Chemotherapy + Atezolizumab for Advanced Liver Cancer

Not currently recruiting at 43 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Antivirals

Must not be taking: Immunosuppressants, Immunostimulatory agents

Disqualifiers: Pregnancy, Autoimmune disease, Brain metastases, 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

Compensation: Varies

Number of Visits: 21

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding a drug called bevacizumab to a treatment mix can more effectively combat advanced liver cancer that cannot be surgically removed. The trial compares two groups: one receiving chemotherapy (including drugs like Cisplatin and Gemcitabine Hydrochloride) and atezolizumab, and another receiving those plus bevacizumab. Atezolizumab is an immunotherapy drug that helps the immune system attack cancer, while bevacizumab prevents blood vessels from feeding the tumor. This trial targets individuals with a specific type of liver cancer (combined hepatocellular carcinoma-cholangiocarcinoma) that has either spread or cannot be surgically removed. Candidates should not have received previous systemic therapy for advanced liver cancer but may have had certain other treatments if at least 6 months have passed since completion. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not be on systemic immunosuppressive medication within 2 weeks before starting the trial, unless it's a low-dose or specific type allowed by the trial.

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

Research has shown that combining atezolizumab, bevacizumab, gemcitabine, and cisplatin appears safe for patients with advanced biliary tract cancer. No major problems emerged, suggesting good tolerance. Specifically, using atezolizumab, bevacizumab, and a similar chemotherapy plan proved safe and effective.

For the combination without bevacizumab (atezolizumab, gemcitabine, and cisplatin), specific data for liver cancer is lacking, but these drugs have been used safely in other cancers. Cisplatin is known for its side effects, which should be considered, but atezolizumab and gemcitabine are generally well-tolerated.

Overall, these treatments seem safe based on previous studies, but side effects can still occur. Staying informed and discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced liver cancer because they combine traditional chemotherapy with a cutting-edge immunotherapy drug, atezolizumab. Atezolizumab is a monoclonal antibody that works by unleashing the immune system to attack cancer cells, which is different from standard chemotherapy options like sorafenib and lenvatinib that primarily target cancer cell growth directly. Additionally, the inclusion of bevacizumab in one treatment arm aims to inhibit blood vessel growth that feeds tumors, a mechanism not typically targeted by existing therapies for liver cancer. This combination of therapies could potentially lead to more effective cancer control by addressing multiple pathways that cancer uses to grow and spread.

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

Research shows that using atezolizumab and bevacizumab together is a preferred treatment for advanced liver cancer that cannot be removed with surgery. Studies have found that this combination can help patients live longer compared to treatments like sorafenib. In this trial, participants in Arm A will receive atezolizumab, bevacizumab, gemcitabine, and cisplatin. Adding bevacizumab to the chemotherapy drugs gemcitabine and cisplatin may slightly extend the time before advanced bile duct cancer worsens. Participants in Arm B will receive atezolizumab, gemcitabine, and cisplatin. Research also indicates that combining atezolizumab with gemcitabine and cisplatin has helped liver cancer patients live longer. Overall, these treatments work by boosting the immune system to fight cancer and stopping the growth of new blood vessels that tumors need. ^{1 5 6 7 8}

Who Is on the Research Team?

David Hsieh

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

Adults with advanced liver cancer that can't be surgically removed or has spread, who've completed certain treatments over 4 weeks ago. They must have adequate blood counts and organ function, not be pregnant/breastfeeding, free from autoimmune diseases or immune deficiencies (with some exceptions), and without a history of severe allergies to trial drugs.

Inclusion Criteria

My cancer cannot be removed by surgery or has spread to other parts of my body.

My hemoglobin level is at least 9 g/dL, possibly after a transfusion.

My white blood cell count is healthy for treatment.

Exclusion Criteria

I do not have any bleeding disorders or significant blood clotting issues.

I haven't taken any immune-boosting drugs in the last 4 weeks or longer.

I have skin conditions like eczema or psoriasis without any related arthritis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive chemotherapy and immunotherapy with atezolizumab, and optionally bevacizumab, in 21-day cycles

Up to 3 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Cisplatin
• Gemcitabine Hydrochloride

Trial Overview The study is testing if adding Bevacizumab (an antiangiogenic agent) to the combination of Chemotherapy (Gemcitabine and Cisplatin) and Atezolizumab (a monoclonal antibody immunotherapy) is more effective in treating unresectable or advanced liver cancer than just Chemotherapy with Atezolizumab.

How Is the Trial Designed?

Group I: Arm A (atezolizumab, bevacizumab, gemcitabine, cisplatin) Experimental Treatment 7 Interventions

Patients receive atezolizumab IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, gemcitabine IV over 30 minutes on days 1 and 8, and cisplatin IV on days 1 and 8. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI throughout the trial. Patients undergo blood specimen collection on study.

Group II: Arm B (atezolizumab, gemcitabine, cisplatin) Active Control 6 Interventions

Patients receive atezolizumab IV over 30-60 minutes on day 1, and gemcitabine IV over 30 minutes and cisplatin IV on days 1 and 8. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or magnetic resonance imaging MRI throughout the trial. Patients undergo blood specimen collection on study.

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A study analyzing adverse event reports from 2017 to 2021 identified 1853 effective adverse event signals for three platinum drugs (Cisplatin, Carboplatin, and Oxaliplatin), highlighting the need for careful monitoring of side effects in cancer treatment.

Cisplatin primarily affects the blood and lymphatic systems, Carboplatin is associated with respiratory issues, and Oxaliplatin impacts the nervous system, indicating that each drug has distinct adverse event profiles that should guide individualized treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum drugs-related safety profile: The latest five-year analysis from FDA adverse event reporting system data. Feng, G., Zhou, X., Chen, J., et al.[2023]

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

In a phase II trial involving 84 patients with advanced pancreatic cancer, the addition of cetuximab to gemcitabine and cisplatin did not significantly improve objective response rates or overall survival compared to gemcitabine and cisplatin alone.

Despite no increase in toxic effects from cetuximab, the study concluded that this combination treatment should not be pursued in further phase III trials, as it did not demonstrate any added benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Cascinu, S., Berardi, R., Labianca, R., et al.[2022]

The combination of atezolizumab (a PD-L1 inhibitor) and bevacizumab has shown unprecedented efficacy in treatment-naive patients with advanced hepatocellular carcinoma (HCC), as demonstrated in the IMbrave150 Phase III trial, which established a new standard of care.

This combination therapy outperformed sorafenib monotherapy, marking a significant advancement in treatment options for HCC after years of limited progress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. Rizzo, A., Ricci, AD., Brandi, G.[2022]

Cisplatin is a widely used cancer treatment but can cause serious dose-dependent toxicities, including nausea, renal insufficiency, and myelosuppression, especially in cases of overdose.

There are currently no specific antidotes for cisplatin overdose, but management strategies include aggressive hydration, monitoring, and supportive therapies, with some experimental treatments showing limited effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin overdose: toxicities and management. Tsang, RY., Al-Fayea, T., Au, HJ.[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]

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]

Cis-diamminedichloroplatinum (II) demonstrated significant efficacy as a single-agent treatment for advanced genitourinary tumors, achieving complete responses in 16.7% of testicular cancer patients and partial responses in 50% of the same group, based on a study of 112 patients with various genitourinary tumors.

The treatment was associated with common adverse reactions such as gastrointestinal issues, nephrotoxicity, and myelosuppression, but also included occasional ototoxicity and peripheral neuropathies, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase II study of cis-diamminedichloroplatinum (II) in genitourinary cancer]. [2013]

In a Phase I study involving 40 patients with urologic and gynecologic cancers, cis-diamminedichloroplatinum(II) (CIS-DDP) was found to have manageable side effects, primarily nausea, vomiting, and anorexia, which resolved quickly after stopping the treatment.

The study indicated low levels of hematopoietic and renal toxicities, with no reported cases of hearing disturbances or tinnitus, suggesting a favorable safety profile for CIS-DDP at doses of 50 mg/m2 for single administration and 20 mg/m2/day for five consecutive days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase I study of a new antineoplastic agent, cis-diamminedichloroplatinum (II)]. [2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10705135/

Real-World Systemic Treatment Patterns after ... Atezolizumab plus bevacizumab (atezo + bev) is a preferred front-line treatment for unresectable hepatocellular carcinoma (HCC).

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.00337

Atezolizumab Plus Chemotherapy With or Without ... In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12213146/

Evaluating the cost-effectiveness of atezolizumab ... The IMbrave150 trial demonstrated that the combination of atezolizumab and bevacizumab resulted in longer overall survival compared to sorafenib ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.491

IMbrave151: A phase 2, randomized, double-blind ... IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin ...

5. jfda-online.com jfda-online.com/cgi/viewcontent.cgi?article=3542&context=journal

Evaluating the cost-effectiveness of atezolizumab- ... Fig. 1. Cost-effectiveness acceptability curve of atezolizumab plus bevacizumab versus sorafenib in advanced hepatocellular carcinoma. Table 3.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05211323

NCT05211323 | A Study to Determine Whether ... Giving bevacizumab and atezolizumab with chemotherapy may kill more tumor cells in patients liver cancer than chemotherapy and atezolizumab. Detailed ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10052479/

Efficacy and safety of a triple combination of atezolizumab ... The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10401838/

Case Report: Atezolizumab plus bevacizumab for ... We present six cases of cHCC-CCA treated with atezolizumab plus bevacizumab. We observed three partial responses and one stable disease as the best responses.