| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable hepatocellular carcinoma (HCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| HCC is the most common type of primary liver cancer. It is different from "secondary" liver cancers, which have spread to the liver from other organs |
|
| 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 | 21.0 |
| 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 | 100000004864 |
|
| 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 plus lenvatinib or sorafenib compared with lenvatinib or sorafenib alone, on basis of overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of atezolizumab plus lenvatinib or sorafenib compared with lenvatinib or sorafenib alone, based on progression free survival (PFS), confirmed objective response rate (ORR), time to progression (TTP) and duration of response (DOR), time to deterioration (TTD), of health-related quality of life (HRQoL)
•To evaluate patient-reported function and general health status/quality of life (GHS/QoL) experienced by patients receiving atezolizumab plus lenvatinib or sorafenib versus lenvatinib or sorafenib alone
•To evaluate the safety of atezolizumab plus lenvatinib or sorafenib compared with lenvatinib or sorafenib alone
•To characterize the pharmacokinetic (PK) profile of atezolizumab when given in combination with lenvatinib or sorafenib
•To evaluate the immune response to atezolizumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•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 American Association for the Study of Liver Diseases criteria in cirrhotic patients
•Patients without cirrhosis require histological confirmation of diagnosis. HCC must be unamenable to curative surgical and/or locoregional therapies, or have progressed after surgical and /or locoregional therapies
•Disease progression following prior atezolizumab plus bevacizumab combination treatment for HCC, for at least 4 consecutive treatment cycles, and two subsequent tumor assessments. It is required that at least
one tumor assessment shows either SD, PR, or CR
•At least one measurable (per response evaluation criteria in solid tumors version 1.1 [RECIST v1.1]) target lesion, that has not been previously treated with local therapy or, if the target lesion is within the field of previous local therapy, has subsequently progressed in accordance with RECIST v1.1
•Eastern Cooperative Oncology Group 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, obtained within 7 days prior to randomization
•Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade <=1 prior to study entry, except for alopecia
•Life expectancy of at least 12 weeks
•Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (HCV) serology tests
•Patients with active HBV must have HBV DNA < 500 international units per milliliter (IU/mL) obtained within 28 days prior to initiation of study treatment and received 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
•Agree to use protocol defined methods of contraceptions.
|
|
| E.4 | Principal exclusion criteria |
•Symptomatic, untreated, or actively progressing central nervous system metastases
•History of leptomeningeal disease
•History of hepatic encephalopathy
•Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
•History of malignancy other than HCC within 5 years prior to screening
•Patients receiving any TKI or PD-L1/PD-1 antibody (excluding atezolizumab)
•Prior treatment with CD137 agonists or immune checkpoint blockade therapies
•Patients who discontinued atezolizumab in a previous treatment line
against HCC primarily for toxicity or intolerability are not eligible for the
study
•Patients on a liver transplantation list
•Uncontrolled tumor-related pain
•Moderate or severe ascites
•Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
•Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume
•Co-infection of HBV and HCV
•Active tuberculosis
•Severe infection within 4 weeks prior to study start
•Treatment with therapeutic oral or intravenous antibiotics within 2 weeks prior to study start
•Treatment with a live, attenuated vaccine within 4 weeks prior to study start, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
•Active or history of autoimmune disease or immune deficiency
•History of idiopathic pulmonary fibrosis, organizing pneumonia, history of non-infectious pneumonitis requiring steroids, or patients with Grade >=2 pneumonitis, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
•Significant cardiovascular disease within 3 months prior to initiation of study treatment
•Uncontrolled hypertension or inadequately controlled arterial hypertension
•Significant vascular disease within 6 months prior to initiation of study treatment
•Thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug
•Evidence of bleeding diathesis or significant coagulopathy
•Esophageal or variceal bleeding
•Patients with signs of portal hypertension/signs of portal hypertension in CT scans
•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
•History of intra-abdominal inflammatory process within 6 months prior to study start
•Prior allogeneic stem cell or solid organ transplantation
•Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
•Radiotherapy within 28 days and abdominal/pelvic radiotherapy within 60 days prior to study start
•Local therapy to liver within 28 days prior to study start
•History of uncorrectable electrolyte disorder affecting serum levels of potassium, calcium, or magnesium
•Uncontrolled hypercalcemia
•Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents
•Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)
•Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study treatment
•Treatment with systemic immunostimulatory within 4 weeks or 5 half-lives of the drug prior to study start
•Treatment with systemic immunosuppressive medication
•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 formulation
•Known allergy or hypersensitivity to any of the investigational medicinal product (IMPs) or constituents of the products
•Treatment with an investigational therapy within 28 days prior to initiation of study treatment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| OS, defined as the time from randomization into the study to death from any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.PFS, defined as the time from randomization into the study to the first occurrence of disease progression or death from any cause
2.ORR, defined as the proportion of patients with a best response of either complete or partial response
3.TTP, defined as the time from randomization to the first occurrence of disease progression
4.DOR, defined as the time from the first occurrence of a documented confirmed objective response to disease progression or death from any cause
5.Time to deterioration (TTD), of health-related quality of life (HRQoL), defined as the time from randomization to first deterioration
6.Incidence and severity of adverse events (AEs), with severity determined according to national cancer institute common terminology criteria for adverse events version 5.0 (NCI CTCAE v5.0)
7.Incidence and severity of AEs for combination treatment, AEs related against atezolizumab and TKI-related AEs according to NCI CTCAE v5.0
8.Incidence of vital sign abnormalities
9.Incidence of clinical laboratory abnormalities
10.Serum concentration of atezolizumab at specified timepoints
11.Prevalence of anti-drug antibodies (ADAs) against atezolizumab at time of study entry
12.Incidence of ADAs against atezolizumab during the study
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-9.Approximately 18 months
10.Day 1 of Cycle 1, 2, 3, 4, 8, 12 and 15 and at treatment/surveillance discontinuation visit
11.At Baseline (Day -28 to Day -1)
12.Day 1 of Cycle 1, 2, 3, 4, 8, 12 and 15 and at treatment/surveillance discontinuation visit
|
|
| 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 | Yes |
| 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) | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 |
| Chile |
| Costa Rica |
| Egypt |
| Philippines |
| Switzerland |
| Taiwan |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Croatia |
| Finland |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Slovenia |
| Spain |
| Turkey |
| United Kingdom |
|
| 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) or safety
follow-up is received from the last patient, whichever occurs later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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