E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or Metastatic hepatocellular carcinoma (HCC) |
|
E.1.1.1 | Medical condition in easily understood language |
HCC is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077738 |
E.1.2 | Term | Hepatocellular carcinoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077736 |
E.1.2 | Term | Hepatocellular carcinoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10077737 |
E.1.2 | Term | Hepatocellular carcinoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of atezolizumab + bevacizumab compared with sorafenib based on overall survival (OS) and progression-free survival
(PFS) as determined by the independent review facility (IRF) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
|
E.2.2 | Secondary objectives of the trial |
To evaluate :
• efficacy of atezolizumab + bevacizumab compared with sorafenib based on objective response (OR)
• time to progression (TTP), duration of response (DOR) determined by investigator ; IRF according to RECIST v 1.1 and OR, PFS, TTP, DOR by IRF according to HCC modified (m) RESIST v 1.1
• the association of prespecified biomarkers with efficacy of atezolizumab+ bevacizumab compared with sorafenib based on PFS as
determined by the investigator and by an IRF according to RECIST v1.1 and OS
• patient-reported outcome of disease/treatment-related symptoms, health-related quality of life / global health status, function experienced
by patients on atezolizumab + bevacizumab versus sorafenib based on time to deterioration (TTD) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/ cytology or clinically by American Association for the Study of Liver Diseases criteria in cirrhotic patients
- 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 (including systemic investigational agents)for HCC
- At least 1 measurable (per RECIST 1.1) untreated lesion
- Patients who received prior local therapy 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 v1.1
- Pre-treatment tumor tissue sample (if available)
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
- Child-Pugh class A within 7 days prior to randomization
- Adequate hematologic and end-organ function
- 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 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 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 6 months after the last dose of sorafenib. Women must refrain from donating eggs during this same period.
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 6 months after the last dose of bevacizumab or 3 months after the last dose of sorafenib |
|
E.4 | Principal exclusion criteria |
- History of leptomeningeal disease, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
- Active or history of autoimmune disease or immune deficiency
- Known active tuberculosis, moderate or severe ascites
- Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- History of congenital long QT syndrome, or corrected QT interval > 500 ms at screening and uncorrectable electrolyte disorder affecting serum level of potassium, calcium, or magnesium
- 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, apart from malignancies with a negligible risk of metastasis or death and hepatic encephalopathy
-Severe infection within 4 weeks prior to initiation of study treatment, or any active infection that, in the opinion of the investigator, could impact patient safety
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment, 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
- Prior allogeneic stem cell or solid organ transplantation, Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti- cytotoxic T-lymphocyte-associated protein 4, anti- Programmed death (PD)-1, and anti-PD-Ligand 1 therapeutic antibodies
- 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
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation
- Fibrolamellar and sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
- Pregnant 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 6 months after the last dose of sorafenib
- Patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
- A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
- Co-infection of hepatitis B and C virus
- Symptomatic, untreated, or actively progressing central nervous system metastases
- Uncontrolled tumor-related pain
- Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Uncontrolled or symptomatic hypercalcemia
- Treatment with investigational therapy within 28 days prior to study treatment
- Strong CYP3A4 inducers within 14 days prior to study treatment
- Systemic immunostimulatory agents and immunosuppressive medication within 4 weeks or 5 half-lives of the drug and 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study
- Inadequately controlled arterial hypertension
- Significant vascular disease within 6 months prior to initiation of study
- Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume
- Evidence of bleeding diathesis or significant coagulopathy
- Current or recent use of aspirin or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol and current or recent use of fulldose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose
- History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess and intra-abdominal inflammatory process within 6 months prior to study treatment, intestinal obstruction and/or clinical signs or symptoms of GI obstruction within 6 months prior to study treatment
- Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure
- Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to initiation of study, except palliative radiotherapy to bone lesions within 7 days prior to study
- Local therapy to liver within 28 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 study or anticipation of need for major surgical procedure during the study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. OS
2. PFS as determined by the IRF according to RECIST v1.1 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From randomization to death from any cause
2. From randomization to the occurrence of disease or death from any
cause |
|
E.5.2 | Secondary end point(s) |
1. OR, by investigator and IRF per RECIST 1.1
2. OR, by an IRF according to HCC mRECIST
3. PFS, by investigator and IRF, per RECIST 1.1
4. PFS, as determined by an IRF according to HCC mRECIST
5. TTP, by investigator and IRF, per RECIST 1.1
6. TTP, as determined by an IRF according to HCC mRECIST
7. DOR, by investigator and IRF, per RECIST 1.1
8. DOR, as determined by an IRF according to HCC mRECIST
9. OS by baseline serum α-fetoprotein level
10. Time to deterioration determined by European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for cancer subscales, including HRQoL/GHS, physical and role functioning |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2. At 6 months after the last patient is enrolled which is anticipated to occur up to 22 months after first patient in
3-4. From randomization to the first occurrence of disease progression or death from any cause
5-6. From the date of randomization to the date of the first documented tumor progression
7-8. From the first occurrence of a documented objective response to disease progression or death from any cause
9. From randomization to death from any cause
10. From time from randomization to first deterioration |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity, Biomarker and Health status objectives |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
China |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Singapore |
Taiwan |
Thailand |
United States |
France |
Germany |
Italy |
Poland |
Spain |
Switzerland |
United Kingdom |
Czechia |
Argentina |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs (i.e., last patient in the global and extended China enrollment phases combined) or safety follow-up is received from the last patient (global and extended China enrollment phases combined), whichever occurs later.
In addition, the Sponsor may decide to terminate the study at any time. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |