Study Comparing BGB-B2033 With Sorafenib or Lenvatinib in Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. It can develop when abnormal cells in the liver grow uncontrollably and may spread to other parts of the body. For people whose cancer has returned or continued to grow after treatment, additional treatment options are needed.

BGB-B2033 is a new investigational drug designed to bind to a protein called glypican-3 (GPC3), a protein found on certain cancer cells and cells of the immune system, helping the immune system to recognize and attack the cancer cells. Lenvatinib and sorafenib are approved medicines that work by blocking signals that help cancer cells grow and form new blood vessels.

The purpose of this study is to test whether BGB-B2033 is safe and can help treat HCC in adults whose cancer has been treated with up to 2 previous treatments that included programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) medicines. The main goal of the study is to see how well BGB-B2033 controls cancer and prolongs survival compared to the treatments selected by the study doctor (either lenvatinib or sorafenib).

This study has 2 treatment groups. Participants will be randomly assigned, like flipping a coin, to receive either:

• BGB-B2033, given by intravenous infusion.
• Sorafenib, taken by mouth or lenvatinib, taken by mouth per their doctor's choice The study will enroll approximately 492 adults with HCC at multiple centers worldwide. Participants will make regular visits to the clinic for treatment, health checks, blood tests, and tumor and imaging tests.

The overall study will last about 3.5 years, not including the screening period.

Participants are randomized to receive BGB-B2033 until disease progression, unacceptable toxicity, withdrawal of consent, death, or the end of the study, whichever occurs first.

Drug: BGB-B2033

Participants are randomized to receive either lenvatinib or sorafenib, selected by the investigator before treatment, until disease progression, unacceptable toxicity, withdrawal of consent, death, or the end of the study, whichever occurs first.

Drug: Lenvatinib · Drug: Sorafenib

Administered intravenously

Administered by mouth as an oral capsule once daily

Administered by mouth as an oral tablet twice daily

Time frame: Up to approximately 3.5 years

OS is defined as the time from randomization to the date of death from any cause.

Time frame: Up to approximately 3.5 years

Defined as the percentage of participants who achieved complete response (CR) or partial response (PR) by investigator assessment and Blinded Independent Central Review (BICR) with confirmation per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Time frame: Up to approximately 3.5 years

DOR is defined as the time from the date that a confirmed response (CR or PR) was first observed to the date of first documented disease progression or death, whichever occurred first. Assessed by BIRC and investigator with confirmation per RECIST v1.1.

Time frame: Up to approximately 3.5 years

PFS is defined as time from randomization to the first documentation of disease progression or death, whichever occurs first as determined by investigator assessment and BIRC with confirmation per RECIST v1.1

Time frame: From first dose until either 30 days after the last dose of study drug(s) or initiation of new anticancer therapy, whichever occurs first (Up to approximately 3.5 years)

Safety will be assessed by monitoring and recording of all adverse events (AEs) graded by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v6.0.

Time frame: From baseline (Cycle 1 Day 1, predose) through the Safety Follow-up Visit (30 days after last dose) with assessments every 2 cycles through EOT. Each cycle is 21 days.

The EORTC QLQ-HCC18 measures health related quality of life outcomes in participants with liver cancer. The 18-item questionnaire is conceptualized as consisting of 6 symptom domains, 2 single items and an Index score: fatigue (3 items), body image (2 items), jaundice (2 items), nutrition (5 items), pain (2 items), fever (2 items), abdominal swelling (1 item), and sex life (1 item). The Index score is a composite of all 18 items. The items are scored using a verbal-descriptive scale rated from 1 to 4 (1 = "not at all"; 4 = "very much"). Higher scores indicate worse symptoms.

Time frame: From baseline (Cycle 1 Day 1, predose) through the Safety Follow-up Visit (30 days after last dose) with assessments every 2 cycles through EOT.

The EORTC QLQ-F17 is a generic core questionnaire that assesses self-reported functioning and GHS in participants with cancer. The EORTC QLQ-F17 includes predefined key participant reported outcomes (PRO) endpoints to measure GHS and physical functioning and role functioning. The functional items are scored on a 4-point verbal-descriptive scale (1 = "not at all"; 4 = "very much"), while the 2 GHS items use a 7-point scale (1 = "very poor"; 7 = "excellent"). Higher scores in GHS and functioning scales indicate better health related quality outcomes.

Time frame: From randomization until the first clinically meaningful deterioration, end of treatment, withdrawal of consent, death, or end of study, as applicable (Up to approximately 3.5 years)

Time to deterioration in fatigue, as measured by the fatigue domain of the EORTC QLQ-HCC18 questionnaire. The fatigue domain consists of 3 items scored from 1 ("not at all") to 4 ("very much"). Higher scores indicate worse fatigue. Time to deterioration is defined as the time from randomization to the first clinically meaningful worsening in the fatigue score from baseline, based on the prespecified scoring criteria.

Time frame: From randomization until the first clinically meaningful deterioration, end of treatment, withdrawal of consent, death, or end of study, as applicable ((Up to approximately 3.5 years).

Time to deterioration in global health status, physical functioning, and role functioning, as measured by the EORTC QLQ-F17 questionnaire. The questionnaire assesses participants' self-reported overall health, physical functioning, and ability to perform daily activities and roles. Higher scores indicate better health-related quality of life. Time to deterioration is defined as the time from randomization to the first clinically meaningful worsening from baseline in global health status, physical functioning, or role functioning, based on prespecified scoring criteria.

A Randomized, Open-Label, Phase 3 Study to Investigate the Efficacy and Safety of BGB-B2033 Compared With Investigator Choice of Sorafenib or Lenvatinib in Patients With Hepatocellular Carcinoma That Progressed Upon Prior Systemic Treatment