Atezolizumab + Multi-Kinase Inhibitor for Liver Cancer

Recruiting at 12 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Academic and Community Cancer Research United

Must be taking: Anti-HBV treatment

Must not be taking: Multi-kinase inhibitors, Immunosuppressants

Disqualifiers: Autoimmune disease, Brain metastasis, 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: 21-day cycles, repeated until disease progression or unacceptable toxicity

122 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding atezolizumab (an immunotherapy that helps the immune system attack cancer) to a treatment of cabozantinib or lenvatinib (drugs that block cancer cell growth) can more effectively treat liver cancer that cannot be surgically removed or has spread. Participants will receive either the combination of atezolizumab with cabozantinib or lenvatinib, or cabozantinib or lenvatinib alone. The trial specifically seeks individuals with advanced or metastatic liver cancer who have previously received atezolizumab and bevacizumab. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain medications like strong inducers or inhibitors of CYP3A4, you may need to stop them 14 days before starting the trial. 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?

Research has shown that combining atezolizumab and cabozantinib is generally safe for patients with advanced liver cancer. In one study, patients managed the side effects well.

Similarly, studies indicate that combining atezolizumab and lenvatinib is safe. Lenvatinib, used in liver cancer treatments, has proven effective and safe. Patients who used lenvatinib after other treatments experienced positive results with manageable side effects.

Overall, previous studies have demonstrated that these treatments are generally safe, with side effects that patients can handle. This suggests they might be suitable for those considering joining this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for liver cancer because they offer a new way to tackle the disease. Unlike the standard treatments like sorafenib, atezolizumab is an immunotherapy that helps the body's immune system target and destroy cancer cells more effectively. Additionally, cabozantinib and lenvatinib are multi-kinase inhibitors that block multiple pathways cancer cells use to grow, making them versatile in disrupting tumor growth. This combination approach aims to enhance effectiveness and potentially improve outcomes for patients compared to traditional therapies.

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

In this trial, participants in Arm A will receive a combination of atezolizumab with either cabozantinib or lenvatinib. Research has shown that cabozantinib with atezolizumab can slow cancer growth in patients with advanced liver cancer. One study found this combination safe and beneficial for patients who hadn't received prior treatment. However, another study found it did not improve overall survival compared to sorafenib for these patients.

Participants in Arm B will receive either cabozantinib or lenvatinib alone. Research indicates that lenvatinib alone is effective, with patients experiencing an average of 5.4 months without cancer progression. Lenvatinib has also shown promise as a second treatment option for unresectable liver cancer, with an average overall survival of 9.8 months. Overall, these drug combinations aim to help the immune system fight cancer and inhibit cancer cell growth. ^{2 3 6 7 8}

Who Is on the Research Team?

Wen Wee Ma

Principal Investigator

Academic and Community Cancer Research United

Are You a Good Fit for This Trial?

This trial is for adults with advanced liver cancer that's inoperable, locally advanced, or metastatic and have previously been treated. Participants must be able to take oral meds, have a specific performance status (ECOG 0 or 1), and their liver function needs to meet certain criteria. Women of childbearing age must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

Consent to using archival tumor tissues, if available

Hemoglobin >= 90 g/L (9 g/dL)

My kidney function, measured by creatinine levels, is within the required range.

Exclusion Criteria

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation

Other uncontrolled, significant intercurrent or recent illness including cardiovascular disorders, uncontrolled hypertensions, stroke, myocardial infarction, or other ischemic event =< 3 months prior to randomization, uncontrolled arrythmia, thromboembolic event =< 3 months prior to randomization, active bacterial infection requiring systemic treatment, known human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS) related illness, prior allogenic stem cell or solid organ transplantation, uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia, uncontrolled tumor-related pain, other malignancy(ies) =< 5 years prior to randomization, pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of study medication, uncontrolled hepatic encephalopathy occurring =< 6 weeks prior to randomization

I don't have any health issues that prevent me from taking new medications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive atezolizumab IV and cabozantinib or lenvatinib PO in 21-day cycles, or cabozantinib or lenvatinib alone in 21-day cycles

21-day cycles, repeated until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 9 weeks for up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Cabozantinib
• Lenvatinib

Trial Overview The study tests atezolizumab combined with cabozantinib or lenvatinib against just the multi-kinase inhibitors alone. Atezolizumab is an immunotherapy drug while cabozantinib and lenvatinib block enzymes that help tumor cells grow. The goal is to see if combining these treatments works better for treating liver cancer.

How Is the Trial Designed?

Group I: Arm A (atezolizumab, cabozantinib or lenvatinib) Experimental Treatment 3 Interventions

Patients receive atezolizumab IV over 30-60 minutes on day 1 and cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (cabozantinib or lenvatinib) Active Control 2 Interventions

Patients receive cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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?

Academic and Community Cancer Research United

Lead Sponsor

Trials

54

Recruited

4,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has been shown to significantly prolong overall survival and progression-free survival in patients with advanced hepatocellular carcinoma (HCC) who have previously been treated with sorafenib, based on the CELESTIAL phase 3 trial.

The tolerability profile of cabozantinib is acceptable, with manageable adverse events that can be addressed through dose modifications and supportive care, making it a viable treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Review in Advanced Hepatocellular Carcinoma. Deeks, ED.[2020]

In a phase Ib study involving 104 patients with unresectable hepatocellular carcinoma (uHCC), the combination of lenvatinib and pembrolizumab demonstrated significant antitumor activity, with an objective response rate of 46% according to modified RECIST criteria.

The treatment was well-tolerated, with manageable toxicities and no new safety signals identified, indicating that this combination could be a viable option for patients with uHCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. Finn, RS., Ikeda, M., Zhu, AX., et al.[2022]

In a study of 13 patients, rechallenging with lenvatinib after treatment with atezolizumab plus bevacizumab showed anti-tumor effects, but the duration of the second lenvatinib treatment was significantly shorter (2.8 months) compared to the first treatment (8.7 months).

While lenvatinib re-administration can be effective, it may lead to deterioration in liver function, highlighting the need for careful monitoring of liver health and patient status during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rechallenge With Lenvatinib After Atezolizumab Plus Bevacizumab Treatment for Hepatocellular Carcinoma. Komatsu, S., Yano, Y., Kido, M., et al.[2022]

In a study of 53 patients with advanced hepatocellular carcinoma (HCC) who received lenvatinib after immunotherapy, the median overall survival was 12.8 months, indicating that lenvatinib can be an effective second-line treatment following immunotherapy failure.

The median progression-free survival was 3.7 months, suggesting that while lenvatinib provides some benefit, the optimal treatment sequence after immunotherapy for advanced HCC still needs further investigation through clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study. Palmer, ME., Gile, JJ., Storandt, MH., et al.[2023]

In a study of 2205 patients with unresectable HCC, there was no significant overall survival advantage for atezolizumab plus bevacizumab compared to lenvatinib, indicating similar efficacy in first-line treatment.

However, the safety profile favored atezolizumab plus bevacizumab, as it had fewer adverse events, and specific patient groups showed differential benefits, with lenvatinib being more effective for those with non-alcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Casadei-Gardini, A., Rimini, M., Tada, T., et al.[2023]

In a study of 648 matched patients with hepatocellular carcinoma, both atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) led to a significant worsening of liver function, as measured by the ALBI score, over 12 weeks, but there was no significant difference in deterioration rates between the two treatments.

Subgroup analyses indicated that LEN-treated patients with advanced BCLC stage or those receiving the full dose experienced a greater decline in liver function, suggesting that caution is needed when using LEN in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the impact of atezolizumab plus bevacizumab and lenvatinib on the liver function in hepatocellular carcinoma patients: A mixed-effects regression model approach. Hatanaka, T., Kakizaki, S., Hiraoka, A., et al.[2023]

Atezolizumab plus bevacizumab (AB) showed significantly better overall survival (OS) and progression-free survival (PFS) compared to sorafenib, with hazard ratios of 0.58 and 0.59 respectively, indicating its strong efficacy in treating advanced hepatocellular carcinoma (HCC).

When comparing AB to lenvatinib plus pembrolizumab (LP), AB was found to be insignificantly more effective for OS and similarly effective for PFS, suggesting that LP could also be a viable first-line immunotherapy option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect Comparisons via Sorafenib for the Comparative Effectiveness of Two PD-1/PD-L1 Inhibitors to Treat Advanced Hepatocellular Carcinoma Patients without Prior Systemic Therapies. Jiang, Y., Cai, D., Shi, S.[2022]

In a study of 139 advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib, the efficacy in terms of objective response rate and progression-free survival was similar for patients with viral and nonviral infections, indicating that lenvatinib is effective regardless of the infection type.

The 1-year survival rates were 68.7% for patients with viral infections and 59.5% for those with nonviral infections, suggesting that while there is a difference in survival rates, lenvatinib remains a viable treatment option for both groups without significant differences in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib for Hepatocellular Carcinoma Patients with Nonviral Infection Who Were Unlikely to Respond to Immunotherapy: A Retrospective, Comparative Study. Hatanaka, T., Kakizaki, S., Nagashima, T., et al.[2021]

Inhibition of the epidermal growth factor receptor (EGFR) is found to be synthetic lethal with lenvatinib in liver cancer, suggesting that combining EGFR inhibitors like gefitinib with lenvatinib could enhance treatment efficacy.

A clinical trial involving 12 patients with advanced hepatocellular carcinoma (HCC) who did not respond to lenvatinib showed meaningful clinical responses when treated with the combination of lenvatinib and gefitinib, indicating a potential new strategy for about 50% of patients with high EGFR levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFR activation limits the response of liver cancer to lenvatinib. Jin, H., Shi, Y., Lv, Y., et al.[2023]

In a study of 304 patients with hepatocellular carcinoma, the combination of atezolizumab and bevacizumab (ATEZO/BEVA) demonstrated significantly better median progression-free survival (8.3 months) and overall survival compared to lenvatinib (LEN) (6.0 months and 20.2 months, respectively).

While ATEZO/BEVA had a lower incidence of severe adverse events like appetite loss and fatigue compared to LEN, it was associated with a higher rate of severe bleeding, indicating a need for careful monitoring in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Efficacy and Safety of Atezolizumab Plus Bevacizumab and Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis. Niizeki, T., Tokunaga, T., Takami, Y., et al.[2022]

In a systematic review of 8 studies involving 6628 patients with advanced hepatocellular carcinoma (HCC), no significant differences in overall survival (OS) or progression-free survival (PFS) rates were found between the treatment options of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib.

However, Atez/Bev was more beneficial for patients with HCC caused by viral hepatitis, while lenvatinib showed better outcomes for patients with Child-Pugh class B liver function, indicating that treatment effectiveness may vary based on patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib in the treatment of advanced hepatocellular carcinoma: A systematic review and meta-analysis. Du, S., Cao, K., Wang, Z., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12545015/

Cost-effectiveness analysis of cabozantinib plus ... Cabozantinib combined with atezolizumab has been shown to prolong progression-free survival in first-line treatment of advanced hepatocellular ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2589537023005539

Cabozantinib plus atezolizumab in previously untreated ... The results of this study show tolerable safety and potential clinical activity of cabozantinib plus atezolizumab among untreated patients with advanced liver ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00326-6/fulltext

Cabozantinib plus atezolizumab versus sorafenib for ... Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial

4. mdpi.com mdpi.com/2072-6694/15/11/2952

Clinical Outcomes of Cabozantinib in Patients Previously ... (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function ( ...

5. targetedonc.com targetedonc.com/view/cabozantinib-plus-atezolizumab-shows-no-survival-benefit-in-hcc

Cabozantinib Plus Atezolizumab Shows No Overall ... Cabozantinib in combination with atezolizumab shows no effect on survival compared to sorafenib in patients with previously untreated advanced ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10251863/

Clinical Outcomes of Cabozantinib in Patients Previously ... (1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06535737

A Phase 2, Single Arm Study of Cabozantinib in Patients ... There have not been proven therapy for patients with advanced HCC previously treated with atezolizumab and bevacizumab. Cabozantinib is a proven therapy for ...

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa1717002

Cabozantinib in Patients with Advanced and Progressing ... In a phase 2, randomized discontinuation trial, cabozantinib showed clinical activity in patients with advanced hepatocellular carcinoma, ...