A Study of Atezolizumab (Tecentriq) in Combination With Bevacizumab to Investigate Safety and Efficacy in Patients With Unresectable Hepatocellular Carcinoma Not Previously Treated With Systemic Therapy-Amethista

Phase 3

Completed

Conditions: Carcinoma, Hepatocellular

Interventions: Drug: Atezolizumab
Drug: Bevacizumab

Registration Number: NCT04487067

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This is a Phase IIIb, one arm, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab + bevacizumab in patients with unresectable HCC who have received no prior systemic treatment.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 152

Inclusion Criteria

Unresectable HCC with diagnosis confirmed by histology, with a biopsy within 6 months from recruitment;
Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies;
No prior systemic therapy for HCC;
At least one measurable untreated lesion;
Patients who received prior local therapy are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST version 1.1;
ECOG Performance Status of 0 or 1 within 7 days prior to recruitment;
Child-Pugh class A within 7 days prior to recruitment;
Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed. In case of varices at high risk of bleeding (corresponding to medium (F2) or large (F3) varices, or F1 varices with cherry red spots or red wale marking) prophylatic treatment per local standard of care must be adopted prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure provided they had no varices at high risk of bleeding;
Adequate hematologic and end-organ function
Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade <= 1 prior to study entry, with the exception of alopecia
Negative HIV test at screening with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥200µL, and have an undetectable viral load;
In patients with viral HCC, documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test;
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.

Exclusion Criteria

History of leptomeningeal disease or brain metastases;
Active or history of autoimmune disease or immune deficiency;
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan;
Known active tuberculosis;
Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina;
History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death;
Prior allogeneic stem cell or solid organ transplantation;
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of atezolizumab and 6 months after the last dose of bevacizumab;
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC;
Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding;
A prior bleeding event due to oesophageal and/or gastric varices within 6 months prior to initiation of study treatment;
Clinically evident ascites;
Co-infection of HBV and HCV;
Co-infection with HBV and hepatitis D viral infection;
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases;
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures;
Clinically significant uncontrolled or symptomatic hypercalcemia;
Inadequately controlled arterial hypertension;
Significant vascular disease within 6 months prior to initiation of study treatment;
History of haemoptysis;
Evidence of bleeding diathesis or significant coagulopathy;
History of gastrointestinal (GI) fistula, 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 including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment;
Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses of large volume;
Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Atezolizumab + Bevacizumab	Atezolizumab	Participants will receive atezolizumab 1200 mg intravenous (IV) infusions Q3W (dosed in 3-week cycles) + bevacizumab 15 mg/kg IV Q3W (dosed in 3-week cycles)
Atezolizumab + Bevacizumab	Bevacizumab	Participants will receive atezolizumab 1200 mg intravenous (IV) infusions Q3W (dosed in 3-week cycles) + bevacizumab 15 mg/kg IV Q3W (dosed in 3-week cycles)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Grade 3-5 National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE V5) Bleeding/Haemorrhage	Up to approximately 47.6 months	An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Severity of AEs was graded using NCI CTCAE v5.0. Grade 3=Severe/medically significant but not immediately life-threatening, hospitalization/prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; Grade 4=Life-threatening consequences, urgent intervention indicated; Grade 5=Death related to AE.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Up to approximately 47.6 months	OS was defined as the time from initiation of study treatment to death from any cause. Kaplan-Meier (K-M) method was used to estimate the OS.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Up to approximately 47.6 months	An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs are defined as AEs with onset date on or after the start of the first study treatment component. Number of participants with any TEAEs are reported here.
Progression-free Survival (PFS)	Up to approximately 47.6 months	PFS was defined as the time from initiation of study treatment to the first occurrence of disease progression (PD) or death from any cause (whichever occurs first), as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm). Participants alive and without any PD were censored at the last assessment date. K-M method was used to estimate the PFS.
Objective Response Rate (ORR)	Up to approximately 47.6 months	ORR was defined as the percentage of participants with complete or partial response (CR or PR), as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR.
Time to Progression (TTP)	Up to approximately 47.6 months	TTP was defined as the time from initiation of study treatment to the first occurrence of PD, as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Participants without any PD were censored at the last assessment date. K-M method was used to estimate the TTP.
Duration of Response (DOR)	Up to approximately 47.6 months	DOR was defined as the time from the first occurrence of a documented objective response (CR or PR) to PD or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Participants who were alive and without any PD were censored at the last assessment date. K-M method was used to estimate the DOR.
Post-progression Survival (PPS)	Up to approximately 47.6 months	PPS was defined as the time from the first occurrence of PD as determined by the investigator according to RECIST v1.1 to death from any cause. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Participants who were alive were censored at the last assessment date. K-M method was used to estimate the PPS.
Number of Participants Reporting Severe Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire	From Cycle 1 Day 1 to Cycle 63 Day 1 (1 Cycle = 21 days)	Participants self-reported symptomatic AEs using PRO-CTCAE, a validated item bank used to characterize presence, frequency of occurrence, severity, \&/or degree of interference with daily function of 78 patient-reportable symptomatic treatment toxicities. PRO-CTCAE contains questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence,severity,\& interference with daily function). Treatment toxicities can occur with observable signs (e.g.,vomiting)/ non-observable symptoms (e.g.,nausea). A subset of 14 symptoms most applicable to current treatments were selected for this study. Symptoms were selected based on toxicities associated with the drug's class, mechanism of action, or mode of administration, and toxicities reported with the drug in another indication. Number of participants who reported severe symptoms per the PRO-CTCAE questionnaire on Day 1 of each cycle is reported here.
Number of Participants Reporting Very Severe Symptoms in PRO-CTCAE Questionnaire	From Cycle 1 Day 1 to Cycle 63 Day 1 (1 Cycle = 21 days)	Participants self-reported symptomatic AEs using PRO-CTCAE, a validated item bank used to characterize presence, frequency of occurrence, severity, \&/or degree of interference with daily function of 78 patient-reportable symptomatic treatment toxicities. PRO-CTCAE contains questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence,severity,\& interference with daily function). Treatment toxicities can occur with observable signs (e.g.,vomiting)/ non-observable symptoms (e.g.,nausea). A subset of 14 symptoms most applicable to current treatments were selected for this study. Symptoms were selected based on toxicities associated with the drug's class, mechanism of action, or mode of administration, \&toxicities reported with the drug in another indication. Number of participants who reported very severe symptoms per the PRO-CTCAE questionnaire on Day 1 of each cycle is reported here.

Trial Locations

Locations (21): IRCCS Ospedale Casa Sollievo Della Sofferenza
🇮🇹
San Giovanni Rotondo, Apulia, Italy
Fondazione Pascale
🇮🇹
Napoli, Campania, Italy
Azienda Osp Uni Seconda Università Degli Studi Di Napoli
🇮🇹
Napoli, Campania, Italy
Ospedale del Mare
🇮🇹
Napoli, Campania, Italy
A.O. S. Orsola Malpighi
🇮🇹
Bologna, Emilia-Romagna, Italy
Arcispedale Santa Maria Nuova
🇮🇹
Reggio Emilia, Emilia-Romagna, Italy
Ospedali Riuniti - Bergamo
🇮🇹
Bergamo, Lombardy, Italy
Fondazione IRCCS Ospedale Maggiore Policlinico
🇮🇹
Milan, Lombardy, Italy
Istituto Nazionale Dei Tumori
🇮🇹
Milan, Lombardy, Italy
Istituto Clinico Humanitas
🇮🇹
Rozzano, Lombardy, Italy
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IRCCS Ospedale Casa Sollievo Della Sofferenza
🇮🇹San Giovanni Rotondo, Apulia, Italy