Standard of care therapy for treatment of advanced hepatocellular carcinoma

Time of randomization to time of any change in classification of PVT type by ≥1 sub-type based on Investigator assessment. At screening and every 8 weeks after, PVT categorized based on dynamic imaging studies as: Type I: segmental, in ≥1 of 8 branches of the portal vein; Type II: branched, left or right branches of the portal vein; Type III: modified on the basis of extension of the tumor thrombus; Type IIIa: eligible for study, thrombus involving the main trunk, allowing blood flow to contralateral lobe (no thrombosis); Type IIIb: NOT eligible for study, thrombus in the main portal trunk occluding blood flow to contralateral lobe; and Type IV: main PVT, NOT eligible for study, extended (mesenteric or splenic veins and/or sovra-hepatic veins). Time to Worsening of PVT (Months)=(Date of event/censor-Date of Randomization+1)/30.4375. Median time to event defined as time it is expected for half of the participants to experience the event. Data analyzed using the Kaplan-Meier method.

TTSP calculated as interval between randomization and symptomatic progression. Symptomatic progression defined as clinical progress to Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 with or without tumor progression on imaging. Deterioration in PS was confirmed at the evaluation 8 weeks later. First date at which ECOG performance status was ≥2 was used as end date in TTSP analysis (assuming next subsequent visit confirmed deterioration). TTSP (Months)=(Date of ECOG >2-Date of Randomization+1)/30.4375. ECOG PS Scale: 0=Asymptomatic and fully active; 1=Symptomatic, fully ambulatory, restricted in physically strenuous activity; 2=Symptomatic, ambulatory, capable of self-care, more than 50% of waking hours are spent out of bed; 4=Completely disabled, no self-care, bedridden. Median time to event defined as time it is expected for half of the participants to experience the event. Data analyzed using the Kaplan-Meier method.

Tumor Response was based on the radiological tumor assessment and was categorized as Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). Tumor response was assessed using RECIST version (v) 1.1, mRECIST, and EASL criteria. Criteria included: CR=disappearance of all enhanced tumor areas (EASL) and disappearance of any intratumoral arterial enhancement in all target lesions (mRECIST); PR= decrease >50% of enhanced areas (EASL) and ≥30% decrease in the sum of diameters of viable target lesions (mRECIST); SD=neither CR, PR, PD (EASL/mRECIST); PD=an increase >25% in the size of ≥1 measurable lesions (EASL) and ≥20% increase in the sum of the diameter of viable of target lesion (mRECIST). RECIST v 1.1 categorized new lesions as Progressive Disease only and the non-target lesions needed to have no progressive disease to be categorized as CR or PR. One month=30.4375 days.

The Functional Assessment Cancer of Therapy-Hepatobiliary (FACT-Hep) Questionnaire uses participant reported outcome (PRO) scores. The FACT-Hep Trial Outcome Index (TOI) is the sum of the subscales scores in Personal Well-Being (PWB), Functional Well-Being (FWB), and Hepatobiliary Cancer Subscale (HCS). The higher the score, the better the QoL, with a range 0-128. Baseline data and change from Baseline data is presented.

TTDQoL was calculated as the interval between the randomization date and deterioration in QoL. The FACT-Hep Questionnaire uses PRO scores. A deterioration in QoL is defined as a >7-point decline in the total score or death, whichever occurred first. The FACT-Hep Total Score is the sum of the subscales scores in PWB, Social/Family Well-Being (SWB), Emotional Well-Being (EWB), FWB, and HCS. The higher the score, the better the QoL, with a range 0-180. TTDQoL (Months)=(Date of change from baseline in FACT-Hep ≥7 or death) - Date of Randomization + 1.

An TEAE is any untoward medical occurrence or undesirable event(s) experienced in a participant that begins or worsens following administration of the study drug or study treatment, whether or not considered related to the treatment by the Investigator. A serious adverse event (SAE) was an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason, death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability/incapacity, or congenital anomaly. AEs included both SAEs and non-serious AEs. AEs were classified according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 (CTCAE) and coded using the Medical Dictionary for Regulatory Activities (MedDRA). A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Participants received sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment was to continue until the participant was no longer clinically benefiting from therapy or until unacceptable toxicity occurred. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity were allowed.

Participants received sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment was to continue until the participant was no longer clinically benefiting from therapy or until unacceptable toxicity occurred. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity were allowed.

Participants received sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment was to continue until the participant was no longer clinically benefiting from therapy or until unacceptable toxicity occurred. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity were allowed.

Participants received sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment was to continue until the participant was no longer clinically benefiting from therapy or until unacceptable toxicity occurred. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity were allowed.

Participants received sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment was to continue until the participant was no longer clinically benefiting from therapy or until unacceptable toxicity occurred. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity were allowed.

Participants received sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment was to continue until the participant was no longer clinically benefiting from therapy or until unacceptable toxicity occurred. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity were allowed.