A Study to Evaluate Atezolizumab and Bevacizumab, with and without Tiragolumab, In Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Oct 2023 → ongoing

Decision date (initial)

2023-10-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Efficacy, Pharmacokinetic

To evaluate the efficacy of atezolizumab plus bevacizumab plus tiragolumab compared with atezolizumab plus bevacizumab on the basis of investigator-assessed progression-free survival (PFS) and overall survival (OS)

Secondary objectives 4

1. To evaluate the efficacy of atezolizumab plus bevacizumab plus tiragolumab compared with atezolizumab plus bevacizumab on the basis of Investigator-assessed confirmed objective response rate (ORR), Investigator-assessed duration of response (DOR), Investigator-assessed PFS rate at 6 and 12 months, OS rate at 1 and 2 years, Investigator-assessed PFS, confirmed ORR, and DOR as determined by the investigator according to HCC modified Response Evaluation Criteria in Solid Tumors (mRECIST), time to confirmed deterioration (TTCD), and Change from baseline in global health status (GHS)/quality-of-life (QoL), Physical Functioning, and Role Functioning, as assessed through use of the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ)-C30
2. To evaluate the safety of atezolizumab plus bevacizumab plus tiragolumab compared with atezolizumab plus bevacizumab
3. To characterize the pharmacokinetic (PK) profile of atezolizumab plus bevacizumab plus tiragolumab
4. To evaluate the immune response to tiragolumab and atezolizumab

Conditions and MedDRA coding

Hepatocellular Carcinoma (HCC)

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002721-PIP04-23

Plan to share IPD

No

IPD plan description

n/a

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants
2. No prior systemic treatment (including systemic investigational agents) for locally advanced or metastatic and/or unresectable HCC
3. Measurable disease (at least one untreated target lesion) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to randomization
5. Child-Pugh Class A within 7 days prior to randomization
6. Adequate hematologic and end-organ function
7. Negative human immunodeficiency virus (HIV) test at screening
8. Documented virology status of hepatitis, as confirmed by screening tests for hepatitis B virus (HBV) and hepatitis C virus (HCV)
9. Agreement to use protocol defined methods of contraception by both male and female participants

Exclusion criteria 12

1. Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo
2. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including, but not limited to, anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti- TIGIT therapeutic antibodies
3. Treatment with locoregional therapy to liver within 28 days prior to initiation of study treatment, or non-recovery from side effects of any such procedure
4. Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
5. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding
6. Active tuberculosis (TB), as documented by a positive purified protein derivative (PPD) skin test, TB blood test or TB PCR test and confirmed by a positive chest X-ray or chest CT scan within 3 months prior to initiation of study treatment
7. History of malignancy other than HCC within 5 years prior to screening
8. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
9. History of hypertensive crisis or hypertensive encephalopathy
10. Known fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma and HCC
11. Co-infection with HBV and HCV
12. Acute Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Investigator-assessed PFS
2. OS

Secondary endpoints 10

1. Investigator-assessed confirmed ORR
2. Investigator-assessed DOR
3. Investigator-assessed PFS rate at 6 and 12 months
4. OS rate at 1 and 2 years
5. Investigator-assessed PFS, confirmed ORR, and DOR as determined by the investigator according to HCC mRECIST
6. TTCD, defined as change from baseline in GHS/QoL, Physical Functioning, and Role Functioning, as assessed through use of the EORTC QLQ-C30
7. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) grading scale, Severity for cytokine release syndrome (CRS) will also be determined according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading scale
8. Serum concentration of atezolizumab and tiragolumab at specified timepoints
9. Prevalence of anti-drug antibodies (ADAs) to tiragolumab at baseline and incidence of ADAs to tiragolumab after treatment
10. Prevalence of ADAs to atezolizumab at baseline and incidence of ADAs to atezolizumab after treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Head of CTRM Clinical Trial Regulatory Management, Product Development Regulatory

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Head of CTRM Clinical Trial Regulatory Management, Product Development Regulatory

Third parties 6

Locations

6 EU/EEA countries · 42 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 120 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications