Atezolizumab + Bevacizumab vs Radiation Therapy for Liver Cancer

(ADVANCE HCC Trial)

Recruiting at 8 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

Trial Summary

What is the purpose of this trial?

A multicentre, parallel group, randomized controlled Phase II clinical trial evaluating neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches. Both arms are considered experimental, and as such, a Simon two-stage design will be initially used within both arms. Only if both arms are deemed of interest for further study will a comparison between arms, using a pick-the-winner design, be conducted. Following the completion of neoadjuvant therapy, study participants will undergo a CT scan or MRI to assess tumour response to neoadjuvant therapy. Hepatic resection will be performed for those participants who meet the surgical resection criteria.

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.

What data supports the effectiveness of the treatment Atezolizumab + Bevacizumab vs Radiation Therapy for Liver Cancer?

The combination of atezolizumab and bevacizumab has been shown to be more effective than sorafenib for treating liver cancer that cannot be removed by surgery, making it a standard treatment. Additionally, radiation therapy, including stereotactic body radiotherapy (SBRT), is known to be a safe and effective local treatment for liver cancer, with response rates between 50% to 97%. ^{1 2 3 4 5}

Is the combination of Atezolizumab, Bevacizumab, and SBRT generally safe for humans?

Combining SBRT with antiangiogenic therapies like Atezolizumab and Bevacizumab can lead to unexpected side effects, particularly affecting the gastrointestinal system. Some studies have reported serious side effects, including liver failure and skin reactions, when these treatments are used together. Therefore, while these treatments can be effective, they may also carry significant risks. ^{6 7 8 9 10}

How does the drug Atezolizumab + Bevacizumab differ from other treatments for liver cancer?

Atezolizumab plus Bevacizumab is unique because it combines an immunotherapy drug (Atezolizumab) with a targeted therapy drug (Bevacizumab) to treat liver cancer, and it has shown better one-year survival rates compared to traditional treatments like transarterial chemoembolization plus radiotherapy. This combination works by helping the immune system attack cancer cells and blocking the blood supply that tumors need to grow. ^{1 3 4 11 12}

Research Team

Brandon Meyers, MD

Principal Investigator

principle investigator

Jim Wright, MD

Principal Investigator

OCOG Director

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

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 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]

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]

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]

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]

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]

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 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]

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]

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. Netherlands pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. 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]

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

Radiation oncology approaches in liver malignancies. [2018]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Recall radiation dermatitis by sorafenib following stereotactic body radiation therapy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study. [2022]

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

Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy. [2018]

9. Ireland 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. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Analysis of the factors affecting the safety of robotic stereotactic body radiation therapy for hepatocellular carcinoma patients. [2022]

11. Switzerland 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. [2023]

12. Germany 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. [2023]