RP3 + Atezolizumab + Bevacizumab for Liver Cancer

Recruiting at 34 trial locations

Overseen By Clinical Trials at Replimune

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Replimune Inc.

Must be taking: Anti-PD-1, Anti-PD-L1

Must not be taking: Antivirals, Anticoagulants

Disqualifiers: HIV, Active tuberculosis, Autoimmune disease, others

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: Unknown

Duration: Up to 3 years

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new combinations of cancer drugs to determine their safety and effectiveness for certain liver and bile duct cancers. For individuals with liver cancer (HCC) that cannot be surgically removed and did not respond to initial treatment, the trial combines RP3 (an experimental treatment), atezolizumab, and bevacizumab. For those with bile duct cancer (BTC) that has spread and remained stable after initial treatment, the trial uses RP2 and durvalumab. Eligible participants are those with advanced liver or bile duct cancer who have not succeeded with specific prior treatments. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain treatments like systemic anticancer therapies, live vaccines, or botanical preparations within specific time frames before the trial starts. It's best to discuss your current medications with the trial team.

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

A previous study showed that patients treated with the combination of atezolizumab and bevacizumab lived longer and experienced manageable side effects. This combination is already used as a first treatment for liver cancer, indicating it is generally well-tolerated.

Research has also explored RP2, a type of cancer treatment, used with atezolizumab and bevacizumab. Early results suggest that RP2 is safe with these drugs, with side effects similar to those already known for atezolizumab and bevacizumab.

Another study combined RP2 with durvalumab for treating bile duct cancer. Patients did not experience any unexpected side effects, similar to those seen with durvalumab alone.

These findings suggest that these drug combinations are reasonably safe, but ongoing research will provide more information. For those considering joining a trial, these results might offer some reassurance. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments in this trial because they combine innovative therapies with existing cancer treatments to target liver cancer and bile duct cancer more effectively. For liver cancer, the combination of Atezolizumab and Bevacizumab with RP3 represents a novel approach by combining immune checkpoint inhibitors with a new investigational drug, potentially enhancing the body’s immune response against cancer cells. For bile duct cancer, the combination of Durvalumab with RP2 is unique because it leverages a new compound alongside a checkpoint inhibitor, aiming to improve outcomes for patients who have already been through standard treatments like gemcitabine and platinum-based chemotherapy. These combinations hold promise for increased effectiveness and potentially better outcomes compared to existing treatments alone.

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

Research has shown that using atezolizumab and bevacizumab together effectively treats liver cancer that cannot be surgically removed. Studies indicate that this combination helps patients live longer compared to older treatments. Atezolizumab aids the immune system in attacking cancer cells, while bevacizumab prevents tumor growth by stopping new blood vessel formation. In this trial, one group of participants will receive atezolizumab and bevacizumab combined with RP2, a new treatment under testing, which early results suggest might enhance these effects.

Another group in this trial, consisting of patients with biliary tract cancer (BTC), will receive a combination of RP2 with durvalumab, a drug that boosts the immune system. This combination appears promising based on its mechanism and early patient outcomes. Overall, these treatments aim to strengthen the body's natural ability to fight cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

May Cho, MD

Principal Investigator

Replimune Inc.

Are You a Good Fit for This Trial?

Adults with advanced, inoperable or metastatic liver cancer (Hepatocellular Carcinoma) who have either not had systemic therapy or have tried one that includes anti-PD-1/PD-L1. They must be generally healthy, with proper kidney, blood and liver function, and no recent use of investigational drugs. Women of childbearing age need a negative pregnancy test and agree to contraception.

Inclusion Criteria

I agree to provide a recent or new tumor biopsy for the study.

I am able to understand and sign the consent form.

I have a tumor that is at least 1cm big, or a lymph node that is at least 1.5cm in its shortest dimension.

Exclusion Criteria

My liver cancer has been confirmed by tissue analysis.

I have a history of serious heart problems.

I am HIV positive.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive RP2 in combination with atezolizumab and bevacizumab as second-line therapy

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

135 days after last dose

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• RP3

Trial Overview The trial is testing RP3 combined with atezolizumab plus bevacizumab as first- or second-line treatments for Hepatocellular Carcinoma. It's an open-label Phase 2 study where all participants know which treatment they're getting.

How Is the Trial Designed?

Group I: RP2+Durvalumab for BTC Cohort Experimental Treatment 2 Interventions

Patients with locally advanced or metastatic BTC (intrahepatic or extrahepatic cholangiocarcinoma or gall bladder carcinoma), who have received treatment with combination gemcitabine, platinum-containing chemotherapy, and checkpoint inhibitor for a minimum of 12 weeks (4 to 8 cycles), and who have had stable disease or partial response on 2 scans and no progressive disease. Patients will receive durvalumab combined with RP2.

Group II: RP2+Bevacizumab and Atezolizumab for HCC Cohort Experimental Treatment 3 Interventions

Patients with locally advanced unresectable, recurrent and/or metastatic HCC who have progressed on 1 prior systemic treatment, which must have included anti-programmed cell death 1 (PD-1)/anti-PD-L1 therapy. Patients will receive atezolizumab plus bevacizumab therapy combined with RP2.

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?

Replimune Inc.

Lead Sponsor

Trials

16

Recruited

1,700+

Roche Pharma AG

Industry Sponsor

Trials

413

Recruited

430,000+

Dr. Thomas Schinecker

Roche Pharma AG

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Dr. Levi Garraway

Roche Pharma AG

Chief Medical Officer since 2019

MD from University of California, San Francisco

Published Research Related to This Trial

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]

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]

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]

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 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 216 patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (AtezoBev), the treatment demonstrated a median overall survival of 14.9 months and a median progression-free survival of 6.8 months, indicating its efficacy in a real-world clinical setting.

Patients with impaired liver function (Child-Pugh class B) experienced similar rates of treatment-related adverse events compared to those with better liver function (Child-Pugh class A), suggesting that AtezoBev is tolerable and may be a viable option for this underserved population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study. D'Alessio, A., Fulgenzi, CAM., Nishida, N., et al.[2023]

In a real-world study of 61 patients with hepatocellular carcinoma (HCC), the combination of atezolizumab and bevacizumab showed a median progression-free survival (PFS) of 5.4 months and an objective response rate (ORR) of 35.3%.

The treatment was found to be safe, with a high incidence of adverse events (98.0%), primarily hepatic disorders, but it remained effective even in patients with prior treatment histories or varying liver function as indicated by albumin-bilirubin (ALBI) grades.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice. Iwamoto, H., Shimose, S., Noda, Y., et al.[2021]

In a study of 49 patients with advanced hepatocellular carcinoma (HCC) who progressed on atezolizumab-bevacizumab, second-line treatment with multikinase inhibitors (MKIs) like sorafenib and lenvatinib showed a median progression-free survival of 3.4 months and an overall survival of 14.7 months, indicating that these therapies can be effective after initial treatment failure.

Lenvatinib demonstrated a significantly longer median progression-free survival compared to sorafenib (6.1 vs. 2.5 months), although overall survival rates were similar between the two treatments, suggesting that while lenvatinib may delay disease progression, both treatments are viable options with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcomes with Multikinase Inhibitors after Progression on First-Line Atezolizumab plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma: A Multinational Multicenter Retrospective Study. Yoo, C., Kim, JH., Ryu, MH., 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]

The combination of atezolizumab and bevacizumab has recently become the new standard of care for patients with advanced hepatocellular carcinoma (HCC), replacing sorafenib, which was the standard for over a decade.

This review highlights practical aspects of using the atezolizumab and bevacizumab combination, including evidence for its efficacy, indications for use, management of side effects, and areas needing further research, making it a valuable resource for clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab as first line therapy in advanced hepatocellular carcinoma: Practical considerations in routine clinical practice. Jain, A., Chitturi, S., Peters, G., et al.[2021]

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 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]

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controlled study of amezalpat (TPST-1120), a peroxisome ... In preclinical studies of HCC, including ß-catenin activated disease, amezalpat exhibits anti-cancer activity as a single agent and demonstrates ...