| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| intermediate-stage hepatocellular carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
| intermediate-stage hepatocellular carcinoma |
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| 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 | 10049010 |
| E.1.2 | Term | Carcinoma hepatocellular |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
The main purpose of this phase IIIb study is to test the efficacy and safety of atezolizumab in combination with bevacizumab compared to TACE in patients with intermediate stage liver cancer.
Primary Efficacy Objective
To assess the efficacy of atezolizumab in combination with bevacizumab compared to Transarterial Chemoembolization (TACE) in patients with intermediate stage liver cancer.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives comprise the assessment of overall survival (OS), Overall Survival Rate at 24 months (OS@24), Objective Response Rate (ORR), Time to Progression (TTP), Time to loss of systemic treatment options (TTSYS), Progression free survival (PFS), Duration of Treatment, Duration of Response (DOR), Time to deterioration of liver function, safety and Quality of Life (QoL).
In addition, tissue, blood and stool samples will be collected to identify prognostic and predictive angiogenic and immune related biomarkers (tissue and circulating) for study endpoints. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Informed Consent Form available
2. Patients* ≥ 18 years of age at time of signing Informed Consent Form (for South Korea: ≥ 19 years and Taiwan: ≥ 20 years)
3. Confirmed hepatocellular carcinoma diagnosis based on histopathological findings from tumor tissue or typical diagnostic imaging on dynamic CT or MRI according to AASLD criteria.
4. Intermediate stage HCC as defined by the following criteria:
• Disease not amenable to curative surgery, liver transplantation or curative ablation BUT disease amenable to TACE at enrollment as judged
by the investigator.
• No massive multinodular pattern preventing adequate TACE
• No tumor of a diffuse infiltrative HCC type (hypovascular infiltrative tumors with ill-defined borders)
• Patent portal vein flow
• No main portal vein invasion/thrombosis on baseline/eligibility imaging. Patients with minimal invasion, (Vp1 and Vp2) may be eligible if no exclusion criteria are violated.
• No extrahepatic disease
Note: Patients with HCC beyond Milan criteria who enter a downstaging protocol may be recruited into the trial if they do not present any exclusion criteria.
5. Patients with recurrence after resection/ablation or after previous TACE (are eligible, if they – according to the investigator – have an indication for (additional) TACE
6. Child-Pugh score class A or B7 without ascites requiring more than 100 mg of spironolactone/day (see exclusion criteria) at enrollment.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at enrollment.
8. Adequate organ and bone marrow function
9. Life expectancy of ≥ 3 months
10. The following laboratory values obtained less than or equal to 7 days prior to randomization.
• Total bilirubin ≤ 3.0 x the upper limit of normal (ULN)Urine dipstick for proteinuria ≤ 2+ (within 7 days prior to randomization) 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
• The following other laboratory values measured within 7 days prior to randomization are either normal or if abnormal do not represent a medical contraindication for TACE and atezolizumab/bevacizumab as judged by the investigator: Platelet count, hemoglobin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine, INR or aPTT, alkaline phosphatase, neutrophil count (ANC), and serum albumin.
11. Negative serum pregnancy test done lesser than or equal to 7 days prior to randomization, for females of childbearing potential only.
12. No presence of untreated or incompletely treated varices with bleeding or high-risk for bleeding: Availability of esophagogastroduodenoscopy (not older than 6 months) in which all size of varices (small to large) had been assessed and varices were treated per local standard of care prior to randomization.
13. Absence of other severe comorbidities
14. Resolution of any acute, clinically significant treatment-related adverse events from prior therapy/procedure to Grade ≤ 1 prior to randomization, with the exception of alopecia.
15. For patients with active hepatitis B virus (HBV):
• HBV DNA ≤ 2000 IU/mL obtained within 28 days prior to randomization, AND
• Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to randomization and willingness to continue
treatment for the length of the study.
16. For patients with active hepatitis C virus (HCV):
• Patients positive for hepatitis C virus (HCV) antibody are eligible, also if polymerase chain reaction testing is positive for HCV ribonucleic acid
(RNA).
• However, anti-viral therapy against HCV is only allowed prior to trial but not during the trial.
• For HBV and HCV co-infection refer to exclusion criterion # 17.
17. 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 TACE procedure.
18. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below (please refer to protocol for further information)
*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently. |
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| E.4 | Principal exclusion criteria |
1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC (only if proven by biopsy).
2. Previous treatment with atezolizumab or bevacizumab.
3. Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of cancer immunotherapy for HCC.
4. Clinically meaningful ascites, defined as ascites requiring non- pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control.
• Patients with ascites requiring pharmacologic intervention (e.g. diuretics) and stable for ≥2 months on low doses of diuretics (spironolactone 100 mg/d or equivalent) for ascites are eligible. Of note, diuretics for other indications such as congestive heart failure are not considered in this regard.
5. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.
6. Significant cardiovascular disease [...] within 3 months prior to randomization [...].
7. Uncontrolled hypertension defined by a systolic blood pressure (BP) ≥150 mmHg or diastolic blood pressure (BP) ≥100 mmHg, with or without antihypertensive medication. Prior history of hypertensive crisis or hypertensive encephalopathy. (For details see study protocol).
8. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose (prophylactic anticoagulation permitted, e.g. new oral anticoagulants [apixaban, dabigatran, rivaroxaban], LMW heparin,
ASA up to 300mg/qd).
9. Arterial or venous thrombotic or embolic events [...] ≤6 months prior to randomization.
10. With regards to eligibility for adequate TACE, patients presenting with either of the following conditions are excluded:
• Past history of bilioenteric anastomosis or biliary procedure (for details see study protocol)
11. Any ongoing infection > grade 2 NCI-CTCAE version 5.0. (For details see study protocol).
12. Patients with seizure disorder requiring medication.
13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
14. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event >CTCAE grade 3 within 4 weeks prior to randomization.
15. Non-healing wound, ulcer, or bone fracture.
16. Renal failure requiring hemo- or peritoneal dialysis.
17. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation [...].
18. Positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) (for exceptions see study protocol).
19. Active tuberculosis
20. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
21. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
22. Persistent proteinuria of CTCAE Grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample).
23. Pregnant or nursing women
24. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
25. Active or history of autoimmune disease (for details see study protocol).
26. Treatment with systemic immunosuppressive medication (for details see study protocol).
27. Use of any herbal remedies known to interfere with the liver or other major organ functions. Patients must notify the investigator of all herbal remedies used during the study.
28. Administration of a live, attenuated vaccine within four weeks prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last TACE procedure.
29. History of malignancy other than HCC within 3 years prior to screening (for exceptions see study protocol).
30. Receipt of an investigational drug within 28 days prior to initiation of study drug
31. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent or patients
with substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is Time to failure of treatment strategy (TTFS [assessed every 8 weeks (±7days)]) defined as the time from randomization until death or need for a further therapeutic option, defined for each arm as follows:
• Arm A: Time from randomization until the failure of strategy* does not allow for further treatment with atezolizumab + bevacizumab; or death, whichever comes first.
• Arm B: Time from randomization until the failure of strategy* does not allow for further TACE therapy; or death, whichever comes first.
* The definition of failure of strategy is given in protocol section 12.3.1. In brief, failure of strategy is reached in case of progressive disease accompanied by ANY of the following: loss of clinical benefit, unacceptable toxicity, liver function deterioration, therapy not further applicable for other reasons. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Overall survival (OS)
Overall Survival Rate at 24 months (OS@24)
Objective Response Rate (ORR)
Time to loss of systemic treatment options (TTSYS)
Progression free survival (PFS)
Duration of Treatment
Duration of Response (DOR)
Time to deterioration of liver function
Safety
Quality of Life (QoL)
translational research
Exploratory endpoint:
Baseline Programmed Death-Ligand 1 (PD-L1) protein expression by immunohistochemistry on available FFPE biopsy tissue samples collected |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Transarterial chemoembolisation (cTACE or DEB-TACE) using Doxorubicin or Epirubicin |
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| 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 | 47 |
| 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 |
| Taiwan |
| Japan |
| Korea, Republic of |
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| 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
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| An independent Data Monitoring Committee (IDMC) will survey the patient’s safety and perform risk/benefit assessments. All IDMC members are financially and scientifically independent from the trial and will not take part as investigators. According to its Charter the IDMC will review the accumulating data from the ongoing trial to fulfill the safety monitoring. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
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