Cabozantinib + Immunotherapy + TACE for Liver Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Farshid Dayyani

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of California, Irvine

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Systemic cancer treatment, Autoimmune disease, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a phase 2 single-arm, open-label clinical trial determining efficacy of cabozantinib in combination with ipilimumab/nivolumab and transarterial chemoembolization (TACE) in subjects with hepatocellular carcinoma (HCC). These are subjects who are not candidates for curative intent treatment.

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.

What data supports the effectiveness of the treatment Cabozantinib + Immunotherapy + TACE for Liver Cancer?

Research shows that combining cabozantinib with immunotherapy drugs like nivolumab and ipilimumab can improve outcomes for patients with advanced liver cancer. Studies have demonstrated that these combinations can enhance the body's immune response against cancer cells, potentially leading to better treatment results. ^{1 2 3 4 5}

Is the combination of Cabozantinib, Immunotherapy, and TACE safe for humans?

The combination of Cabozantinib (Cabometyx) with immunotherapy drugs like Nivolumab (Opdivo) and Ipilimumab (Yervoy) has been studied for safety in liver cancer and other conditions. Common side effects include hand-foot syndrome (skin reaction on palms and soles), high blood pressure, tiredness, and diarrhea. These treatments have been used in advanced liver and kidney cancers, showing a safety profile that includes these manageable side effects. ^{1 4 6 7 8}

What makes the Cabozantinib + Immunotherapy + TACE treatment unique for liver cancer?

This treatment is unique because it combines cabozantinib, a multikinase inhibitor that targets cancer growth pathways, with immunotherapy drugs like nivolumab and ipilimumab, which help the immune system attack cancer cells, and TACE (transarterial chemoembolization), a procedure that delivers chemotherapy directly to the liver tumor. This combination aims to enhance the immune response and directly target the tumor, offering a potentially more effective approach for advanced liver cancer. ^{1 3 4 9 10}

Research Team

Farshid Dayyani

Principal Investigator

Chao Family Comprehensive Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Cabozantinib (Tyrosine Kinase Inhibitor)
• Ipilimumab/Nivolumab (Checkpoint Inhibitor)
• Transarterial Chemoembolization (Procedure)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Chad T. Lefteris

University of California, Irvine

Chief Executive Officer since 2019

MBA from University of California, Irvine

Michael J. Stamos

University of California, Irvine

Chief Medical Officer since 2019

MD, PhD from University of California, Irvine

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

Findings from Research

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 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 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]

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 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]

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 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]

References

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

Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma. [2023]

2. United States 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. [2022]

4. United States 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. [2023]

5. United States 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). [2023]

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

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

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

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. [2023]

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

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

9. England pubmed.ncbi.nlm.nih.gov

Cabozantinib plus atezolizumab for the treatment of advanced hepatocellular carcinoma: shedding light on the preclinical rationale and clinical trials. [2022]

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

Cabozantinib Following Immunotherapy in Patients with Advanced Hepatocellular Carcinoma. [2023]