Phase 3 Randomized Study of Nemtabrutinib Versus Investigator’s Choice of Ibrutinib or Acalabrutinib in Untreated CLL/SLL

The primary objective of this Phase 3, randomized study is to compare **nemtabrutinib** to ibrutinib or acalabrutinib in participants with untreated **Chronic Lymphocytic Leukemia**/**Small Lymphocytic Lymphoma**. The comparison focuses on the **Overall Response Rate (ORR)** and **Progression-Free Survival (PFS)**, both assessed per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria by Blinded Independent Central Review (BICR). These endpoints are clinically relevant as they provide insights into the efficacy of nemtabrutinib in achieving and maintaining disease control compared to established treatments.

Secondary objectives include:

• Comparing nemtabrutinib to ibrutinib or acalabrutinib with respect to **Overall Survival (OS)**.
• Evaluating the **Duration of Response (DOR)** per iwCLL criteria 2018 as assessed by BICR.
• Assessing the safety and tolerability of nemtabrutinib.

The clinical trial involves a total of **948 participants** diagnosed with **Small Lymphocytic Lymphoma (SLL)** or **Untreated Chronic Lymphocytic Leukemia (CLL)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a confirmed diagnosis of CLL/SLL and the presence of active disease necessitating therapy initiation. The trial does not include vulnerable populations. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are in relatively good health. Lifestyle considerations such as the ability to swallow and retain oral medication are noted, and individuals with controlled hepatitis B, hepatitis C, or HIV are eligible if they meet all other criteria. The selection process ensures a diverse and representative sample of the target patient population for evaluating the efficacy of nemtabrutinib compared to ibrutinib or acalabrutinib.

The clinical trial is a **Phase 3**, randomized, double-blind, controlled study designed to compare the efficacy and safety of **nemtabrutinib** against a comparator, which is the investigator's choice of either **ibrutinib** or **acalabrutinib**, in participants with untreated **chronic lymphocytic leukemia** (CLL) or **small lymphocytic lymphoma** (SLL). The trial aims to evaluate the **objective response rate** (ORR) and **progression-free survival** (PFS) as primary endpoints, assessed by a blinded independent central review (BICR) according to the 2018 iwCLL criteria. Secondary endpoints include overall survival (OS), duration of response (DOR), and the incidence of adverse events (AEs).

The trial is expected to last until September 2032, with recruitment starting in June 2024. Participants will be involved in the study for a maximum treatment period of 108 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as a confirmed diagnosis of CLL/SLL, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and the ability to swallow oral medication. Follow-up visits will be conducted to monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial is not a low-intervention study and is designed to confirm the safety and efficacy of the investigational product in the target population. The study drugs are administered orally, with **nemtabrutinib** having a maximum daily dose of 65 mg, **ibrutinib** 420 mg, and **acalabrutinib** 200 mg. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Acalabrutinib**, a chemical-origin medication, as a comparator treatment. Acalabrutinib is provided in a pharmaceutical form designated as PHF00006MIG and is administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 657 g over a treatment period of 108 weeks. The medication is not formulated for pediatric use and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Nemtabrutinib** serves as the experimental treatment in this study. It is available in two pharmaceutical forms: a tablet and a film-coated tablet, both administered orally. The maximum daily dose for Nemtabrutinib is 65 mg, with a total maximum dose of 213.7 g over the same 108-week treatment period. The active substance, also of chemical origin, is not intended for pediatric use and is not an orphan drug. The trial will ensure adherence to the dosing regimen through regular monitoring.

**Ibrutinib** is another comparator treatment used in the study, also of chemical origin. It is provided in the same pharmaceutical form as Acalabrutinib, PHF00006MIG, and is administered orally. The maximum daily dose for Ibrutinib is 420 mg, with a total maximum dose of 1381 g over the 108-week treatment period. Similar to the other medications, Ibrutinib is not formulated for pediatric use and is not classified as an orphan drug. Compliance with the dosing schedule will be closely monitored to ensure accurate data collection.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoints include the **Objective Response Rate (ORR)** and **Progression-Free Survival (PFS)**, both evaluated according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and assessed by Blinded Independent Central Review (BICR). These endpoints are designed to measure the effectiveness of **nemtabrutinib** compared to the investigator's choice of **ibrutinib** or **acalabrutinib** in participants with untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).

Secondary endpoints will include Overall Survival (OS), Duration of Response (DOR) per iwCLL criteria as assessed by BICR, the number of participants experiencing one or more adverse events (AEs), and the number of participants who discontinue study treatment due to an AE. These parameters will provide additional insights into the long-term benefits and safety profile of the treatments under investigation.