| 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 | 100000004864 |
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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
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. Disease not amenable to curative surgery or transplantation or curative ablation BUT disease amenable to TACE
5. Extent of disease according to the following parameters:
• Multifocal HCC beyond Milan criteria (i.e. >3 lesions of any size OR ≥2 lesions with at least one of them being ≥ 3cm)
• More than one untreated HCC untreated nodule > 10 mm showing arterial hyperenhancement
• No massive multinodular pattern preventing adequate TACE
• No tumor of a diffuse infiltrative HCC type
• Patent portal vein flow
• No portal vein invasion/thrombosis (even segmental) on baseline/eligibility imaging
• No extrahepatic disease
6. Patients with recurrence after resection/ablation are eligible if initially having achieved complete response AND recurrence developed within 2 years (i.e. ≤730 days) before trial inclusion AND if ≥ 2 untreated nodules with > 10 mm with arterial enhancement are present at timepoint of trial inclusion.
7. Child-Pugh score class A without ascites requiring more than 100 mg of spironolactone/day (see exclusion criteria) at enrollment.
8. ECOG performance status of 0 at enrollment.
9. Adequate organ and bone marrow function
10. Life expectancy of ≥ 3 months
11. The following laboratory values obtained less than or equal to 7 days prior to randomization.
• Platelet count ≥ 75,000 per µL
• Hemoglobin ≥ 9.0 g per dL [transfusion allowed]
• Total bilirubin ≤ 2.0 x the upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCL) ≥ 50mL/min (calculated using the Cockcroft-Gault formula)
• Urine dipstick for proteinuria ≤ 2+ (within 7 days prior to initiation of study treatment)
• INR or aPTT ≤ 1.5 x ULN (therapeutic anticoagulation prohibited – see exclusion criterion #13; prophylactic anticoagulation permitted, e.g. LMW heparin, ASS up to 250mg/qd)
• Alkaline phosphatase ≤ 2.5 x ULN
• Absolute neutrophil count (ANC) ≥ 1.500 per µL without granulocyte colony-stimulating factor support
• Serum albumin ≥ 2.8 g per dL
12. Pre-treatment tumor tissue sample (if available)
• If tumor tissue is not available (e.g., patient has never undergone biopsy or tissue depleted because of prior diagnostic testing), patients are still eligible.
13. Negative serum pregnancy test done lesser than or equal to 7 days prior to randomization, for females of childbearing potential only.
14. 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 enrollment.
15. Absence of other severe comorbidities
16. Resolution of any acute, clinically significant treatment-related adverse events from prior therapy/procedure to Grade ≤ 1 prior to study entry, with the exception of alopecia.
17. 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.
18. For patients with active hepatitis C virus (HCV):
• Patients positive for 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.
19. 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.
20. 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 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 1 month after the last TACE procedure. 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 1 month after the last TACE procedure. |
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| E.4 | Principal exclusion criteria |
1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
2. Disease still amenable to curative surgery or transplantation or curative ablation.
3. Previous treatment with atezolizumab or bevacizumab.
4. Previous treatment with a PD1, PD-L1, or CTLA-4 inhibitors, or any form of cancer immunotherapy for HCC.
5. Previous TACE or any other transarterial treatment for HCC
6. Extent of disease too advanced (Evidence of macrovascular invasion (even segmental) on baseline / eligibility imaging; Massive multinodular pattern preventing adequate TACE; Extrahepatic disease)
7. Tumor of diffuse infiltrative HCC type (hypovascular infiltrative tumors with ill-defined borders)
8. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose.
9. Previous radiotherapy for HCC
10. 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.
11. Significant cardiovascular disease within 3 months prior to randomization (for details see study protocol)
12. Uncontrolled hypertension defined by a systolic BP ≥150 mmHg or diastolic BP ≥100 mmHg, with or without antihypertensive medication.
13. 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.
14. History of or current pheochromocytoma.
15. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism ≤6 months prior to randomization.
16. 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 s. study protocol)
17. Ongoing infection > grade 2 NCI-CTCAE v5.0.
18. Patients with seizure disorder requiring medication.
19. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
20. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event >CTCAE grade 3 within 4 weeks prior to randomization.
21. Non-healing wound, ulcer, or bone fracture.
22. Renal failure requiring hemo- or peritoneal dialysis.
23. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
24. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation including a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein; known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation.
25. Positive test for HIV
26. Active tuberculosis
27. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
28. 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
29. Persistent proteinuria of CTC Grade 3 or higher
30. Any malabsorption conditions.
31. Pregnant or nursing women
32. 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.
33. Active or history of autoimmune disease (for details s. study protocol)
34. Treatment with systemic immunosuppressive medication (for details s. study protocol) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment.
35. Use of any herbal remedies known to interfere with the liver or other major organ functions.
36. 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.
37. History of malignancy other than HCC within 3 years prior to screening (for exception see study protocol)
38. Receipt of an investigational drug within 28 days prior to initiation of study drug
39. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent. |
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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 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
Quality of Life (QoL)
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 | 10 |
| 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 |
| Japan |
| Korea, Democratic People's Republic of |
| Taiwan |
| Austria |
| France |
| Germany |
| Italy |
| Spain |
| Switzerland |
| United Kingdom |
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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 | 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 |
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