
• Evaluating overall survival (OS) with acalabrutinib plus R-CHOP compared to placebo plus R-CHOP in the specified patient group.

The clinical trial involves a total of **405 participants** diagnosed with **diffuse large B-cell lymphoma** (DLBCL). The study population includes both men and women aged between 18 and 75 years, with a focus on those who have not received prior treatment for DLBCL. Participants were selected based on specific criteria, including a pathologically confirmed diagnosis of DLBCL, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and an International Prognostic Index (IPI) score ranging from 1 to 5. The disease stage of participants is classified as Stage II to IV according to the Ann Arbor Classification. All participants are required to have adequate organ and marrow function and must agree to use highly effective forms of contraception during the study and for 12 months following the last dose of rituximab. The trial includes a vulnerable population, and the selection process ensures that sufficient diagnostic material is available for gene expression profiling and pathology review. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of adding **acalabrutinib** to the R-CHOP regimen in subjects aged 18 to 75 years with previously untreated non-germinal center **diffuse large B-cell lymphoma** (DLBCL). The primary objective is to assess whether the addition of acalabrutinib prolongs progression-free survival (PFS) compared to placebo plus R-CHOP. The trial is expected to run from September 2020 to September 2029, with the estimated end date being September 3, 2029.

Participants will be randomly assigned to one of two arms: Arm A, receiving acalabrutinib in combination with R-CHOP, or Arm B, receiving placebo with R-CHOP. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a pathologically confirmed diagnosis of DLBCL, an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2, and an International Prognostic Index (IPI) score of 1 to 5, among other criteria. Participants must also agree to use highly effective contraception during the study and for 12 months after the last dose of **rituximab**.

The expected duration of participant involvement is up to 168 days, corresponding to the maximum treatment period for rituximab. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, would make continued participation detrimental to the participant's health. The primary endpoint is progression-free survival per the Lugano Classification for NHL, with secondary endpoints including event-free survival, complete response rate, and overall survival. The trial is not classified as low intervention and is conducted under the standard regulatory framework for Phase 3 trials.

The clinical trial involves the administration of several **experimental medications** and a **placebo**. The primary experimental medication is **Acalabrutinib**, marketed as Calquence, which is provided in the form of 100 mg hard capsules. Acalabrutinib is administered orally at a dosage of 100 mg twice daily (BID), with a maximum daily dose of 200 mg and a total maximum dose of 29,400 mg over a treatment period of up to 147 days. The active ingredient, acalabrutinib, is of chemical origin and is used in its authorized pharmaceutical form for this trial.

**Prednisone** is another experimental medication used in this study. It is administered in tablet form for oral use. The maximum daily dose of prednisone is 100 mg, with a total maximum dose of 12,600 mg over a treatment period of 126 days. Prednisone is a chemically derived substance and is utilized in its standard pharmaceutical form.

**Cyclophosphamide** is administered as a solution for injection or infusion, with a maximum daily dose of 750 mg/m² and a total maximum dose of 94,500 mg/m² over 126 days. This medication is administered intravenously and is of chemical origin.

**Doxorubicin** is provided as a solution for injection or infusion, with a maximum daily dose of 50 mg/m² and a total maximum dose of 6,300 mg/m² over 126 days. Doxorubicin is administered intravenously and is chemically derived.

**Rituximab** is administered as a concentrate for solution for infusion, with a maximum daily dose of 375 mg and a total maximum dose of 59,976 mg over a treatment period of 168 days. Rituximab is administered intravenously and is of chemical origin.

**Vincristine** is provided as a solution for injection, with a maximum daily dose of 2 mg/m² and a total maximum dose of 252 mg/m² over 126 days. Vincristine is administered intravenously and is chemically derived.

The **placebo** used in this study is provided in the form of 100 mg hard capsules, identical in appearance to the investigational medicinal product (IMP) but lacking the active substance. The placebo is administered orally, following the same schedule as the experimental medication, to maintain the double-blind nature of the trial.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of acalabrutinib in combination with the R-CHOP regimen compared to the placebo plus R-CHOP in subjects with previously untreated non-germinal center diffuse large B-cell lymphoma.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, evaluated according to the Lugano Classification for Non-Hodgkin Lymphoma (NHL) in Arm A compared to Arm B. Secondary endpoints include investigator-assessed event-free survival (EFS) for NHL, the percentage of participants who achieve a complete response (CR) per the 2014 Lugano Classification for NHL, and overall survival in Arm A compared to Arm B.

These efficacy parameters will be measured and collected at specified timepoints throughout the trial. The trial is designed to evaluate the addition of acalabrutinib to the R-CHOP regimen in subjects aged 75 years or younger with previously untreated non-germinal center diffuse large B-cell lymphoma (non-GCB DLBCL). The assessments will be based on investigator-assessed responses, with the primary objective being to determine if acalabrutinib prolongs PFS compared to placebo plus R-CHOP alone. The trial will follow a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the efficacy assessments.