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

Phase 3TerminatedNCT01887717

Boston Scientific Corporation36 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Hepatocellular Carcinoma

Interventions

TheraSphere®DEVICE

Intrahepatic treatment of advanced hepatocellular carcinoma

SorafenibDRUG

Standard of care therapy for treatment of advanced hepatocellular carcinoma

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (19)

Northwestern Medical Faculty Foundation, Div of Hematology/Oncology

Chicago, Illinois, United States

Mount Sinai School of Medicine

New York, New York, United States

Outcomes

Primary Outcomes

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.

Time frame: Randomization up to participant's death (maximum time = up to Month 30)

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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Cliniques Universitaires Saint-Luc

Brussels, Belgium

Paoli-Calmettes Institute

Marseille, France

UO Radiologia, Ospedali Riuniti di Bergamo

Bergamo, Italy

Azienda Ospedaliero-Universitaria di Bologna

Bologna, Italy

ASO-Santa Croce e Carle di Cuneo

Cuneo, Italy

Fondazione IRCCS Ca Grande

Milan, Italy

S.C Radiologia Interventistica, A.O.Ospedale Niguarda Ca Granda

Milan, Italy

Fondazione Istituto Nazionale Tumori di Milano

Milan, Italy

...and 9 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Randomization up to participant's death (maximum time = up to Month 30)