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Efficacy Evaluation of TheraSphere to Treat Inoperable Liver Cancer With Blockage of the Portal Vein (YES-P)

Primary Purpose

Hepatocellular Carcinoma

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

TheraSphere®

Sorafenib

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring hepatocellular carcinoma, portal vein thrombosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Northwestern Medical Faculty Foundation, Div of Hematology/Oncology
Mount Sinai School of Medicine
Cliniques Universitaires Saint-Luc
Paoli-Calmettes Institute
UO Radiologia, Ospedali Riuniti di Bergamo
Azienda Ospedaliero-Universitaria di Bologna
ASO-Santa Croce e Carle di Cuneo
Fondazione IRCCS Ca Grande
S.C Radiologia Interventistica, A.O.Ospedale Niguarda Ca Granda
Fondazione Istituto Nazionale Tumori di Milano
Azienda Ospedaliera Ospedali Riuniti "Villa Sofia-Cervello"
University of Pisa
Policlinico A. Gemelli
Hospital Clínic Barcelona. IDIBAPS. CIBEREHD. Liver Unit
Bulevar Sur s/n
Hospital Universitario Puerta de Hierro, Gastroenterology & Hepatology Dept
Hospital Universitari i Politecnic la Fe
University Hospitals Birmingham NHS Foundation Trust
Royal Free London NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

TheraSphere

Sorafenib

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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 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.

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.

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.

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 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.

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.

Full Information

NCT ID

NCT01887717

First Posted

June 3, 2013

Last Updated

April 19, 2021

Sponsor

Boston Scientific Corporation

Collaborators

Biocompatibles UK Ltd

1. Study Identification

Unique Protocol Identification Number

NCT01887717

Brief Title

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

Acronym

YES-P

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Terminated

Why Stopped

Poor Accrual.

Study Start Date

February 27, 2014 (Actual)

Primary Completion Date

May 23, 2017 (Actual)

Study Completion Date

May 23, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Boston Scientific Corporation

Collaborators

Biocompatibles UK Ltd

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatocellular Carcinoma

Keywords

hepatocellular carcinoma, portal vein thrombosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TheraSphere

Arm Type

Experimental

Arm Description

Arm Title

Sorafenib

Arm Type

Active Comparator

Arm Description

Intervention Type

Device

Intervention Name(s)

TheraSphere®

Other Intervention Name(s)

yttrium-90 microspheres

Intervention Description

Intrahepatic treatment of advanced hepatocellular carcinoma

Intervention Type

Drug

Intervention Name(s)

Sorafenib

Other Intervention Name(s)

Nexavar®

Intervention Description

Standard of care therapy for treatment of advanced hepatocellular carcinoma

Primary Outcome Measure Information:

Title

Overall Survival (OS) From Time of Randomization

Description

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 Outcome Measure Information:

Title

Time to Progression (TTP)

Description

Time Frame

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

Title

Time to Worsening Portal Vein Thrombosis (PVT)

Description

Time Frame

Baseline (Randomization) up to participant's death (maximum time = up to Month 30)

Title

Time to Symptomatic Progression (TTSP)

Description

Time Frame

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

Title

Number of Participants With Tumor Response

Description

Time Frame

Baseline up to participant's death (maximum time = up to Month 30)

Title

Change From Baseline in Quality of Life (QoL) as Assessed by the FACT-Hep Questionnaire

Description

Time Frame

Baseline (Randomization), participant's death (maximum time = up to Month 30)

Title

Time to Deterioration QoL (TTDQoL)

Description

Time Frame

Baseline (Randomization) up to participant's death (maximum time = up to Month 30)

Title

Number of Participants With Treatment Emergent Adverse Events (TEAE)

Description

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Vincenzo Mazzaferro, MD

Organizational Affiliation

Istituto Tumori Nazionale, Milan, Italy

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Riad Salem, MD

Organizational Affiliation

Northwestern University Chicago Illinois

Official's Role

Principal Investigator

Facility Information:

Facility Name

Northwestern Medical Faculty Foundation, Div of Hematology/Oncology

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

Mount Sinai School of Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Cliniques Universitaires Saint-Luc

City

Brussels

ZIP/Postal Code

1200

Country

Belgium

Facility Name

Paoli-Calmettes Institute

City

Marseille

ZIP/Postal Code

13273

Country

France

Facility Name

UO Radiologia, Ospedali Riuniti di Bergamo

City

Bergamo

ZIP/Postal Code

24128

Country

Italy

Facility Name

Azienda Ospedaliero-Universitaria di Bologna

City

Bologna

ZIP/Postal Code

40138

Country

Italy

Facility Name

ASO-Santa Croce e Carle di Cuneo

City

Cuneo

ZIP/Postal Code

12100

Country

Italy

Facility Name

Fondazione IRCCS Ca Grande

City

Milano

ZIP/Postal Code

20122

Country

Italy

Facility Name

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

City

Milano

ZIP/Postal Code

20162

Country

Italy

Facility Name

Fondazione Istituto Nazionale Tumori di Milano

City

Milano

ZIP/Postal Code

I-20133

Country

Italy

Facility Name

Azienda Ospedaliera Ospedali Riuniti "Villa Sofia-Cervello"

City

Palermo

ZIP/Postal Code

90147

Country

Italy

Facility Name

University of Pisa

City

Pisa

ZIP/Postal Code

56100

Country

Italy

Facility Name

Policlinico A. Gemelli

City

Rome

ZIP/Postal Code

8 - 00168

Country

Italy

Facility Name

Hospital Clínic Barcelona. IDIBAPS. CIBEREHD. Liver Unit

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

Bulevar Sur s/n

City

Madrid

ZIP/Postal Code

28041

Country

Spain

Facility Name

Hospital Universitario Puerta de Hierro, Gastroenterology & Hepatology Dept

City

Madrid

ZIP/Postal Code

28222

Country

Spain

Facility Name

Hospital Universitari i Politecnic la Fe

City

Valencia

ZIP/Postal Code

46026

Country

Spain

Facility Name

University Hospitals Birmingham NHS Foundation Trust

City

Birmingham

ZIP/Postal Code

B15 2WB

Country

United Kingdom

Facility Name

Royal Free London NHS Foundation Trust

City

London

ZIP/Postal Code

NW3 2QG

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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