| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced liver cancers originate in the liver and spread either to the lymph nodes or to 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027479 |
| E.1.2 | Term | Metastatic liver carcinoma |
| 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 immunotherapy-based treatment combinations based on objective response rate
• To evaluate the safety of immunotherapy-based treatment combinations
|
|
| E.2.2 | Secondary objectives of the trial |
| • To evaluate the efficacy of immunotherapy-based treatment combinations based on progression-free survival, overall survival after randomization, overall survival at specific timepoints, duration of response, disease control |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Stage 1
• Aged >= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases criteria in cirrhotic patients
• Child-Pugh class A within 7 days prior to randomization
• Disease that is not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for HCC
• Life expectancy >= 3 months
• Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status via central testing
Stage 1 and Stage 2
• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1
• Adequate hematologic and end-organ function within 7 days prior to initiation of study treatment
• Documented virology status of hepatitis, as confirmed by screening tests for hepatitis B virus (HBV) and hepatitis C virus (HCV)
• Negative HIV test at screening
• For women of childbearing potential:agreement to remain abstinent or use contraception and for men:agreement to remain abstinent or use contraception and agreement to refrain from donating sperm
Stage 2
• ECOG Performance Status of 0, 1 or 2
• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if deemed clinically feasible) |
|
| E.4 | Principal exclusion criteria |
Stage 1
•Prior treatment with CD137 agonists or immune checkpoint inhibitors
•Treatment with investigational therapy within 28 days prior to initiation of study
•Treatment with locoregional therapy to liver within 28 days prior to initiation of study or non-recovery from side effects of any such procedure
•Untreated or incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding
•Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study
•AEs from prior anti-cancer therapy that have not resolved to Grade<= 1 or better with the exception of alopecia of any grade
•Inadequately controlled hypertension
•History of hypertensive crisis or hypertensive encephalopathy
•Significant vascular disease
•History of hemoptysis within 1 month prior to initiation of study
•Evidence of bleeding diathesis or significant coagulopathy
•Current or recent use of asprin (>325 mg/day) or treatment with clopidogrel,dipyramidole,ticlopidine or cilostazol
•Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
•Core biopsy or other minor surgical procedure within 3 days prior to initiation of study
•History of abdominal or tracheoesophageal fistula,GI perforation or intra-abdominal abscess,intestinal obstruction and/or clinical signs/symptoms of GI obstruction
•Evidence of abdominal free air not explained by paracentesis or recent surgery
•Serious, non-healing/dehiscing wound,active ulcer or untreated bone fracture
•Grade >=2 proteinuria
•Metastatic disease involving major airways/blood vessels or centrally located mediastinal tumor masses of large volume
•History of intra-abdominal inflammatory process
•Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to initiation of study with the exception of palliative radiotherapy to bone lesions within 7 days prior to initiation of study
•Major surgery, open biopsy or significant traumatic injury within 28 days prior to initiation of study;or abdominal surgery,abdominal interventions or significant abdominal traumatic injury within 60 days prior to initiation of study;or anticipation of need for major surgery during study or non-recovery from side effects of any such procedure
•Chronic daily treatment with NSAID
•Eligible only for control arm
Stage 1 and 2
•Fibrolamellar or sarcomatoid HCC or mixed cholangiocarcinoma and HCC
•History of hepatic encephalopathy
•Moderate or severe ascites
•HBV and HCV coinfection
•Symptomatic,untreated or actively progressing CNS metastases
•History of leptomeningeal disease
•Uncontrolled tumor-related pain
•Uncontrolled pleural effusion,pericardial effusion or ascites requiring recurrent drainage procedures
•Uncontrolled or symptomatic hypercalcemia
•Active or history of autoimmune disease or immune deficiency
•History of IPF organizing pneumonia,drug-induced or idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT scan
•Active TB
•Significant CV disease within 3 months prior to initiation of study,unstable arrhythmia or unstable angina
•Major surgery other than for diagnosis within 4 weeks prior to initiation of study or anticipated major surgery during study
•History of malignancy other than HCC within 5 years prior to screening
•Severe infection within 4 weeks prior to initiation of study
•Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study
•Prior allogeneic stem cell or solid organ transplantation
•Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
•History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
•Known allergy or hypersensitivity to any of the study drugs or any of their excipients
•Treatment with systemic immunostimulatory,immunosuppressive agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study
•Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study
•Patients entering Stage 2:immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at time of consent
Tiragolumab-Containing Arm
•Prior treatment with an anti-TIGIT agent
•Active EBV infection or known or suspected chronic active EBV infection at screening
Tocilizumab-Containing Arm
•Preexisting CNS demyelinating or seizure disorders
•History of diverticulitis, chronic ulcerative lower GI disease or other symptomatic lower GI conditions that might predispose a patient to GI perforation
•Active current infection or history of recurrent infection
•Untreated latent TB
•History of or currently active,primary or secondary immunodeficiency |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Objective response rate
2. Incidence, nature, and severity of adverse events and laboratory abnormalities
3. Change from baseline in vital signs and ECG parameters
4. Change from baseline in targeted clinical laboratory test results
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From randomization until loss of clinical benefit (up to 5 years)
2-4. From first study treatment administration until 135 days after the last dose or unitl initiation of new systemic anti-cancer therapy, whichever occurs first (up to 5 years)
|
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival
2. Overall survival after randomization
3. Overall survival at specified timepoints
4. Duration of response
5. Disease control
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From randomization to the first occurrence of disease progression (up to 5 years)
2. From randomization to death from any cause (up to 5 years)
3. Approximately every 6 months, up to 5 years
4. From the date of the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 5 years)
5. From randomization until loss of clinical benefit (up to 5 years)
|
|
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| China |
| France |
| Israel |
| Korea, Republic of |
| New Zealand |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 completes the last visit (LPLV), including survival follow-up visits conducted by telephone or in the clinic. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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