Atezolizumab + Bevacizumab +/- Tiragolumab for Liver Cancer

(SKYSCRAPER-14 Trial)

Not currently recruiting at 299 trial locations

Overseen By Reference Study ID Number: CO44668 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Hoffmann-La Roche

Must not be taking: Immunostimulatory, Immunosuppressive

Disqualifiers: Autoimmune disease, CNS metastases, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment combination for liver cancer. It evaluates how well tiragolumab works with two other drugs, atezolizumab (Tecentriq) and bevacizumab (Avastin), for advanced liver cancer that cannot be removed by surgery. Individuals with advanced liver cancer who have not received systemic therapy and whose condition is not manageable with surgery or local treatments may qualify for this trial. As a Phase 3 trial, it represents the final step before FDA approval, providing access to a potentially groundbreaking treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot have had prior systemic treatment for liver cancer or be on systemic immunosuppressive or immunostimulatory medications.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it excludes those on systemic immunosuppressive or immunostimulatory medications, so you might need to stop those if you're taking them.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that combining tiragolumab with atezolizumab and bevacizumab is generally safe for people with liver cancer. Research indicates that adding tiragolumab does not significantly increase serious side effects compared to using only atezolizumab and bevacizumab. These two drugs have already been used successfully to treat liver cancer and are usually well-tolerated. While the combination is generally safe, every treatment can have some side effects. Prospective participants should discuss potential risks and benefits with a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of atezolizumab, bevacizumab, and tiragolumab for liver cancer because this approach brings a fresh angle to treatment. Unlike the current standard, which often involves therapies like sorafenib or lenvatinib, this combination leverages a potent trio of immune-based treatments. Atezolizumab and bevacizumab work by unleashing the immune system against cancer and cutting off its blood supply, while tiragolumab adds a novel layer by targeting the TIGIT pathway, a recently explored immune checkpoint. This unique mechanism might enhance immune response beyond what's possible with existing therapies, offering hope for more effective liver cancer treatment.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Research has shown that the combination of atezolizumab and bevacizumab is a standard treatment for advanced liver cancer, helping patients live longer. This combination blocks proteins that aid cancer cell growth. In this trial, one group of participants will receive atezolizumab, bevacizumab, and tiragolumab, while another group will receive atezolizumab, bevacizumab, and a placebo. Researchers initially thought that adding tiragolumab might enhance effectiveness. However, recent studies found that including tiragolumab did not significantly extend the time patients lived without their cancer worsening compared to using only atezolizumab and bevacizumab. Despite this, the combination of atezolizumab and bevacizumab remains a proven first-choice treatment for liver cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for adults with advanced liver cancer (HCC) who haven't had systemic treatment before. They should be in good enough health to participate, not have a history of certain lung or autoimmune diseases, and can't be pregnant or breastfeeding. Men and women must use contraception to prevent pregnancy during the trial.

Inclusion Criteria

My liver function is classified as Child-Pugh Class A.

I will use protection or abstain from sex to prevent pregnancy during and after treatment.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have had lung conditions like pulmonary fibrosis or pneumonitis.

Pregnancy or breastfeeding 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

I had bleeding from esophageal or stomach varices in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atezolizumab and bevacizumab, with or without tiragolumab, every 3 weeks until unacceptable toxicity or loss of clinical benefit

Up to approximately 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Tiragolumab

Trial Overview

The study tests tiragolumab combined with atezolizumab and bevacizumab as a first-line treatment for liver cancer. Participants will either receive this combination or a placebo alongside standard treatments to compare effectiveness and safety.

How Is the Trial Designed?

Group I: Atezolizumab + Bevacizumab + Tiragolumab Experimental Treatment 3 Interventions

Atezolizumab plus bevacizumab plus tiragolumab will be administered every 3 weeks (Q3W) until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Group II: Atezolizumab + Bevacizumab + Placebo Placebo Group 3 Interventions

Atezolizumab, bevacizumab plus placebo will be administered Q3W until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Chugai Pharmaceutical

Industry Sponsor

Trials

105

Recruited

25,000+

Dr. Osamu Okuda

Chugai Pharmaceutical

Chief Executive Officer since 2020

MD from Kyoto University

Dr. Mariko Y. Momoi

Chugai Pharmaceutical

Chief Medical Officer

MD from Jichi Medical University

Published Research Related to This Trial

The combination of atezolizumab and bevacizumab has been shown to significantly increase overall survival in patients with advanced hepatocellular carcinoma (HCC) compared to sorafenib.

The FDA's approval of this combination therapy marks a significant advancement in the treatment of HCC, potentially changing how the disease is managed across all stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. Castet, F., Willoughby, CE., Haber, PK., et al.[2022]

In a multicenter study of 121 patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev), the objective response rate was 24% and the disease control rate was 76%, demonstrating real-world efficacy similar to phase III trial results.

The most common severe side effect was an increase in aspartate aminotransferase levels (10.7%), and factors like elevated baseline neutrophil-to-lymphocyte ratio were linked to poorer progression-free and overall survival, indicating the need for careful monitoring in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. Cheon, J., Yoo, C., Hong, JY., et al.[2022]

In a study of 1447 patients treated with tyrosine-kinase inhibitors for hepatocellular carcinoma, only 29% were eligible for the combination therapy of atezolizumab-bevacizumab based on the IMbrave-150 trial criteria, indicating limited real-world applicability.

Eligible patients showed a median overall survival of 14.9 months, which was longer than non-eligible patients, suggesting that those who meet the criteria have better baseline health and cancer characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors. Stefanini, B., Bucci, L., Santi, V., et al.[2022]

In a study of 191 patients with unresectable hepatocellular carcinoma (HCC), the combination therapy of atezolizumab and bevacizumab showed similar overall survival and progression-free survival rates in older patients (≥65 years) compared to younger patients (<65 years), indicating its efficacy across age groups.

The safety profile of the combination therapy was comparable between older and younger patients, with similar rates of treatment-related adverse events, including severe adverse events, suggesting that older patients can tolerate this treatment as well as younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. Vithayathil, M., D'Alessio, A., Fulgenzi, CAM., et al.[2023]

In a study of 88 Japanese patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab, hyperprogressive disease (HPD) occurred in 10.2% of patients, leading to significantly shorter overall survival (4.3 months) compared to those without HPD.

An elevated neutrophil-to-lymphocyte ratio (NLR) of ≥3 at baseline was identified as the only independent risk factor for developing HPD, suggesting that this measure could help identify patients at higher risk for poor treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy. Maesaka, K., Sakamori, R., Yamada, R., et al.[2022]

Atezolizumab in combination with bevacizumab has been approved by the FDA for treating unresectable hepatocellular carcinoma (HCC), showing improved overall survival (OS) and progression-free survival (PFS) compared to sorafenib, with a hazard ratio of 0.58 for OS.

The combination therapy resulted in a median PFS of 6.8 months versus 4.3 months for sorafenib, although it was associated with a higher incidence of hemorrhage (25% vs. 17%), highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma. Casak, SJ., Donoghue, M., Fashoyin-Aje, L., et al.[2022]

In a study of 766 patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab, those who met the IMbrave150 trial inclusion criteria had significantly longer overall survival (16.3 months) compared to those who did not (14.3 months).

Among patients who did not meet the IMbrave150 criteria, those with a better liver function (ALBI grade 1) experienced a notable survival benefit, with a median overall survival of 16.7 months compared to 5.9 months for those with ALBI grade 2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis? Rimini, M., Persano, M., Tada, T., et al.[2023]

In the Phase 3 IMbrave150 trial, atezolizumab combined with bevacizumab showed a similar safety profile to sorafenib in patients with unresectable hepatocellular carcinoma (HCC), regardless of whether they had hepatitis B or C infections.

The rates of viral reactivation were low and comparable between the two treatment groups, with no cases of hepatitis flare reported in patients treated with atezolizumab + bevacizumab, suggesting it is a safe option for patients with HCC and viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic Events and Viral Kinetics in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab. Hsu, C., Ducreux, M., Zhu, AX., et al.[2023]

Atezolizumab plus bevacizumab therapy shows promising efficacy for advanced hepatocellular carcinoma (HCC), achieving an objective response rate of 15.6% and a high disease control rate of 93.8% among 34 patients, regardless of liver function or treatment line.

Following the failure of atezolizumab plus bevacizumab therapy, lenvatinib treatment can also be effective, but careful monitoring of liver function is necessary, as indicated by significant reductions in liver function scores in patients receiving lenvatinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Role of Atezolizumab Plus Bevacizumab Therapy in the Sequential Treatment of Unresectable Hepatocellular Carcinoma. Komatsu, S., Yano, Y., Fujishima, Y., et al.[2022]

Atezolizumab combined with bevacizumab demonstrated good efficacy in treating advanced hepatocellular carcinoma (HCC), with a pooled overall response rate of 26% and a median overall survival of 14.7 months based on a review of 23 studies involving 3168 patients.

The treatment was well-tolerated, with 83% of patients experiencing any grade adverse events, and 30% experiencing grade 3 or higher adverse events, indicating that while side effects are common, the combination therapy remains a viable first-line option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. Gao, X., Zhao, R., Ma, H., et al.[2023]

In a study of 286 patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab, treatment-related hypertension was linked to better progression-free survival, with a median of 12.6 months compared to 6.5 months for those without hypertension.

Conversely, treatment-related fatigue was associated with shorter overall survival, indicating that while hypertension may signal a positive response to treatment, fatigue could indicate poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events as potential predictive factors of therapeutic activity in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Tada, T., Kumada, T., Hiraoka, A., et al.[2023]

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