Radiotherapy + Immunotherapy for Liver Cancer

(MacroTrans Trial)

Recruiting at 1 trial location

Overseen By Clinical Research Manager

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University Health Network, Toronto

Disqualifiers: Poorly differentiated HCC, Obesity class III, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 26

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for advanced liver cancer, specifically hepatocellular carcinoma (HCC) with macrovascular invasion. It combines locoregional therapy (targeted treatment directly to the tumor area) and immunotherapy (a treatment that helps the immune system fight cancer) using Atezolizumab (Tecentriq) and Bevacizumab (Avastin) to determine if this approach can help patients qualify for a liver transplant. The study aims to find out how many patients can successfully receive a transplant and their survival chances five years later. Suitable participants are those diagnosed with HCC, with a certain type of tumor growth within the liver's blood vessels but no spread to other parts of the body. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Previous studies have shown that the combination of atezolizumab and bevacizumab is generally safe for patients with liver cancer. These medicines, when used together, are usually well-tolerated. Common side effects include high blood pressure and tiredness, but many patients manage these effectively.

For radiotherapy options, both stereotactic body radiotherapy (SBRT) and Yttrium-90 (Y-90) have undergone safety studies. SBRT can control liver cancer in most cases and is considered safe, especially for patients awaiting a liver transplant. Y-90 effectively targets liver tumors while sparing healthy liver tissue, which helps minimize side effects.

Overall, the treatments in this trial have been tested previously and are known to be safe for most people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining radiotherapy with immunotherapy for liver cancer because it offers a potentially powerful one-two punch against the disease. Traditional treatments often rely on surgery, chemotherapy, or localized radiation alone. However, this new approach leverages the precision of stereotactic body radiotherapy or Yttrium-90 radioembolization to target cancer cells, followed by the immune-boosting effects of Atezolizumab and Bevacizumab. Atezolizumab blocks the PD-L1 pathway to help the immune system detect and attack cancer cells, while Bevacizumab inhibits blood vessel growth that tumors need to thrive. This combination aims to not only reduce tumor size but also enhance the body's natural defenses, potentially leading to improved outcomes for patients.

What evidence suggests that this treatment might be an effective treatment for liver cancer?

Research has shown that using atezolizumab and bevacizumab together effectively treats liver cancer. One study found that patients with liver cancer that cannot be surgically removed lived longer and experienced slower tumor growth with this treatment compared to those taking sorafenib. Long-term results support its effectiveness in managing liver cancer.

In this trial, participants will receive either stereotactic body radiotherapy (SBRT) or Yttrium-90 (Y-90) radioembolization as part of the standard-of-care protocol. SBRT has successfully controlled liver tumors over time, with few serious side effects. Y-90 radioembolization also effectively manages liver tumors and offers good survival rates without major side effects. After radiotherapy, participants will begin treatment with atezolizumab and bevacizumab. Combining these treatments could provide promising outcomes for liver cancer patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Gonzalo Sapisochin, MD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

This trial is for patients with advanced liver cancer (HCC) who have cancer invasion in blood vessels and are potential candidates for a liver transplant. Participants will undergo a tumor biopsy, receive radiotherapy (SBRT or Y-90), followed by immunotherapy drugs Atezolizumab & Bevacizumab before being considered for transplantation.

Inclusion Criteria

My liver function is moderately impaired.

My cancer has spread to large blood vessels.

I have no health issues preventing me from having a liver transplant.

Exclusion Criteria

My BMI is 40 or higher.

I have had treatments for liver cancer that were not surgery or ablation.

My cancer has spread to the main blood vessel of my liver.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiotherapy

Participants receive locoregional radiotherapy (SBRT or Y90-RE) as part of the study

1-2 weeks

5 fractions, preferably every other day

Immunotherapy

Participants receive Atezolizumab and Bevacizumab starting 2-6 weeks after radiotherapy, administered in approximately 21-day intervals

Up to 9 months

Every 21 days

Liver Transplantation Evaluation

Participants are evaluated for liver transplantation eligibility if they meet criteria during treatment

Ongoing during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, with data collection for 5 years post-transplant

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Stereotactic body radiotherapy (SBRT)
• Yttrium-90 (Y-90)

Trial Overview

The study tests if combining locoregional therapies like SBRT or Y-90 with immunotherapy agents Atezolizumab & Bevacizumab can help patients become eligible for a liver transplant. It also looks at long-term survival and recurrence rates post-transplant over five years.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 3 Interventions

This is a pilot, single-arm study enrolling 48 patients to evaluate the feasibility of locoregional therapy followed by immunotherapy in patients with advanced liver cancer. Patients will receive stereotactic body radiotherapy or Yttrium-90 radioembolization as per the standard-of-care (SOC) protocol, determined during Multidisciplinary Rounds. Starting two to six weeks after radiotherapy, patients will begin treatment with Atezolizumab and Bevacizumab administered in approximately 21-day intervals, following SOC procedures, for a maximum of 9 months. Clinical follow-up will align with SOC protocols, and imaging will be performed every 2-3 months during immunotherapy. If a patient is sufficiently responding to treatment at any follow-up, patients will be referred for transplant evaluation and added to the waitlist if no contraindications are found. Patients with disease progression or who become ineligible for LT due to other factors will be transitioned off the study.

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?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Atezolizumab plus bevacizumab (AteBeva) has been established as the first-line treatment for untreated, unresectable hepatocellular carcinoma (HCC), showing superiority over sorafenib in the IMbrave150 trial.

A case study demonstrated that combining radiotherapy with AteBeva resulted in a near complete response in a patient with advanced HCC and significant portal vein tumor thrombosis, suggesting that reducing tumor burden through radiotherapy may enhance the effectiveness of immunotherapy in advanced HCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable response of hepatocellular carcinoma with portal vein tumor thrombosis after radiotherapy combined with atezolizumab plus bevacizumab. Kim, YT., Kim, J., Seong, J.[2023]

The combination of atezolizumab and bevacizumab (AB) has been established as the preferred treatment for hepatocellular carcinoma (HCC) patients at Barcelona Liver Cancer Clinic stage C, showing better outcomes than sorafenib.

Despite its effectiveness, many patients do not experience significant survival benefits or responses, highlighting the urgent need for predictive biomarkers to guide treatment decisions for those receiving AB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting Outcomes of Atezolizumab and Bevacizumab Treatment in Patients with Hepatocellular Carcinoma. Han, JW., Jang, JW.[2023]

The CRAFITY score, developed from baseline serum alpha-fetoprotein and C-reactive protein levels, effectively predicts overall survival in patients with hepatocellular carcinoma (HCC) undergoing immunotherapy, with a significant correlation between score levels and median survival times.

Patients with a CRAFITY-low score (0 points) had the longest median overall survival of 27.6 months, while those with a CRAFITY-high score (2 points) had a median survival of only 6.4 months, indicating that this score can help guide treatment decisions and patient counseling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. Scheiner, B., Pomej, K., Kirstein, MM., et al.[2022]

Bevacizumab (Avastin) effectively targets VEGF to inhibit tumor angiogenesis, showing a safety profile that includes mostly mild to moderate side effects such as hypertension and proteinuria, which are manageable in clinical settings.

The side effects associated with bevacizumab, including rare but serious events like gastrointestinal perforation and arterial thrombosis, do not typically exacerbate the toxicity of standard chemotherapy, making it a suitable adjunct treatment for metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. Gordon, MS., Cunningham, D.[2015]

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]

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 seven patients with advanced hepatocellular carcinoma (HCC) receiving atezolizumab and bevacizumab, the addition of radiotherapy (RT) was found to be feasible, with no severe hematologic adverse events reported.

Despite the addition of RT, disease progression occurred in 85.7% of patients, indicating that while RT may be safe, its effectiveness in improving progression-free survival (PFS) and overall survival (OS) remains uncertain and requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Kim, TH., Kim, BH., Cho, YR., et al.[2023]

In the phase 3 IMbrave050 study involving 668 patients with high-risk hepatocellular carcinoma, adjuvant treatment with atezolizumab plus bevacizumab significantly improved recurrence-free survival compared to active surveillance, indicating its potential efficacy as a post-surgery treatment.

However, the treatment was associated with a higher incidence of severe adverse events (41% of patients) compared to the active surveillance group (13%), highlighting the need for careful consideration of the benefit-risk profile in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Qin, S., Chen, M., Cheng, AL., et al.[2023]

In a phase 1b study involving 223 patients with unresectable hepatocellular carcinoma, the combination of atezolizumab and bevacizumab resulted in a significantly longer median progression-free survival of 5.6 months compared to 3.4 months for atezolizumab alone, indicating enhanced efficacy of the combination treatment.

The most common serious treatment-related adverse events included hypertension and proteinuria, with a treatment-related death rate of 3% in the combination group, suggesting that while the combination therapy is effective, it does carry some safety risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lee, MS., Ryoo, BY., Hsu, CH., et al.[2020]

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 multicenter study involving 30 patients with unresectable hepatocellular carcinoma and extrahepatic portal vein tumor thrombus, the combination of intensity-modulated radiotherapy (IMRT) with systemic atezolizumab and bevacizumab (atezo/bev) resulted in a high objective response rate of 76.6% and a median overall survival of 9.8 months.

The treatment was found to have an acceptable safety profile, with neutropenia being the most common adverse event, and no treatment-related deaths reported, suggesting that this combination therapy could be a promising option for patients with this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiotherapy combined with systemic atezolizumab and bevacizumab in treatment of hepatocellular carcinoma with extrahepatic portal vein tumor thrombus: A preliminary multicenter single-arm prospective study. Wang, K., Xiang, YJ., Yu, HM., et al.[2023]

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