Cabozantinib + Immunotherapy + TACE for Liver Cancer

Overseen By Chao Family Comprehensive Cancer Center University of California, Irvine

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Irvine

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Systemic cancer treatment, 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: 9-12 weeks

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of combining drugs and a procedure to treat liver cancer that surgery cannot remove. It uses cabozantinib (Cabometyx) with two immunotherapy drugs, ipilimumab and nivolumab, alongside transarterial chemoembolization (TACE), which delivers chemotherapy directly to the liver. The trial targets individuals diagnosed with hepatocellular carcinoma (a type of liver cancer) who have at least one tumor treatable with TACE. 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 does not specify if you need to stop taking your current medications, but you cannot be on certain blood thinners like warfarin or certain other investigational drugs. It's best to discuss your current medications with the trial team to see if they are allowed.

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

Research has shown that combining cabozantinib with nivolumab and ipilimumab may help treat advanced liver cancer. Although this combination can be effective, safety remains a major concern. Patients often experience side effects common to cancer treatments, such as tiredness, diarrhea, and changes in liver function. Earlier studies on similar treatments have demonstrated that, while effective, they may also cause serious side effects. Participants should discuss these potential risks with their doctors before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Cabozantinib, Ipilimumab/Nivolumab, and TACE for liver cancer because it brings together multiple innovative approaches. Unlike traditional treatments that may focus solely on one method, this combination harnesses the power of targeted therapy with Cabozantinib, which inhibits tumor growth by blocking specific proteins in cancer cells. It also leverages the immune-boosting effects of immunotherapies like Ipilimumab and Nivolumab, which help the body's immune system recognize and destroy cancer cells more effectively. Finally, TACE (Transarterial Chemoembolization) directly targets the liver tumor, delivering chemotherapy precisely where it's needed while minimizing exposure to the rest of the body. This multi-pronged approach has the potential to offer more comprehensive and effective treatment for liver cancer compared to existing options.

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

This trial will evaluate the combination of cabozantinib, ipilimumab, nivolumab, and transarterial chemoembolization (TACE) for treating advanced liver cancer, specifically hepatocellular carcinoma (HCC). Research has shown that cabozantinib, ipilimumab, and nivolumab together may improve patient outcomes and survival rates. Early results from the CheckMate 040 study suggested that this drug combination can be effective for patients with HCC who have already tried other treatments. These drugs work by boosting the body's immune system to fight cancer cells. The trial will also investigate whether adding TACE can enhance the effectiveness of these treatments. ^{1 2 3 5 6}

Who Is on the Research Team?

Farshid Dayyani

Principal Investigator

Chao Family Comprehensive Cancer Center

Are You a Good Fit for This Trial?

Adults with hepatocellular carcinoma (HCC) who can't have curative treatments like surgery or transplantation. They must be physically able to perform daily activities with minimal assistance, have a tumor treatable by TACE, good liver function (Child-Pugh A-B7), and adequate blood and organ function. Women of childbearing potential and men must use contraception during the trial.

Inclusion Criteria

My blood and organ tests meet the required levels for treatment.

I agree to use birth control or abstain from sex during and for 4 months after the study.

I am using effective birth control while being treated with ipilimumab and will continue for 3 months after the last dose.

Exclusion Criteria

You cannot be taking any other experimental drugs.

I have received treatments that travel through my bloodstream to reach cancer cells anywhere in my body.

All my side effects from cancer treatment have improved, except for hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Cabozantinib, Ipilimumab/Nivolumab, and TACE. Cabozantinib is administered daily on days 1-28 of a 28-day cycle, Nivolumab on day 1 of a 28-day cycle (cycle 2 and beyond), and Ipilimumab on day 1 of a 21-day cycle. TACE may be done up to 3 times within 9-12 weeks.

9-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of overall survival and adverse events.

4 weeks

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival up to 18 months after the last patient is enrolled.

Up to 18 months

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab/Nivolumab
• Transarterial Chemoembolization

Trial Overview The trial is testing the effectiveness of cabozantinib combined with ipilimumab/nivolumab and transarterial chemoembolization (TACE) in treating HCC. It's an open-label study where all participants receive the same treatment without being compared to a control group.

How Is the Trial Designed?

Group I: Cabozantinib with Ipilimumab/Nivolumab and TACE Experimental Treatment 4 Interventions

Subjects receive Cabozantinib 40 mg daily on days 1-28 of a 28 day cycle, this is to be started 7-14 days after the last TACE procedure. Nivolumab 480 mg IV on day 1 of a 28 day cycle (cycle 2 and beyond), this is to be started 7-14 days after the last TACE procedure. Nivolumab: 3mg/kg IV on day 1 of a 21 day cycle x 1 dose. Ipilimumab: 1 mg/kg on day 1 of a 21 day cycle x 1 dose TACE: Within 3-4 weeks of cycle 1 day 1; may be done up to 3 times (9-12 weeks total), the intervals between each TACE treatment can vary based on investigator's discretion

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

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

In a study of 71 patients with advanced hepatocellular carcinoma, the combination of nivolumab and cabozantinib showed promising antitumor activity, with an objective response rate of 17% for the doublet therapy and 29% for the triplet therapy including ipilimumab.

Both treatment combinations had manageable safety profiles, with 50% of patients in the doublet arm and 74% in the triplet arm experiencing grade 3-4 treatment-related adverse events, but no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. Yau, T., Zagonel, V., Santoro, A., et al.[2023]

The combination of cabozantinib and anti-PD1 significantly improved antitumor efficacy in experimental models of hepatocellular carcinoma (HCC) compared to either treatment alone, indicating a promising therapeutic strategy.

Cabozantinib alone increased neutrophil infiltration and reduced certain T-cell populations, while its combination with anti-PD1 further enhanced these effects and improved overall T-cell proportions, suggesting a mechanism that boosts both innate and adaptive immune responses against HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma. Esteban-Fabró, R., Willoughby, CE., Piqué-Gili, M., et al.[2023]

In a phase 1/2 study involving 148 patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, the combination of nivolumab and ipilimumab showed a promising objective response rate of 32% in one treatment arm, indicating potential efficacy for this patient population.

The treatment regimen was generally manageable in terms of safety, although 94% of patients in one arm experienced treatment-related adverse events, highlighting the need for careful monitoring; notably, this combination therapy received accelerated approval in the US based on these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. Yau, T., Kang, YK., Kim, TY., et al.[2022]

In a study of 346 patients receiving cabozantinib (CABO) as second-line therapy after various first-line treatments, the median overall survival was 21.4 months for those who previously received ipilimumab-nivolumab (IPI-NIVO), indicating that CABO is effective regardless of the initial treatment.

The median time to treatment failure for CABO was 7.6 months, suggesting that it provides a clinically meaningful benefit as a second-line option after different first-line therapies, including immunotherapy and VEGF inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CABOSEQ: The Effectiveness of Cabozantinib in Patients With Treatment Refractory Advanced Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Navani, V., Wells, JC., Boyne, DJ., et al.[2023]

In the COSMIC-312 trial involving 837 patients with advanced hepatocellular carcinoma, the combination of cabozantinib and atezolizumab showed a median progression-free survival of 6.8 months, significantly longer than the 4.2 months observed with sorafenib, indicating improved efficacy for the combination treatment.

While the overall survival rates were similar between the combination treatment and sorafenib (15.4 months vs. 15.5 months), the combination was associated with a higher incidence of serious treatment-related adverse events, suggesting a need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Kelley, RK., Rimassa, L., Cheng, AL., et al.[2022]

In a study of 26 patients with advanced hepatocellular carcinoma (HCC) who progressed on immunotherapy, cabozantinib treatment resulted in a median overall survival of 7.7 months, suggesting it may provide a benefit after immunotherapy failure.

The median progression-free survival on cabozantinib was 2.1 months, indicating that while the treatment may extend survival, the duration of benefit may be limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib Following Immunotherapy in Patients with Advanced Hepatocellular Carcinoma. Storandt, MH., Gile, JJ., Palmer, ME., et al.[2023]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., et al.[2023]

Combining cabozantinib, a multikinase inhibitor, with atezolizumab, an immune checkpoint inhibitor, shows promising synergistic effects in treating advanced hepatocellular carcinoma (HCC), supported by preclinical studies and early-phase clinical trials.

The phase 3 COSMIC-312 trial is evaluating this combination as a first-line treatment for advanced HCC, indicating a potential shift in treatment strategies, although careful patient selection and study design will be crucial for future approvals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus atezolizumab for the treatment of advanced hepatocellular carcinoma: shedding light on the preclinical rationale and clinical trials. Cammarota, A., Zanuso, V., D'Alessio, A., et al.[2022]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

Cabozantinib is an effective treatment for advanced hepatocellular carcinoma (HCC) after failure of sorafenib, showing significant improvement in overall survival and progression-free survival compared to placebo in the phase 3 CELESTIAL trial.

Common side effects of cabozantinib include palmar-plantar erythrodysesthesia, hypertension, fatigue, and diarrhea, which are important to manage in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. Trojan, J.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04472767

Study Details | NCT04472767 | Cabozantinib Combined ... This is a phase 2 single-arm, open-label clinical trial determining efficacy of cabozantinib in combination with ipilimumab/nivolumab and transarterial ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38247721/

Combining cabozantinib, nivolumab and ipilimumab in ... Combining cabozantinib, nivolumab and ipilimumab in advanced hepatocellular carcinoma: does benefit outweigh toxicity?

3. aging.networkofcare.org aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT04472767?keyword=%22TACE%22

Cabozantinib Combined With Ipilimumab/Nivolumab and ... This is a phase 2 single-arm, open-label clinical trial determining efficacy of cabozantinib in combination with ipilimumab/nivolumab and transarterial ...

4. targetedonc.com targetedonc.com/view/nivolumab-plus-cabozantinib-shows-early-promise-in-advanced-hcc

Nivolumab Plus Cabozantinib Shows Early Promise in ... According to early results from CheckMate 040, nivolumab plus cabozantinib with or without ipilimumab showed good clinical activity and survival.

5. gastroenterologyandhepatology.net gastroenterologyandhepatology.net/archives/february-2021/nivolumab-and-ipilimumab-combination-therapy-for-second-line-treatment-of-hepatocellular-carcinoma/

Nivolumab and Ipilimumab Combination Therapy for Second ... Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 ...

6. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-cabozantinib-combination-nivolumab-and

Press Releases - Exelixis, Inc. ... (OS), the combination of cabozantinib, nivolumab and ipilimumab versus the combination of nivolumab and ipilimumab did not demonstrate a significant benefit.