Clinical Trials List
Protocol NumberYO40245
NCT Number(ClinicalTrials.gov Identfier)NCT03434379
2018-03-01 - 2023-12-31
Phase III
Terminated5
ICD-10C22.0
Liver cell carcinoma
ICD-10C22
Malignant neoplasm of liver and intrahepatic bile ducts
A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
-
Trial Applicant
-
Sponsor
Hoffmann-La Roche
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Yi-Ping Hung Division of Hematology & Oncology
- Rheun-Chuan Lee Division of Radiology
- Ming-Huang Chen Division of Hematology & Oncology
- Yi-Hsiang Huang Digestive System Department
- Chung-Pin Li Digestive System Department
The Actual Total Number of Participants Enrolled
3 Completed
Audit
None
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- Yih-Jyh Lin Division of General Surgery
- Shang-Yin Wu Division of General Internal Medicine
The Actual Total Number of Participants Enrolled
0 Completed
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
楊再勝
Co-Principal Investigator
- Chia-Hsun Hsieh Division of Hematology & Oncology
- 呂嘉偉 Division of Radiology
- Ming-Mo Hou Division of Hematology & Oncology
- Cheng-Lung Hsu Division of Hematology & Oncology
- Mengting Peng Division of Hematology & Oncology
- Jen-Shi Chen Division of Hematology & Oncology
- Yung-Chia Kao Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
8 Completed
Audit
None
Co-Principal Investigator
- Chiun Hsu Division of Hematology & Oncology
- 呂理駿 Division of Hematology & Oncology
- 林宗哲 Division of Hematology & Oncology
- Chien-Hung Chen Division of General Internal Medicine
- Ying-Chun Shen Division of Hematology & Oncology
- Ming-Chih Ho Division of General Surgery
- Chih-Hung Hsu Division of Hematology & Oncology
- YU-YUN SHAO Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Audit
None
Condition/Disease
Hepatocellular Carcinoma (HCC)
Objectives
This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have received no prior systemic treatment.
Test Drug
Atezolizumab; Bevacizumab; Sorafenib
Active Ingredient
Atezolizumab
Bevacizumab
Sorafenib
Bevacizumab
Sorafenib
Dosage Form
injection
injection
tablet
injection
tablet
Dosage
400mg/16ml
1200mg/20mL
200mg
1200mg/20mL
200mg
Endpoints
Primary Outcome Measures :
Overall Survival (OS) [ Time Frame: Randomization to death from any cause, through the end of study (up to approximately 4 years) ]
Progression Free Survival (PFS) as Determined by an Independent Review Facility (IRF) According to Response Evalutaion Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 4 years) ]
Overall Survival (OS) [ Time Frame: Randomization to death from any cause, through the end of study (up to approximately 4 years) ]
Progression Free Survival (PFS) as Determined by an Independent Review Facility (IRF) According to Response Evalutaion Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: Randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 4 years) ]
Inclution Criteria
Inclusion Criteria
Patients must meet the following criteria for study entry:
Signed Informed Consent Form
Age 18 years at time of signing Informed Consent Form
Ability to comply with the study protocol, in the investigator's judgment Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed
by histology/ cytology or clinically by AASLD criteria in cirrhotic patients
Patients without cirrhosis require histological confirmation of diagnosis.
Disease that is not amenable to curative surgical and/or locoregional therapies, or
progressive disease after surgical and /or locoregional therapies
No prior systemic therapy for HCC
At least one measurable (per RECIST 1.1) untreated lesion
Patients who received prior local therapy (e.g., radiofrequency ablation,
percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused
ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are
eligible provided the target lesion(s) have not been previously treated with local
therapy or the target lesion(s) within the field of local therapy have subsequently
progressed in accordance with RECIST version 1.1.
Pre-treatment tumor tissue sample (if available)
If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor
specimen in a paraffin block (preferred) or approximately 1015 slides
containing unstained, freshly cut, serial sections should be submitted along with
an associated pathology report within 4 weeks of randomization.
If FFPE specimens described above are not available, any type of specimens
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural
effusion], and lavage samples) are also acceptable. This specimen should be
accompanied by the associated pathology report. See Section 4.5.6 for further
details.
If tumor tissue is not available (e.g., depleted because of prior diagnostic
testing), patients are still eligible.
ECOG Performance Status of 0 or 1
Child-Pugh class A (see Appendix 10)
Adequate hematologic and end-organ function, defined by the following laboratory
test results, obtained within 14 days prior to initiation of study treatment, unless
otherwise specified:
– ANC 1.5 109
/L (1500/L) without granulocyte colony-stimulating factor
support
– Lymphocyte count 0.5109
/L (500/L)
– Platelet count 75 109
/L (75,000/L) without transfusion
– Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
– AST, ALT, and alkaline phosphatase (ALP) 5 upper limit of normal (ULN)
– Serum bilirubin 3 ULN
– Serum creatinine 1.5ULN or creatinine clearance 50 mL/min (calculated
using the Cockcroft-Gault formula)
– Serum albumin 28 g/L (2.8 g/dL)
– For patients not receiving therapeutic anticoagulation: INR or aPTT 2ULN
– Urine dipstick for proteinuria 2 (within 7 days prior to initiation of study
treatment)
Patients discovered to have 2 proteinuria on dipstick urinalysis at
baseline should undergo a 24-hour urine collection and must demonstrate
1 g of protein in 24 hours.
Resolution of any acute, clinically significant treatment-related toxicity from prior
therapy to Grade 1 prior to study entry, with the exception of alopecia
Negative HIV test at screening
Documented virology status of hepatitis, as confirmed by screening HBV and HCV
serology test
For patients with active hepatitis B virus (HBV):
HBV DNA 500 IU/mL obtained within 28 days prior to initiation of study
treatment, and
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum
of 14 days prior to study entry and willingness to continue treatment for the
length of the study
For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of
1% per year during the treatment period and for at least 5 months after the last
dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after
the last dose of sorafenib
A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (12 continuous months of
amenorrhea with no identified cause other than menopause), and has not
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine
devices.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm, as
defined below:
With female partners of childbearing potential, men must remain abstinent or
use a condom plus an additional contraceptive method that together result in a
failure rate of 1% per year during the treatment period and for 6 months after
the last dose of bevacizumab or 3 months after the last dose of sorafenib. Men
must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom
during the treatment period and for 6 months after the last dose of bevacizumab
or 3 months after the last dose of sorafenib to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
For the extended China enrollment phase: Chinese ancestry and residence in
Mainland China, Hong Kong, or Taiwan with enrollment at sites recognized by the
China FDA
Patients must meet the following criteria for study entry:
Signed Informed Consent Form
Age 18 years at time of signing Informed Consent Form
Ability to comply with the study protocol, in the investigator's judgment Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed
by histology/ cytology or clinically by AASLD criteria in cirrhotic patients
Patients without cirrhosis require histological confirmation of diagnosis.
Disease that is not amenable to curative surgical and/or locoregional therapies, or
progressive disease after surgical and /or locoregional therapies
No prior systemic therapy for HCC
At least one measurable (per RECIST 1.1) untreated lesion
Patients who received prior local therapy (e.g., radiofrequency ablation,
percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused
ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are
eligible provided the target lesion(s) have not been previously treated with local
therapy or the target lesion(s) within the field of local therapy have subsequently
progressed in accordance with RECIST version 1.1.
Pre-treatment tumor tissue sample (if available)
If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor
specimen in a paraffin block (preferred) or approximately 1015 slides
containing unstained, freshly cut, serial sections should be submitted along with
an associated pathology report within 4 weeks of randomization.
If FFPE specimens described above are not available, any type of specimens
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural
effusion], and lavage samples) are also acceptable. This specimen should be
accompanied by the associated pathology report. See Section 4.5.6 for further
details.
If tumor tissue is not available (e.g., depleted because of prior diagnostic
testing), patients are still eligible.
ECOG Performance Status of 0 or 1
Child-Pugh class A (see Appendix 10)
Adequate hematologic and end-organ function, defined by the following laboratory
test results, obtained within 14 days prior to initiation of study treatment, unless
otherwise specified:
– ANC 1.5 109
/L (1500/L) without granulocyte colony-stimulating factor
support
– Lymphocyte count 0.5109
/L (500/L)
– Platelet count 75 109
/L (75,000/L) without transfusion
– Hemoglobin 90 g/L (9 g/dL)
Patients may be transfused to meet this criterion.
– AST, ALT, and alkaline phosphatase (ALP) 5 upper limit of normal (ULN)
– Serum bilirubin 3 ULN
– Serum creatinine 1.5ULN or creatinine clearance 50 mL/min (calculated
using the Cockcroft-Gault formula)
– Serum albumin 28 g/L (2.8 g/dL)
– For patients not receiving therapeutic anticoagulation: INR or aPTT 2ULN
– Urine dipstick for proteinuria 2 (within 7 days prior to initiation of study
treatment)
Patients discovered to have 2 proteinuria on dipstick urinalysis at
baseline should undergo a 24-hour urine collection and must demonstrate
1 g of protein in 24 hours.
Resolution of any acute, clinically significant treatment-related toxicity from prior
therapy to Grade 1 prior to study entry, with the exception of alopecia
Negative HIV test at screening
Documented virology status of hepatitis, as confirmed by screening HBV and HCV
serology test
For patients with active hepatitis B virus (HBV):
HBV DNA 500 IU/mL obtained within 28 days prior to initiation of study
treatment, and
Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum
of 14 days prior to study entry and willingness to continue treatment for the
length of the study
For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of
1% per year during the treatment period and for at least 5 months after the last
dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after
the last dose of sorafenib
A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (12 continuous months of
amenorrhea with no identified cause other than menopause), and has not
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine
devices.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm, as
defined below:
With female partners of childbearing potential, men must remain abstinent or
use a condom plus an additional contraceptive method that together result in a
failure rate of 1% per year during the treatment period and for 6 months after
the last dose of bevacizumab or 3 months after the last dose of sorafenib. Men
must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom
during the treatment period and for 6 months after the last dose of bevacizumab
or 3 months after the last dose of sorafenib to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
For the extended China enrollment phase: Chinese ancestry and residence in
Mainland China, Hong Kong, or Taiwan with enrollment at sites recognized by the
China FDA
Exclusion Criteria
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
History of leptomeningeal disease
Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
– Rash must cover 10% of body surface area
– Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
– No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
within the previous 12 months
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Active tuberculosis
Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
study
History of malignancy other than HCC within 5 years prior to screening, with the
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year
OS rate 90%), such as adequately treated carcinoma in situ of the cervix,
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ,
or Stage I uterine cancer
Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract
infection or chronic obstructive pulmonary disease exacerbation) are eligible for
the study.
Prior allogeneic stem cell or solid organ transplantation
Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from treatment
complications
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during atezolizumab treatment
or within 5 months after the last dose of atezolizumab
History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
Known hypersensitivity to Chinese hamster ovary cell products or to any component
of the atezolizumab or bevacizumab formulation
Pregnancy or breastfeeding, or intention of becoming pregnant during study
treatment or within at least 5 months after the last dose of atezolizumab, 6 months
after the last dose of bevacizumab, or 1 month after the last dose of sorafenib
Women of childbearing potential must have a negative serum pregnancy test
result within 14 days prior to initiation of study treatment.
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and
HCC
Patients with untreated or incompletely treated varices with bleeding or high-risk for
bleeding
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size
of varices (small to large) must be assessed and treated per local standard of
care prior to enrollment. Patients who have undergone an EGD within
6 months of prior to initiation of study treatment do not need to repeat the
procedure.
Moderate or severe ascites
History of hepatic encephalopathy
Co-infection of HBV and HCV
Patients with a history of HCV infection but who are negative for HCV RNA by
PCR will be considered non-infected with HCV.
Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of
the following criteria are met:
– Measurable disease, per RECIST v1.1, must be present outside the CNS.
– The patient has no history of intracranial hemorrhage or spinal cord
hemorrhage.
– Metastases are limited to the cerebellum or the supratentorial region
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
– There is no evidence of interim progression between completion of
CNS-directed therapy and initiation of study treatment.
– The patient has not undergone stereotactic radiotherapy within 7 days
prior to initiation of study treatment, whole-brain radiotherapy within
14 days prior to initiation of study treatment, neurosurgical resection within
28 days prior to initiation of study treatment.
– The patient has no ongoing requirement for corticosteroids as therapy for
CNS disease. Anticonvulsant therapy at a stable dose is permitted.
Asymptomatic patients with CNS metastases newly detected at screening are
eligible for the study after receiving radiotherapy or surgery, with no need to
repeat the screening brain scan.
Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment. Patients should be recovered from the effects of radiation. There is
no required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not
currently associated with spinal cord compression) should be considered
for loco-regional therapy if appropriate prior to enrollment.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX
) are allowed.
Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L,
calcium 12 mg/dL or corrected serum calcium ULN)
Treatment with investigational therapy within 28 days prior to initiation of study
treatment
Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study
treatment, including rifampin (and its analogues) or St. John's wort
Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
(whichever is longer) prior to initiation of study treatment
Treatment with systemic immunosuppressive medication (including, but not limited
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
antiTNF- agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study
treatment, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant
medication or a one-time pulse dose of systemic immunosuppressant
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible
for the study after Medical Monitor approval has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
for the study.
Inadequately controlled arterial hypertension (defined as systolic blood pressure
(BP) 150 mmHg and/or diastolic blood pressure 100 mmHg), based on an
average of 3 BP readings on 2 sessions
Anti-hypertensive therapy to achieve these parameters is allowable.
Prior history of hypertensive crisis or hypertensive encephalopathy
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month prior
to initiation of study treatment
Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)
Current or recent (within 10 days of first dose of study treatment) use of aspirin
( 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
Current or recent (within 10 days prior to study treatment start) use of full-dose oral
or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to
prophylactic) purpose
Prophylactic anticoagulation for the patency of venous access devices is
allowed provided the activity of the agent results in an INR 1.5 ULN and
aPTT is within normal limits within 14 days prior to initiation of study treatment.
Prophylactic use of low molecular-weight heparin (i.e., enoxaparin 40 mg/day)
is allowed.
Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 3 days prior to the first dose of bevacizumab
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation,
or intra-abdominal abscess within 6 months prior to initiation of study treatment
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction
including sub-occlusive disease related to the underlying disease or requirement for
routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months
prior to initiation of study treatment
Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction
at time of initial diagnosis may be enrolled if they had received definitive
(surgical) treatment for symptom resolution.
Evidence of abdominal free air that is not explained by paracentesis or recent
surgical procedure
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
Metastatic disease that involves major airways or blood vessels, or centrally located
mediastinal tumor masses ( 30 mm from the carina) of large volume
Patients with vascular invasion of the portal or hepatic veins may be enrolled.
History of intra-abdominal inflammatory process within 6 months prior to initiation of
study treatment, including but not limited to peptic ulcer disease, diverticulitis, or
colitis
Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior
to initiation of study treatment, except palliative radiotherapy to bone lesions within
7 days prior to initiation of study treatment Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to initiation of study treatment, or abdominal surgery, abdominal interventions
or significant abdominal traumatic injury within 60 days prior to initiation of study
treatment or anticipation of need for major surgical procedure during the course of
the study or non-recovery from side effects of any such procedure
Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID)
Occasional use of NSAIDs for the symptomatic relief of medical conditions such
as headache or fever is allowed.
Patients who meet any of the following criteria will be excluded from study entry:
History of leptomeningeal disease
Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list of
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
– Rash must cover 10% of body surface area
– Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
– No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
within the previous 12 months
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Active tuberculosis
Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
study
History of malignancy other than HCC within 5 years prior to screening, with the
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year
OS rate 90%), such as adequately treated carcinoma in situ of the cervix,
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ,
or Stage I uterine cancer
Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract
infection or chronic obstructive pulmonary disease exacerbation) are eligible for
the study.
Prior allogeneic stem cell or solid organ transplantation
Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of an investigational drug, may affect
the interpretation of the results, or may render the patient at high risk from treatment
complications
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine during atezolizumab treatment
or within 5 months after the last dose of atezolizumab
History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
Known hypersensitivity to Chinese hamster ovary cell products or to any component
of the atezolizumab or bevacizumab formulation
Pregnancy or breastfeeding, or intention of becoming pregnant during study
treatment or within at least 5 months after the last dose of atezolizumab, 6 months
after the last dose of bevacizumab, or 1 month after the last dose of sorafenib
Women of childbearing potential must have a negative serum pregnancy test
result within 14 days prior to initiation of study treatment.
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and
HCC
Patients with untreated or incompletely treated varices with bleeding or high-risk for
bleeding
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size
of varices (small to large) must be assessed and treated per local standard of
care prior to enrollment. Patients who have undergone an EGD within
6 months of prior to initiation of study treatment do not need to repeat the
procedure.
Moderate or severe ascites
History of hepatic encephalopathy
Co-infection of HBV and HCV
Patients with a history of HCV infection but who are negative for HCV RNA by
PCR will be considered non-infected with HCV.
Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of
the following criteria are met:
– Measurable disease, per RECIST v1.1, must be present outside the CNS.
– The patient has no history of intracranial hemorrhage or spinal cord
hemorrhage.
– Metastases are limited to the cerebellum or the supratentorial region
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
– There is no evidence of interim progression between completion of
CNS-directed therapy and initiation of study treatment.
– The patient has not undergone stereotactic radiotherapy within 7 days
prior to initiation of study treatment, whole-brain radiotherapy within
14 days prior to initiation of study treatment, neurosurgical resection within
28 days prior to initiation of study treatment.
– The patient has no ongoing requirement for corticosteroids as therapy for
CNS disease. Anticonvulsant therapy at a stable dose is permitted.
Asymptomatic patients with CNS metastases newly detected at screening are
eligible for the study after receiving radiotherapy or surgery, with no need to
repeat the screening brain scan.
Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment. Patients should be recovered from the effects of radiation. There is
no required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not
currently associated with spinal cord compression) should be considered
for loco-regional therapy if appropriate prior to enrollment.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX
) are allowed.
Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L,
calcium 12 mg/dL or corrected serum calcium ULN)
Treatment with investigational therapy within 28 days prior to initiation of study
treatment
Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study
treatment, including rifampin (and its analogues) or St. John's wort
Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
(whichever is longer) prior to initiation of study treatment
Treatment with systemic immunosuppressive medication (including, but not limited
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
antiTNF- agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study
treatment, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant
medication or a one-time pulse dose of systemic immunosuppressant
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible
for the study after Medical Monitor approval has been obtained.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
for the study.
Inadequately controlled arterial hypertension (defined as systolic blood pressure
(BP) 150 mmHg and/or diastolic blood pressure 100 mmHg), based on an
average of 3 BP readings on 2 sessions
Anti-hypertensive therapy to achieve these parameters is allowable.
Prior history of hypertensive crisis or hypertensive encephalopathy
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent
peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month prior
to initiation of study treatment
Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)
Current or recent (within 10 days of first dose of study treatment) use of aspirin
( 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
Current or recent (within 10 days prior to study treatment start) use of full-dose oral
or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to
prophylactic) purpose
Prophylactic anticoagulation for the patency of venous access devices is
allowed provided the activity of the agent results in an INR 1.5 ULN and
aPTT is within normal limits within 14 days prior to initiation of study treatment.
Prophylactic use of low molecular-weight heparin (i.e., enoxaparin 40 mg/day)
is allowed.
Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 3 days prior to the first dose of bevacizumab
History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation,
or intra-abdominal abscess within 6 months prior to initiation of study treatment
History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction
including sub-occlusive disease related to the underlying disease or requirement for
routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months
prior to initiation of study treatment
Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction
at time of initial diagnosis may be enrolled if they had received definitive
(surgical) treatment for symptom resolution.
Evidence of abdominal free air that is not explained by paracentesis or recent
surgical procedure
Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
Metastatic disease that involves major airways or blood vessels, or centrally located
mediastinal tumor masses ( 30 mm from the carina) of large volume
Patients with vascular invasion of the portal or hepatic veins may be enrolled.
History of intra-abdominal inflammatory process within 6 months prior to initiation of
study treatment, including but not limited to peptic ulcer disease, diverticulitis, or
colitis
Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior
to initiation of study treatment, except palliative radiotherapy to bone lesions within
7 days prior to initiation of study treatment Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to initiation of study treatment, or abdominal surgery, abdominal interventions
or significant abdominal traumatic injury within 60 days prior to initiation of study
treatment or anticipation of need for major surgical procedure during the course of
the study or non-recovery from side effects of any such procedure
Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID)
Occasional use of NSAIDs for the symptomatic relief of medical conditions such
as headache or fever is allowed.
The Estimated Number of Participants
-
Taiwan
60 participants
-
Global
480 participants
