Atezolizumab + Bevacizumab vs Radiation Therapy for Liver Cancer

(ADVANCE HCC Trial)

No longer recruiting at 9 trial locations

Overseen By Erin McGean

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ontario Clinical Oncology Group (OCOG)

Must be taking: Anti-HBV treatment

Must not be taking: Immunosuppressants, Anticoagulants

Disqualifiers: Cardiovascular disease, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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

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: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments for liver cancer: a combination of drugs (Atezolizumab and Bevacizumab) and a type of radiation therapy called SBRT (Stereotactic Body Radiation Therapy). The goal is to determine which treatment more effectively reduces the cancer before surgery. Individuals with a single liver tumor involving certain veins, but no spread to other areas, might be suitable candidates. After treatment, scans will assess the cancer's response. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but it does require stopping certain medications like strong CYP3A4 inducers, immunosuppressive medications, and specific blood thinners before joining. It's best to discuss your current medications with the trial team to see if any need to be paused or adjusted.

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

Research has shown that the combination of Atezolizumab and Bevacizumab is generally well-tolerated by people with liver cancer. Studies have found that high blood pressure and tiredness are the most common side effects, affecting about 30% of patients. Most people find these side effects manageable and not severe.

Similarly, Stereotactic Body Radiation Therapy (SBRT) is considered safe for treating liver cancer. Many studies indicate that SBRT effectively controls the cancer with a low risk of liver damage. This evidence suggests that both treatments have been tested and are considered safe for many patients, although they may have some manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Atezolizumab and Bevacizumab for liver cancer because this duo works by boosting the immune system and cutting off the blood supply to the tumor, which is different from traditional chemotherapy. Atezolizumab is an immunotherapy that helps the body's immune system recognize and attack cancer cells, while Bevacizumab is an angiogenesis inhibitor that prevents the growth of blood vessels that feed tumors. On the other hand, the use of Stereotactic Body Radiation Therapy (SBRT) offers a highly focused radiation treatment that can deliver high doses to the tumor in just a few sessions, potentially sparing surrounding healthy tissue. These innovative approaches could offer more targeted and effective options for patients compared to the current treatments, which often involve more generalized chemotherapy or surgery.

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

Research has shown that using Atezolizumab and Bevacizumab together effectively treats advanced liver cancer, specifically hepatocellular carcinoma (HCC). Studies have found that this combination can extend patients' lives and slow tumor growth or spread. Patients with HCC that cannot be surgically removed have shown better survival rates with this treatment. In this trial, one group of participants will receive Atezolizumab and Bevacizumab.

Similarly, Stereotactic Body Radiation Therapy (SBRT) has proven effective for treating primary liver cancer like HCC. It provides high local control, effectively targeting and managing liver cancer. Patients who received SBRT experienced long-term survival, and the treatment is known for its safety and low side effects. Another group in this trial will receive SBRT. Both treatments have shown promising results against liver cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Brandon Meyers, MD

Principal Investigator

principle investigator

Jim Wright, MD

Principal Investigator

OCOG Director

Are You a Good Fit for This Trial?

Adults over 18 with a specific liver cancer (HCC) and blood clots in the portal vein, without spread to other areas or severe liver damage. They must not have had previous HCC treatments or certain other health conditions like recent serious infections, bleeding issues, significant heart disease, autoimmune diseases, or be pregnant.

Inclusion Criteria

I am older than 18 years.

My liver cancer has spread to the main branches of the portal vein.

Your tumor is smaller than 10 centimeters when measured by CT or MRI.

Exclusion Criteria

I have not had major surgery or a significant injury in the last 28 days.

I have coughed up blood in the last 4 weeks.

I haven't had a stroke or blood clot in the arteries in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive either neoadjuvant Atezolizumab/Bevacizumab or SBRT prior to hepatic resection

12 weeks

4 cycles of treatment every 3 weeks for Atezolizumab/Bevacizumab; 5 sessions over 10 days for SBRT

Surgical Resection

Participants undergo hepatic resection if they meet surgical criteria

1 week

Follow-up

Participants are monitored for safety, effectiveness, and postoperative complications

2 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab/Bevacizumab
• SBRT

Trial Overview The trial is testing two pre-surgery treatments for liver cancer: Atezolizumab/Bevacizumab versus radiation therapy (SBRT). It's a Phase II study where patients are randomly assigned to one of these experimental groups. The effectiveness will be measured by tumor response before surgery.

How Is the Trial Designed?

Group I: Neoadjuvant SBRT Experimental Treatment 1 Intervention

• Arm 2: neoadjuvant stereotactic body radiation therapy (SBRT), target volume 30 40 Gy, in 6-8 Gy per day over five days, delivered every other day

Group II: Neoadjuvant Atezolizumab/Bevacizumab Experimental Treatment 1 Intervention

• Arm 1: neoadjuvant atezolizumab 1200 mg IV q3weeks x 4 cycles, and bevacizumab 15 mg/kg IV q3weeks x 4 cycles

Who Is Running the Clinical Trial?

Ontario Clinical Oncology Group (OCOG)

Lead Sponsor

Trials

65

Recruited

42,000+

Hoffmann-La Roche

Industry 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

Published Research Related to This Trial

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]

A 63-year-old man with hepatocellular carcinoma and a thrombus in the inferior vena cava showed a dramatic tumor response to stereotactic body radiation therapy (SBRT) with a total dose of 48 Gy delivered in 6 fractions over 2 weeks.

Following SBRT, the patient was treated with sorafenib, which led to the development of grade 2 radiation dermatitis, highlighting the need to carefully monitor for adverse effects when combining radiation therapy with sorafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recall radiation dermatitis by sorafenib following stereotactic body radiation therapy. Hsieh, CH., Lin, SC., Shueng, PW., et al.[2022]

Liver stereotactic body radiotherapy (SBRT) is a safe and effective treatment for patients with primary hepatocellular carcinoma or liver metastases, showing a 1-year local control rate of 81% and overall survival rate of 62% after a median follow-up of 12.7 months.

The treatment demonstrated manageable toxicity, with 47% of patients experiencing grade 2 acute toxicity and only 7% experiencing grade 3 toxicity, indicating that prior liver-directed therapies did not negatively impact the safety or efficacy of SBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective study of the safety and efficacy of liver stereotactic body radiotherapy in patients with and without prior liver-directed therapy. Moon, DH., Wang, AZ., Tepper, JE.[2022]

In a study of 74 hepatocellular carcinoma (HCC) patients treated with robotic stereotactic body radiation therapy (SBRT), 13 patients experienced significant hepatic adverse reactions, indicating potential safety concerns with this treatment.

The study identified that having a total liver volume greater than 1,162 mL and a normal liver volume greater than 1,148 mL are important factors that can help reduce the risk of severe liver reactions after SBRT, suggesting that careful patient selection is crucial for improving treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the factors affecting the safety of robotic stereotactic body radiation therapy for hepatocellular carcinoma patients. Liu, X., Song, Y., Liang, P., et al.[2022]

In a study of 31 patients with advanced biliary tract carcinoma, combining radiotherapy (RT) with PD-1 inhibitors and lenvatinib resulted in an objective response rate of 32.3% and a disease control rate of 87.1%, indicating significant antitumor effectiveness.

The median overall survival was 11.7 months and median progression-free survival was 7.9 months, with no excessive toxicity observed from the combined treatment, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of radiotherapy plus programmed death-1 inhibitors and lenvatinib in patients with advanced biliary tract carcinoma: a real-world study. Wang, Y., Yang, X., Wang, Y., 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 stereotactic body radiation therapy (SBRT) with targeted biologic agents, especially those that inhibit angiogenesis, has shown promise in cancer treatment but has also led to unexpected late gastrointestinal toxicities.

Understanding the biological mechanisms behind these toxicities is crucial for safely expanding the use of SBRT and antiangiogenic therapies in clinical practice, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy. Pollom, EL., Deng, L., Pai, RK., et al.[2018]

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]

Radiation therapy, including techniques like brachytherapy and stereotactic body radiotherapy (SBRT), is safe and effective for treating liver cancers, with response rates ranging from 50% to 97% in recent studies.

Technological advancements in imaging and radiation delivery have improved the ability to treat difficult-to-reach tumors while minimizing damage to surrounding healthy tissue, making these therapies increasingly viable for patients with compromised liver function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation oncology approaches in liver malignancies. Kennedy, AS.[2018]

Stereotactic body radiation therapy (SBRT) was found to be feasible and effective for treating primary and metastatic liver tumors, achieving local control rates of 94% at 1 year and 82% at 2 years among 25 patients with 45 lesions.

While SBRT showed acceptable toxicity overall, caution is advised for patients with Child B liver disease due to a higher risk of severe toxicity, including one case of liver failure and infection leading to death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study. Méndez Romero, A., Wunderink, W., Hussain, SM., et al.[2022]

In a study of 97 hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis, those treated with atezolizumab-plus-bevacizumab (Ate/Bev) had a significantly higher one-year survival rate compared to those receiving transarterial chemoembolization plus radiotherapy (TACE + RT), particularly in patients with extensive HCC burden.

While Ate/Bev showed superior outcomes overall, TACE + RT remains a viable alternative for patients with unilobar intrahepatic HCC, indicating that treatment choice may depend on the specific characteristics of the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis. Lee, SK., Kwon, JH., Lee, SW., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10777975/

Atezolizumab and Bevacizumab Combination Therapy in ... Conclusions: The combination of Atezolizumab and Bevacizumab is shown to be effective in the treatment of advanced hepatocellular carcinoma, although it is ...

2. tecentriq.com tecentriq.com/hcc/results/how-tecentriq-may-help.html

How TECENTRIQ + Avastin ® (bevacizumab) May Help TECENTRIQ + Avastin was more effective in treating HCC than sorafenib. More patients LIVED LONGER and HAD A LOWER CHANCE of tumors growing or spreading ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1915745

Atezolizumab plus Bevacizumab in Unresectable ... In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival ...

4. tecentriq-hcp.com tecentriq-hcp.com/hcc/efficacy/key-secondary-endpoints-orr.html

IMbrave150 efficacy results: Key secondary endpoints - ORR The key secondary endpoints reported in IMbrave150 for TECENTRIQ® (atezolizumab) + Avastin® (bevacizumab) in unresectable or metastatic hepatocellular carcinoma

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10327339/

Efficacy and safety of atezolizumab plus bevacizumab ... Atezolizumab in combination with bevacizumab showed good efficacy and tolerability in the treatment of advanced HCC. Compared with short-term, non-first-line, ...

6. tecentriq-hcp.com tecentriq-hcp.com/hcc/patient-reported-outcomes.html

Patient-reported outcomes - TECENTRIQ-HCP.com The most common adverse reactions (rate ≥20%) in patients who received TECENTRIQ in combination with bevacizumab for HCC were hypertension (30%), fatigue/ ...

7. roche.com roche.com/media/releases/med-cor-2023-04-16

Roche's Tecentriq plus Avastin reduced the risk of cancer ... The Tecentriq investigational combination reduced the risk of cancer returning by 28%, compared with active surveillance, at a median follow-up of 17.4 months.

8. sciencedirect.com sciencedirect.com/science/article/pii/S2059702924018817

Atezolizumab plus bevacizumab as first-line treatment of ... The treatment of advanced hepatocellular carcinoma (HCC) with atezolizumab and bevacizumab led to significant improvements in overall survival (OS), progression ...