Efficacy and Safety of Golcadomide with R-CHOP Versus Placebo with R-CHOP in High-risk Large B-cell Lymphoma: A Phase 3 Randomized Controlled Trial

The primary objective of this study is to evaluate **Progression-Free Survival (PFS)** in participants with previously untreated high-risk large B-cell lymphoma. PFS is a critical endpoint in oncology trials, representing the duration from the start of the study until the cancer progresses or the participant passes away, whichever occurs first. This measure is clinically relevant as it provides insight into the effectiveness of the treatment in delaying disease progression, which is crucial for improving patient outcomes.

Secondary objectives include:

• Evaluating the efficacy of golcadomide plus R-CHOP versus placebo plus R-CHOP in terms of **Overall Survival (OS)**, which is the time from study initiation until death from any cause. This is a vital measure of treatment impact on longevity.
• Assessing **Event-Free Survival (EFS)**, defined as the time from study start until any of the following events: death, cancer progression, initiation of new lymphoma treatment, or signs of disease post-treatment. EFS provides a comprehensive view of treatment efficacy by considering multiple adverse outcomes.
• Evaluating **Complete Metabolic Response (CMR)**, indicating no detectable cancer signs in the body at treatment completion, which is a strong indicator of treatment success.
• Assessing **Minimal Residual Disease (MRD) negativity**, meaning no cancer traces are found in the blood at the end of treatment, which is a prognostic marker for long-term remission.

The clinical trial involves a total of **608 participants** diagnosed with **High-risk Large B-cell Lymphoma**. The study population includes both male and female subjects, aged between **18 to 80 years**. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of de novo, previously untreated large B-cell lymphoma, as per the 2022 WHO classification. The trial includes individuals with an International Prognostic Index (IPI) score of 1 or 2 with elevated lactate dehydrogenase (LDH) levels and/or bulky disease, or an IPI score of 3 or higher. Participants must have at least one bi-dimensionally measurable lesion and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, with ECOG 3 allowed if disease-related. The trial population is characterized by a range of health statuses, with specific laboratory value thresholds for neutrophil count, platelets, hemoglobin, liver enzymes, bilirubin, and creatinine clearance. The study also includes a vulnerable population, and participants are required to adhere to a pregnancy prevention program and comply with the study visit schedule and protocol requirements.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy and safety of Golcadomide in combination with R-CHOP chemotherapy compared to a placebo plus R-CHOP in participants with previously untreated high-risk large B-cell lymphoma. The primary objective is to assess **progression-free survival** (PFS), while secondary endpoints include overall survival (OS), event-free survival (EFS), complete metabolic response (CMR), and minimal residual disease (MRD) negativity. The trial is expected to commence recruitment on June 24, 2024, and conclude by November 20, 2029, with an estimated duration of 18 months for each participant's involvement.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of the disease, and specific laboratory values. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. 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 period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.

The trial involves the administration of Golcadomide orally, with a maximum daily dose of 0.4 mg and a total dose of 16.8 mg over the treatment period. R-CHOP components, including **cyclophosphamide monohydrate**, **vincristine sulfate**, **doxorubicin hydrochloride**, and **prednisone**, will be administered according to standard protocols. Participants will also receive supportive care with **pegfilgrastim** to manage chemotherapy-induced neutropenia. Conditions leading to early termination from the study include significant adverse events, non-compliance with the study protocol, or any other reason deemed necessary by the investigator. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Cyclophosphamide Monohydrate** is provided as a solution for injection, with a maximum daily dose of 750 mg/m² and a total dose not exceeding 4500 mg/m² over a treatment period of 18 weeks. The administration route is intravenous. **Vincristine Sulfate** is also administered as a solution for injection, with a maximum daily dose of 1.4 mg/m² and a total dose of 8.4 mg/m², delivered intravenously over the same treatment period.

**Doxorubicin Hydrochloride** is administered intravenously as a solution for injection, with a maximum daily dose of 50 mg/m² and a total dose of 300 mg/m². **Rituximab** is provided in two forms: a solution for infusion with a maximum daily dose of 375 mg/m² and a total dose of 2250 mg/m², administered intravenously, and a solution for injection with a maximum daily dose of 1400 mg and a total dose of 7000 mg, administered subcutaneously over 15 weeks.

**Golcadomide** is administered orally in capsule form, with a maximum daily dose of 0.4 mg and a total dose of 16.8 mg over 18 weeks. **Prednisone** is provided as a tablet for oral use, with a maximum daily dose of 100 mg and a total dose of 3000 mg. **Apixaban** is administered as a film-coated tablet for oral use, with a maximum daily dose of 999 mg and a total dose of 999 mg over an extended period.

**Pegfilgrastim** is administered subcutaneously as a solution for injection, with a maximum daily dose of 6 mg and a total dose of 36 mg over 18 weeks. **Betamethasone Sodium Phosphate** is administered intravenously, with a maximum daily dose of 100 mg and a total dose of 600 mg. The trial also includes a placebo group for comparison.

Participant compliance is monitored through regular assessments and adherence checks to ensure accurate dosing and administration. The trial aims to evaluate the efficacy and safety of these treatments in participants with previously untreated high-risk large B-cell lymphoma.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. PFS is defined as the duration from the start of the study until the disease progresses or the participant passes away, whichever occurs first. This primary endpoint will provide a direct measure of the treatment's effectiveness in delaying disease progression in participants with previously untreated high-risk large B-cell lymphoma.

Secondary endpoints include the assessment of **Overall Survival (OS)**, which measures the time from the start of the trial until death from any cause. Additionally, **Event-Free Survival (EFS)** will be evaluated, defined as the time from the start of the trial until the occurrence of any of the following events: death, disease progression, initiation of new treatment for lymphoma, or signs of disease post-treatment. The trial will also assess **Complete Metabolic Response (CMR)**, indicating a complete response to treatment at the end of the treatment period, and **Minimal Residual Disease (MRD) negativity**, which signifies the absence of detectable cancer DNA in the participant's body at the end of treatment.