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Patients receive yttrium Y 90 glass microspheres IA on day 0. Patients may receive additional treatment 4-12 weeks after initial treatment at the discretion of the study physician.

yttrium Y 90 glass microspheres

laboratory biomarker analysis

TheraSphere is delivered into the liver tumor through a catheter placed into the hepatic artery.

TheraSphere

Rikabi Ali, M.D.

This clinical trial studies radiolabeled glass beads (yttrium Y 90 glass microspheres) in treating patients with unresectable hepatocellular carcinoma. Internal radiation therapy uses radioactive material placed directly into or near a tumor to kill tumor cells. Using radiolabeled glass beads to kill tumor cells may be an effective treatment for liver cancer.

PRIMARY OBJECTIVES:

I. Provide oversight to treatment with TheraSphere to eligible patients with hepatocellular carcinoma (HCC) of the liver who are not surgical resection candidates.

II. Evaluate patient experience, toxicities and overall survival associated with TheraSphere treatment.

OUTLINE:

Patients receive yttrium Y 90 glass microspheres intra-arterially (IA) on day 0, and may receive a second dose within 30-90 days of initial treatment. Patients may receive additional treatment 4-12 weeks after initial treatment at the discretion of the study physician.

After completion of study treatment, patients are followed up at 3-6 weeks and annually for 2 years.

Radiolabeled Glass Beads in Treating Patients With Liver Cancer That Cannot be Removed by Surgery

A Humanitarian Device Exemption Treatment Protocol of TheraSphere® For Treatment of Unresectable Hepatocellular Carcinoma

Ohio State University Comprehensive Cancer Center

Principal Investigator

TheraSphere® consists of insoluble glass microspheres where yttrium-90 is an integral constituent of the glass. TheraSphere® is delivered into the liver tumor through a catheter placed into the hepatic artery. This artery provides the main blood supply to the tumor in the liver. TheraSphere® being unable to traverse the tumor vasculature is embolized within the tumor and exerts a local beta radiation radiotherapeutic effect with relatively limited concurrent injury to surrounding normal tissue.

TheraSphere®

Lawrence Wagman, M.D., F.A.C.S.

This is an interdisciplinary study that falls into the Humanitarian Use Device category. There are no hypotheses to be tested in this treatment protocol. The study has the following objectives:

1. Provide supervised access to treatment with TheraSphere® to eligible patients with primary cancer to the liver who are not surgical resection candidates.
2. Evaluate patient experience and toxicities associated with TheraSphere® treatment.
3. Measure tumor response rates

The purpose of this protocol is to provide supervised access at this institution to TheraSphere® treatment for a heterogeneous population of patients with unresectable primary liver tumors, with the liver being the only dominant site of disease. Based on experience gained in previous studies and well-established interventional radiology techniques, this protocol allows multiple treatments with TheraSphere® that may be delivered on an inpatient or out patient basis. Patients may receive a single dose to the whole liver, or lobar treatment delivered as a sequence of treatments approximately 30 - 90 days apart. The investigator, working with co-investigators in radiation oncology, interventional radiology and nuclear medicine, will develop a specific treatment plan for each patient, based upon the presenting condition of the patient, the vascular anatomy, and the desired goal of treatment.

A Treatment of Unresectable Hepatocellular Carcinoma With TheraSphere®

The number of eligible patients provided with supervised access to treatment with TheraSphere with primary cancer to the liver who are not surgical resection candidates.

Evaluation of patient experience and toxicities associated with Therasphere via patient follow-ups with clinician notes.

Diagnostic imaging studies for assessment of tumor response will be performed according to usual standard of care as established by the referring oncologist.

St. Joseph Hospital of Orange

Heart and Blood Diseases

Thrombosis

Venous Thrombosis

Antineoplastic Agents

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

Intrahepatic treatment of advanced hepatocellular carcinoma

Standard of care therapy for treatment of advanced hepatocellular carcinoma

Vincenzo Mazzaferro, MD

Riad Salem, MD

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.

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

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)

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.

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 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.

Biocompatibles UK Ltd

Boston Scientific Corporation

Participants received TheraSphere at a dose consistent with the approved package insert to the treated lobe of the liver. TheraSphere was administered through the hepatic artery. The targeted dose was 120 Gy + 10%. Dose reduction to a minimum dose of 80 Gy + 10% was permitted to manage radiation exposure to the lungs. Re-treatment of the same participant/lobe with further cycles of TheraSphere was permitted if a treatable progression was detected during follow-up evaluations. Any re-treatment took place at least 28 days after the previous TheraSphere treatment administered to that lobe. Participants could receive a subsequent TheraSphere administration in the absence of radiological progression criteria at the Investigator's discretion. A maximum of 3 TheraSphere administrations was permitted.

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.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Participants who received at least 1 dose of TheraSphere or Sorafenib.

On 23 May 2017, the Sponsor announced early termination of the study because fewer than half of the participants remained in follow-up resulting in to few participants for the study to be continued.

Manager of Clinical Development

Overall Survival (OS) From Time of Randomization

RECIST 1.1 Criteria

mRECIST Criteria

EASL Criteria

Time to Progression (TTP)

Time to Worsening Portal Vein Thrombosis (PVT)

Time to Symptomatic Progression (TTSP)

RECIST CR

RECIST PR

mRECIST CR

mRECIST PR

EASL CR

EASL PR

Participants who received at least 1 dose of TheraSphere or Sorafenib and with available Tumor Response data.

Number of Participants With Tumor Response

Baseline TOI

Month 30 TOI

Participants who received at least 1 dose of TheraSphere or Sorafenib and with evaluable TOI data.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Radiolabeled Glass Beads in Treating Patients With Liver Cancer That Cannot be Removed by Surgery	NCT02072356	Adult Primary H... Advanced Adult ... Localized Unres... Recurrent Adult...	yttrium Y 90 gl... laboratory biom... TheraSphere	8 Years -	Ohio State University Comprehensive Cancer Center
A Treatment of Unresectable Hepatocellular Carcinoma With TheraSphere®	NCT00877136	Liver Tumors Hepatocellular ... Hepatoma Neoplasms	TheraSphere®	18 Years -	St. Joseph Hospital of Orange
A Treatment of Unresectable Hepatocellular Carcinoma With TheraSphere®	NCT00877136	Liver Tumors Hepatocellular ... Hepatoma Neoplasms	TheraSphere®	18 Years -	St. Joseph Hospital of Orange
Efficacy Evaluation of TheraSphere to Treat Inoperable Liver Cancer With Blockage of the Portal Vein	NCT01887717	Hepatocellular ...	TheraSphere® Sorafenib	18 Years -	Boston Scientific Corporation

Spots Global Cancer Trial Database for therasphere®