Unresectable hepatocellular carcinoma (HCC) MedDRA version: 21.0 Level: LLT Classification code 10019828 Term: Hepatocellular carcinoma non-resectable System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Avastin
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: BEVACIZUMAB
CAS Number: 216974-75-3
Trade Name: Tecentriq
Pharmaceutical Form: Concentrat
Sponsors
Klinikum der Ludwig-Maximilians-Universität München -
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient’s signed informed consent 2. Age = 18 years at time of signing Informed Consent Form 3. Ability to comply with the study protocol, according to investigator's judgement 4. Life expectancy of at least 12 weeks 5. HCC with histologically confirmed diagnosis. If no archival sample is available and the specific risk of performing the biopsy according to the investigator’s opinion is considered to outweigh the benefits of diagnostic confirmation, HCC can be diagnosed based on typical diagnostic imaging on dynamic CT or MRI according to AASLD criteria, after consultation with the sponsor. 6. Disease that is not amenable to curative surgical and/or local ablation treatment according to consensus resolution of the multidisciplinary tumor board of the trial center but eligible for TACE, with tumor burden below 50% of liver volume. 7. At least one measurable (per RECIST 1.1) untreated lesion 8. ECOG Performance Status of 0 or 1 9. Child-Pugh class A or B7 10. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization, unless otherwise specified (deviations of individual laboratory values are permitted with the sponsor's consent if an integrated assessment of all findings does not suggest organ dysfunction that would be incompatible with the study): – ANC =1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support – Lymphocyte count = 0.5 x 109/L (500/µL) – Platelet count = 50 x109/L (50,000/µL) without transfusion – Hemoglobin = 90 g/L (9 g/dL); patients may be transfused to meet this criterion. – AST, ALT, and alkaline phosphatase = 5 x upper limit of normal (ULN) – Serum bilirubin = 3 x ULN – Serum creatinine = 1.5 x ULN or creatinine clearance = 50 mL/min (calculated using the Cockcroft-Gault formula) – Serum albumin = 28 g/L (2.8 g/dL) – For patients not receiving therapeutic anticoagulation: INR <1.25 – Urine dipstick for proteinuria < 2+ (within 14 days prior to initiation of study treatment), unless a subsequent 24-hour urine collection demonstrates < 1 g of protein in 24 hours. 11. Negative HIV test at screening 12. Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test. For patients with active hepatitis B virus (HBV): HBV DNA < 500 IU/mL obtained within 28 days prior to randomization, and Anti-HBV treatment (per local standard of care) for a minimum of 14 days prior to randomization and willingness to continue treatment for the length of the study 13. For females of childbearing potential (FCBP): negative pregnancy test within 14 days before randomization and 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 or 6 months after the last dose of bevacizumab. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual ab
Exclusion criteria
Exclusion criteria: 1.Diffuse HCC or presence of vascular invasion or extrahepatic spread or more than 7 lesions or at least one lesion = 7 cm 2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC 3. Clin. rel. ascites (defined by protocol) 4. Uncontrolled pleural Effusion/ pericardial effusion. 5. History or presence of hepatic encephalopathy 6. Co-infection of HBV and HCV (History of HCV infection but negative for HCV RNA by PCR are considered non-infected with HCV) 7. Patients act. listed for transplantation or not yet listed but potentialy eligible for Transplantation (see protocol) 8. Prior systemic therapy for HCC 9. Prior treatment with TACE or SIRT (within six months before randomization) 10. Prior local or locoregional treatment (refer to protocol for Detail) 11. Any contraindication to TACE 12. Major gastrointestinal bleeding within last 4 weeks 13. Patients with untreated or incompletely treated varices with bleeding or high-risk for bleeding (please refer to protocol) 14. Active or history of autoimmune disease or immune deficiency (described in protocol) 15. Prior allogeneic stem cell or solid organ transplantation 16. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening CT scan (more Details in Protocol) 17. Active tuberculosis (defined by protocol) 18. Severe infection within last 4 weeks 19. Significant cardiovascular disease (more Details in protocol) 20. History of congenital long QT syndrome or corrected QT interval >500 ms or repeated demonstration of a corrected QT interval >450 ms 21. Inadequately controlled arterial hypertension (defined by protocol) 22. Significant vascular disease including aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with last 6 months 23. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess within last 6 months 24. History or clinical signs of gastrointestinal obstruction or requirement for routine parenteral Hydration/nutrition, or tube feeding. Evidence of abdominal free air (not explained by paracentesis/recent surgical procedure) 25. History of intra-abdominal inflammatory process within last 6 months 26. Evidence of bleeding diathesis or significant coagulopathy 27. Any other conditions that contraindicates participation in the sstudy 28. Uncontrolled tumor-related pain. 29. Severe, non healing or dehisced wound, active ulcer, or untreated bone fracture 30. Prior or concomitant malignancy other than HCC unless it has been adequately treated or is considered not to affect the staging and prognosis of the patient 31. Current therapy with dual antiplatelet treatment 32. Current use of full dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose. Prophylactic use of anticoagulation is allowed. 33. Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed 34. Treatment with a live, attenuated vaccine within 4 weeks prior to randomization, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab. 35. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti?CTLA-4, anti?PD-1, and anti?PD-L1 therapeutic antibodies 36. Hype
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of up-front atezolizumab/ bevacizumab (Atezo/Bev) followed by on-demand selective transarterial chemoembolization (sdTACE) and of initial synchronous treatment with TACE and Atezo/Bev in the treatment of unresectable HCC patients.;Secondary Objective: To evaluate the efficacy, safety and quality of life of treatment with Atezo/Bev in combination with TACE;Primary end point(s): To evaluate the efficacy of up-front atezolizumab/ bevacizumab (Atezo/Bev) followed by on-demand selective transarterial chemoembolization (sdTACE) and of initial synchronous treatment with TACE and Atezo/Bev in the treatment of unresectable HCC patients Corresponding primary endpoint: Objective response rate (according to RECIST v1.1) (as assessed by local investigator) (ORR);Timepoint(s) of evaluation of this end point: Objective response rate will be evaluated continiously | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): To evaluate the efficacy, safety and quality of life of treatment with Atezo/Bev in combination with TACE Corresponding secondary endpoints: Efficacy • Overall survival (OS) • 24-months survival rate • Progression-free survival (PFS) • Complete response rate (CRR) • Disease control rate (DCR) • Time to deterioration of liver function, defined as time from randomization to worsening of CTCAE grade compared with baseline and persisting for = 30 days for any of these parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, and international normalized ratio (INR); separately for patients in Arm A and Arm B • Time to locally/locoregional untreatable progression (TTuP), defined as time from randomization to occurrence of any of the following conditions: progression which would require targeting of more than 3 pretreated lesions as determined by the latest staging investigation, progression occurring due to diffuse tumor growth, occurrence of vascular invasion, occurrence of extrahepatic spread, worsening of liver function to Child-Pugh score 8 or higher • Time to stage progression (defined as time from randomization to disease progression to BCLC C) • Time to first TACE (only in Arm A) Response and progression will be determined according to RECIST 1.1 by the investigator. Quality of Life • QoL evaluated with EORTC QLQ-C30 and EORTC QLQ-HCC18 Safety • Type, incidence, causal relationship and severity of adverse events according to NCI CTCAE version 5 Exploratory objectives - To evaluate efficacy by central review Corresponding exploratory endpoints: • PFS • ORR • CRR • DCR Response and progression will be determined according to RECIST 1.1 and mRECIST by central review. ;Timepoint(s) of evaluation of this end point: Efficacy: - OS will be evaluated continously during study Treatment, after Study - Response Evaluation will be done according to RECIST V.1.1 6 weeks after Treatment Initiation | — |
Countries
Germany
Contacts
Public ContactStudiensekretariat
Klinikum der Ludwig-Maximilians-Universität München -
Outcome results
None listed