Radiotherapy + Immunotherapy for Liver Cancer

(MacroTrans Trial)

Recruiting at 1 trial location

Overseen By Clinical Research Manager

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: University Health Network, Toronto

Disqualifiers: Poorly differentiated HCC, Obesity class III, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn if locoregional therapy and immunotherapy can be used together to help patients with hepatocellular carcinoma (HCC) and macrovascular invasion achieve liver transplantation. The main questions it aims to answer are: * How many patients will achieve transplant with this treatment strategy? * What will the 5-year survival and recurrence-free survival rates be for these patients? Participants will: * Undergo a biopsy of the tumor. * Receive locoregional therapy (SBRT or Y90) followed by immunotherapy (atezolizumab and bevacizumab) 2 to 6 weeks later, for a maximum of 9 months. * Be referred for a liver transplant and undergo the procedure if deemed eligible and safe. * If applicable, be followed for five years post-transplant with regular data collection.

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.

What data supports the effectiveness of the treatment Atezolizumab and Bevacizumab for liver cancer?

The combination of atezolizumab and bevacizumab has been shown to be more effective than sorafenib for treating unresectable liver cancer, making it the preferred systemic treatment for this condition. ^{1 2 3 4 5}

Is the combination of radiotherapy and immunotherapy safe for liver cancer treatment?

The combination of atezolizumab and bevacizumab has shown a generally manageable safety profile in patients with advanced liver cancer, with side effects like high blood pressure and minor bleeding being mild to moderate. Bevacizumab, when used with other treatments, has been associated with some uncommon but manageable side effects such as wound healing issues and gastrointestinal perforations. ^{1 6 7 8 9}

How is the treatment of radiotherapy combined with atezolizumab and bevacizumab unique for liver cancer?

This treatment is unique because it combines radiotherapy, which can enhance the immune response, with atezolizumab and bevacizumab, a combination that has shown superior results over traditional treatments like sorafenib for advanced liver cancer. This approach aims to reduce tumor burden and improve outcomes in patients with advanced hepatocellular carcinoma. ^{1 3 8 10 11}

Research Team

Gonzalo Sapisochin, MD

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Atezolizumab (Checkpoint Inhibitor)
• Bevacizumab (Monoclonal Antibodies)
• Stereotactic body radiotherapy (SBRT) (Radiation)
• Yttrium-90 (Y-90) (Anti-tumor antibiotic)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Findings from Research

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 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 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 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]

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]

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]

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 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]

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]

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 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]

References

1. Korea (South) pubmed.ncbi.nlm.nih.gov

Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. [2020]

3. England 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. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. [2015]

8. Switzerland 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. [2023]

9. United States 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. [2023]

10. Korea (South) pubmed.ncbi.nlm.nih.gov

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

11. Netherlands pubmed.ncbi.nlm.nih.gov

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. [2022]