Efficacy Evaluation of TheraSphere to Treat Inoperable Liver Cancer With Blockage of the Portal Vein

Study Overview
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Brief Summary
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This is a two-arm, open-label, prospective, multi-center, randomized, active-controlled clinical trial to assess efficacy and safety of TheraSphere in comparison to standard of care therapy (sorafenib) in the treatment of participants with inoperable liver cancer and blockage of the portal vein.

Detailed Description
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The objective of this Phase III, prospective randomized trial is to determine whether TheraSphere provides a meaningful benefit in survival in comparison with the standard of care (sorafenib) in participants with good hepatic function and advanced hepatocellular carcinoma (HCC) associated with portal vein thrombosis (PVT). This is an open-label prospective, multi-center, randomized, controlled clinical trial that will evaluate the use of TheraSphere compared to standard-of-care sorafenib alone.

Official Title
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A Prospective Randomized Clinical Trial on 90Yttrium Trans-arterial Radio-Embolization (TheraSphere®) vs. Standard of Care (Sorafenib) for the Treatment of Advanced Hepatocellular Carcinoma (HCC) With Portal Vein Thrombosis (PVT)

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Device: TheraSphere®
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants over 18 years of age, regardless of race or gender Advanced unresectable hepatocellular carcinoma with branch portal vein thrombosis (confirmed by non-invasive criteria European Association for the Study of the Liver [EASL]/American Association for the Study of Liver Diseases [AASLD], mandatory by histology in non-cirrhotic participants); can be naive or recurrent HCC after curative treatment ( >6 months before randomization) Unilobar disease Child Pugh A Tumor volume ≤70% of liver volume (determined by visual estimation) At least one uni-dimensional HCC target lesion assessable by computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Platelets ≥ 50*10^3/microliter (µL) White blood cell (WBC) ≥1.5*10^3/microliter (µL) Aspartate transaminase (AST)/ alanine aminotransferase (ALT) ≤5 times upper limit of normal Creatinine ≤2.0 mg/deciliter (dL) Life expectancy >3 months Signed informed consent Exclusion Criteria: Confirmed extra hepatic metastases. Participants with indeterminate hepatic hilar lymph nodes up to 2.5 centimeters (cm) in greatest dimension, or with indeterminate lung nodules (single lesion between 1-1.5 cm, or multiple smaller lesions with a total diameter of ≤2 cm) may be included if metastatic disease is deemed unlikely Known contraindication to standard-of-care sorafenib including allergic reaction, pill swallowing difficulty, uncontrolled hypertension or history of cardiac disease, significant GI bleed within 30 days, and renal failure including dialysis Evidence of hepatic vein invasion or caval thrombosis Evidence of chronic obstructive pulmonary disease Indication for any possible curative treatment after multidisciplinary assessment (surgery, ablation, transplantation) Previous treatment with sorafenib for more than 4 weeks during the previous 2 months; prior sorafenib-related toxicity Initiation of anti-tumor therapy including chemotherapy or investigational drug treatment within 30 days before beginning study Prior transarterial chemoembolization (TACE) <6 months prior to screening phase in case of participants progressing from an intermediate to an advanced stage due to occurrence of PVT On a transplant list History of organ allograft Contraindications to angiography or selective visceral catheterization History of severe allergy or intolerance to contrast agents, narcotics, sedatives, or atropine that cannot be managed medically Prior external beam radiation therapy to the liver Evidence of continuing adverse effect of prior therapy Active gastrointestinal (GI) bleeding and any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents Evidence of any disease or condition that would place the participant at undue risk and preclude safe use of TheraSphere treatment Females of child-bearing potential must have a negative serum test No participation in concurrent clinical trials

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TheraSphere<br>Participants will receive TheraSphere at a dose consistent with the approved product label to the treated lobe of the liver. TheraSphere will be administered through the hepatic artery. The target dose will be 120 Gy + 10%. Dose reduction to a minimum dose of 80 Gy + 10% will be permitted to manage radiation exposure to the lungs. Re-treatment of the same participant/lobe with further cycles of TheraSphere will be permitted if a treatable progression is detected during follow-up evaluations. Any re-treatment will take place at least 28 days after the previous TheraSphere treatment administered to that lobe. Participants can receive a subsequent TheraSphere administration in the absence of radiological progression criteria at the Investigator's discretion. A maximum of 3 TheraSphere administrations will be permitted. | Device: TheraSphere®<br>* Intrahepatic treatment of advanced hepatocellular carcinoma<br>* Other names: yttrium-90 microspheres;|
| Active Comparator: Sorafenib<br>Participants will receive sorafenib, oral tablets, 400 milligrams (mg) twice daily in accordance with the package insert. Treatment is to continue until the participant is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Medically appropriate dose adjustments and drug holidays due to adverse events (AEs) and toxicity will be allowed. | Drug: Sorafenib<br>* Standard of care therapy for treatment of advanced hepatocellular carcinoma<br>* Other names: Nexavar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) From Time of Randomization | OS was calculated as the interval between the randomization date and the date of death for any cause, with censoring at the date of last contact for participants alive. | Randomization up to participant's death (maximum time = up to Month 30) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | TTP was defined as the time from randomization until date of first radiological progression (including new liver lesions and extra-hepatic lesions) separately according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 criteria, modified RECIST (mRECIST) criteria, and European Association for the Study of the Liver (EASL) criteria (assessed bi-dimensionally on enhancing tissue) as assessed by Investigator determination. Progression was defined as 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 v1.1 categorized new lesions as Progressive Disease. TTP (Months)=(Date of event/censor - Date of Randomization + 1)/ 30.4375. | Randomization up to participant's death (maximum time = up to Month 30) | 
| Time to Worsening Portal Vein Thrombosis (PVT) | 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. | Baseline (Randomization) up to participant's death (maximum time = up to Month 30) | 
| Time to Symptomatic Progression (TTSP) | 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. | Randomization up to participant's death (maximum time = up to Month 30) | 
| Number of Participants With Tumor Response | 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. | Baseline up to participant's death (maximum time = up to Month 30) | 
| Change From Baseline in Quality of Life (QoL) as Assessed by the FACT-Hep Questionnaire | 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. | Baseline (Randomization), participant's death (maximum time = up to Month 30) | 
| Time to Deterioration QoL (TTDQoL) | 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. | Baseline (Randomization) up to participant's death (maximum time = up to Month 30) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAE) | 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. | Randomization up to participant's death (maximum time = up to Month 30) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatocellular carcinoma, portal vein thrombosis