Unresectable Hepatocellular Carcinoma
Conditions
Brief summary
The safety and effectiveness of TheraSphere will be evaluated in patients with unresectable hepatocellular carcinoma in whom treatment with standard-of-care sorafenib is planned. All patients receive the standard-of-care sorafenib with or without the addition of TheraSphere.
Interventions
DEVICETheraSphere
Yttrium 90 microspheres
Sponsors
Biocompatibles UK Ltd
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent prior to any study-related evaluation * Male or female patients over 18 years of age * Unresectable HCC confirmed by histology or by non-invasive AASLD criteria * Measurable disease defined as at least one uni-dimensional measurable lesion by CT or MRI according to RECIST 1.1 * Child Pugh score ≤ 7 points * Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤ 1 * Life expectancy of 12 weeks or more * Eligible to receive standard-of-care sorafenib * Platelet count of \> 50 x 10⁹/L or \> 50% prothrombin activity * Hemoglobin ≥ 8.5 g/dL * Bilirubin ≤ 2.5 mg/dL * Alanine transaminase (ALT) and Aspartate Aminotransferase (AST)\< 5 X upper limit of normal * Amylase or lipase ≤ 2X upper limit of normal * Serum creatinine ≤ 1.5 X upper limit of normal * International normalized ratio (INR) \< 2.0
Exclusion criteria
* Main portal vein thrombosis * Eligible for curative treatment (ablation or transplantation) * History of previous or concurrent cancer other than HCC unless treated curatively 5 or more years prior to entry * Confirmed presence of extra-hepatic disease except lung nodules and mesenteric or portal lymph nodes ≤ 2.0 cm each * Risk of hepatic or renal failure * Tumor replacement ≥ 70% of total liver volume based on visual estimation by investigator OR tumor replacement ≥ 50% of total liver volume in the presence of albumin \<3 mg/dL * History of severe allergy or intolerance to contrast agents, narcotics sedatives or atropine that cannot be managed medically * Contraindications to angiography and selective visceral catheterization. * History of organ allograft * Known contraindications to sorafenib including allergic reaction, pill-swallowing difficulty, evidence of severe or systemic diseases, uncontrolled severe hypertension or history of cardiac arrhythmias, congestive heart failure . New York Heart Association class 2, myocardial infarct within 6 months, prolonged QT/QTc \>450ms, evidence of torsades de pointe, or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial, significant GI bleed within 30 days, metastatic brain disease, renal failure requiring dialysis * Taking any of the following: Rifampicin, St. John's Wort, phenytoin, carbamazepine, phenobarbital, dexamethasone * Taking any other systemic anticancer agent (docetaxel, doxorubicin, irinotecan) * Taking any substrate agents for Cytochrome P450 (CYP) 2B6 (bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone, paclitaxel, amodiaquine, repaglinide) * Taking any UDP-glucuronosyltransferase (UGT) 1A1 and UGT 1A9 substrates (e.g. irinotecan) * Taking P-Gp substrates (e.g. Digoxin) * Prior liver resection must have taken ≥2 months prior to randomization * Treatment with other locoregional therapies (other than study treatment) has not been planned for the duration of the clinical study period * Prior external beam radiation treatment to the chest, liver or abdomen * Prior yttrium-90 microsphere treatment to the liver * Prior treatment with transarterial chemoembolization (TACE) or bland embolization must have occurred \>2 months prior to randomization and must have been applied to a treatment field and/or lobe not targeted for treatment under this protocol. For patients with tumor progression in the treatment field and /or lobe previously treated with TACE, vessels feeding the tumor(s) must be assessed for adequate blood flow using angiography (cone beam computerized tomography (CBCT) strongly recommended), and TACE or bland embolization must have been applied \>6 months prior to randomization. * Anti-cancer therapy or any treatment with an investigational agent within 30 days prior to randomization * Adverse effects due to prior therapy unresolved at randomization * Prior systemic treatment for the treatment of HCC, including sorafenib given for more than 4 weeks during the 2 previous months prior to randomization, no prior sorafenib related toxicity * Evidence of pulmonary insufficiency or inadequately treated moderate grade or severe/very severe grade chronic obstructive pulmonary disease * Intervention for, or compromise of, the Ampulla of Vater * Clinically evident ascites (trace ascites on imaging is acceptable) * Pregnancy or breast feeding * Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization * Disease or condition that would preclude safe use of TheraSphere, including concurrent dialysis treatment, or unresolved serious infections. Patients infected with HIV can be considered, however, they must be well managed and well controlled with undetectable viral load * Participation in concurrent clinical trials evaluating treatment intervention(s)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Results Are Based on the Modified Intent-to-treat (mITT) | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | Time from randomization until date of death due to any cause as reported by study site. |
| Overall Survival (OS) Per Protocol (PP) Population | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | Per Protocol = subset of the mITT population excluding patients with major protocol deviations which may affect the efficacy evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) From Time of Randomization Based on Investigator, According RECIST Criteria. | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | Time to progression (TTP) will be calculated as the interval between the randomization date and the date of first disease progression, including the appearance of new lesion(s) (per RECIST 1.1) and death for any cause or of last contact for patients alive. |
| Time to Untreatable Progression (TTUP) From the Time of Randomization Based One or More of the Following: Investigator Assessment According to RECIST Criteria | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | Time to progression (TTP) will be calculated as the interval between the randomization date and the date of first disease progression, including the appearance of new lesion(s) and death for any cause or of last contact for patients alive. |
| Tumor Response | From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months | Objective Response Rate by investigator determination per RECIST 1.1 |
Countries
Belgium, Canada, France, Germany, Italy, Netherlands, Singapore, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
In total 526 participants were randomized to either the Control Group (Sorafenib + Standard of Care) or the Treatment Group (TheraSphere + Sorafenib + Standard of Care).
Pre-assignment details
The Overall Survival (OS) efficacy endpoints analyzed on the modified Intent-To-Treat (mITT) population, comprising 481/526 randomized patients who met eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib + Standard of Care Control group: Standard-of-care sorafenib, with no added therapy | 241 |
| TheraSphere + Sorafenib + Standard of Care Treatment group: Standard-of-care sorafenib plus TheraSphere
TheraSphere: Yttrium 90 microspheres | 240 |
| Total | 481 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Survival (OS) | Untreated Patients who Discontinued/Completed from Study | 12 | 18 |
| Randomized Patients Summary | Protocol Violation | 22 | 23 |
Baseline characteristics
| Characteristic | Total | Sorafenib + Standard of Care | TheraSphere + Sorafenib + Standard of Care |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 231 Participants | 111 Participants | 120 Participants |
| Age, Categorical Between 18 and 65 years | 250 Participants | 130 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 280 Participants | 144 Participants | 136 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 191 Participants | 91 Participants | 100 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 107 Participants | 55 Participants | 52 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 182 Participants | 85 Participants | 97 Participants |
| Race (NIH/OMB) White | 174 Participants | 95 Participants | 79 Participants |
| Region of Enrollment Belgium | 3 participants | 2 participants | 1 participants |
| Region of Enrollment Canada | 43 participants | 22 participants | 21 participants |
| Region of Enrollment France | 174 participants | 80 participants | 94 participants |
| Region of Enrollment Germany | 4 participants | 1 participants | 3 participants |
| Region of Enrollment Hong Kong | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Netherlands | 8 participants | 4 participants | 4 participants |
| Region of Enrollment Singapore | 4 participants | 1 participants | 3 participants |
| Region of Enrollment South Korea | 90 participants | 47 participants | 43 participants |
| Region of Enrollment Spain | 43 participants | 28 participants | 15 participants |
| Region of Enrollment United Kingdom | 50 participants | 28 participants | 22 participants |
| Region of Enrollment United States | 60 participants | 26 participants | 34 participants |
| Sex: Female, Male Female | 56 Participants | 26 Participants | 30 Participants |
| Sex: Female, Male Male | 425 Participants | 215 Participants | 210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 239 / 274 | 178 / 207 |
| other Total, other adverse events | 259 / 274 | 189 / 207 |
| serious Total, serious adverse events | 111 / 274 | 94 / 207 |
Outcome results
Primary
Overall Survival (OS) Per Protocol (PP) Population
Per Protocol = subset of the mITT population excluding patients with major protocol deviations which may affect the efficacy evaluation.
Time frame: From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Standard of Care | Overall Survival (OS) Per Protocol (PP) Population | 13.2 Months |
| TheraSphere + Sorafenib + Standard of Care | Overall Survival (OS) Per Protocol (PP) Population | 13.8 Months |
p-value: 0.062695% CI: [0.61, 1.01]Log Rank
Primary
Overall Survival (OS) Results Are Based on the Modified Intent-to-treat (mITT)
Time from randomization until date of death due to any cause as reported by study site.
Time frame: From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months
Population: All participants were analyzed, and the count of participants is reporting the number of events (deaths).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sorafenib + Standard of Care | Overall Survival (OS) Results Are Based on the Modified Intent-to-treat (mITT) | 200 Participants |
| TheraSphere + Sorafenib + Standard of Care | Overall Survival (OS) Results Are Based on the Modified Intent-to-treat (mITT) | 206 Participants |
p-value: 0.455295% CI: [0.89, 1.31]Log Rank
Secondary
Time to Progression (TTP) From Time of Randomization Based on Investigator, According RECIST Criteria.
Time to progression (TTP) will be calculated as the interval between the randomization date and the date of first disease progression, including the appearance of new lesion(s) (per RECIST 1.1) and death for any cause or of last contact for patients alive.
Time frame: From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Standard of Care | Time to Progression (TTP) From Time of Randomization Based on Investigator, According RECIST Criteria. | 5.6 Months |
| TheraSphere + Sorafenib + Standard of Care | Time to Progression (TTP) From Time of Randomization Based on Investigator, According RECIST Criteria. | 8.1 Months |
p-value: 0.022795% CI: [0.59, 0.96]Log Rank
Secondary
Time to Untreatable Progression (TTUP) From the Time of Randomization Based One or More of the Following: Investigator Assessment According to RECIST Criteria
Time to progression (TTP) will be calculated as the interval between the randomization date and the date of first disease progression, including the appearance of new lesion(s) and death for any cause or of last contact for patients alive.
Time frame: From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Standard of Care | Time to Untreatable Progression (TTUP) From the Time of Randomization Based One or More of the Following: Investigator Assessment According to RECIST Criteria | 8.0 Months |
| TheraSphere + Sorafenib + Standard of Care | Time to Untreatable Progression (TTUP) From the Time of Randomization Based One or More of the Following: Investigator Assessment According to RECIST Criteria | 12.2 Months |
p-value: 0.004395% CI: [0.52, 0.89]Log Rank
Secondary
Tumor Response
Objective Response Rate by investigator determination per RECIST 1.1
Time frame: From time of randomization up to date of death or last date known to be alive (data cut-off 30Apr2022), an average of 16.3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sorafenib + Standard of Care | Tumor Response | 20 Participants |
| TheraSphere + Sorafenib + Standard of Care | Tumor Response | 57 Participants |
p-value: 0.000195% CI: [8.6, 22.3]2 sided calculated using continuity
Post Hoc
Summary of Protocol Deviations
A modified Intention To Treat (mITT) Population was used to analyze all efficacy endpoints. This population is defined as randomized patients who met the study eligibility criteria at randomization. This outcome analysis is based on the mITT population, which includes patients with major protocol deviations.
Time frame: From time of randomization up to date of death or last date known to bealive (data cut-off 30Apr2022), an average of 16.3 months
Population: Percentages are based on the number of patients in each treatment group. A major protocol deviation is a deviation that may affect efficacy evaluation and results in removal of a patient from Per Protocol Population. Of the Major protocol deviations 156/159 patients had treatment related exclusions.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib + Standard of Care | Summary of Protocol Deviations | Patients with a Major Protocol Deviation | 23 Participants |
| Sorafenib + Standard of Care | Summary of Protocol Deviations | Patients with a Protocol Deviation | 193 Participants |
| TheraSphere + Sorafenib + Standard of Care | Summary of Protocol Deviations | Patients with a Major Protocol Deviation | 136 Participants |
| TheraSphere + Sorafenib + Standard of Care | Summary of Protocol Deviations | Patients with a Protocol Deviation | 225 Participants |