Chemotherapy + Atezolizumab for Advanced Liver Cancer

Recruiting at 42 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

88 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial compares the effect of adding bevacizumab and atezolizumab to gemcitabine and cisplatin (chemotherapy) versus chemotherapy and atezolizumab in treating patients with liver cancer that cannot be removed by surgery (unresectable) or that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bevacizumab and atezolizumab with chemotherapy may kill more tumor cells in patients liver cancer than chemotherapy and atezolizumab.

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.

What data supports the effectiveness of the drug combination used in the trial for advanced liver cancer?

Research shows that the combination of gemcitabine and cisplatin, which are part of the trial's treatment, has been effective in improving survival in patients with advanced non-small-cell lung cancer and pancreatic cancer. This suggests potential effectiveness in treating other advanced cancers, like liver cancer. ^{1 2 3 4 5}

Is the combination of chemotherapy and Atezolizumab safe for treating advanced liver cancer?

Cisplatin, a chemotherapy drug often used in combination treatments, can cause side effects like nausea, vomiting, kidney issues, and hearing problems. These side effects are generally dose-dependent, meaning they can be more severe with higher doses. While specific safety data for the combination with Atezolizumab in liver cancer isn't provided, these known side effects of Cisplatin should be considered. ^{6 7 8 9 10}

How is the chemotherapy and atezolizumab treatment for advanced liver cancer different from other treatments?

This treatment combines chemotherapy drugs cisplatin and gemcitabine with atezolizumab, an immune checkpoint inhibitor, which is different from the current standard treatment of atezolizumab plus bevacizumab for advanced liver cancer. The combination aims to enhance the immune system's ability to fight cancer cells while also using chemotherapy to directly target and kill cancer cells. ^{11 12 13 14 15}

Research Team

David Hsieh

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 (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]

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]

References

1. United States 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. [2023]

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

Gemcitabine and cisplatin combination in early-stage non-small-cell lung cancer. [2022]

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

Pemetrexed in pancreatic cancer. [2022]

4. England 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. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Combination of gemcitabine and cisplatin in the treatment of advanced non-small cell lung cancer]. [2010]

6. Japan pubmed.ncbi.nlm.nih.gov

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

7. Japan pubmed.ncbi.nlm.nih.gov

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

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

Cis-platinum vestibular toxicity. [2019]

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

Cisplatin overdose: toxicities and management. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Platinum drugs-related safety profile: The latest five-year analysis from FDA adverse event reporting system data. [2023]

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

Conversion to Curative Resection and Pathological Complete Response Following Targeted Therapies With Atezolizumab and Bevacizumab for Initially Unresectable Hepatocellular Carcinoma: A Case Report. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment. [2023]

13. Greece pubmed.ncbi.nlm.nih.gov

Current Role of Atezolizumab Plus Bevacizumab Therapy in the Sequential Treatment of Unresectable Hepatocellular Carcinoma. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. [2022]

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

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. [2022]