Cabozantinib for Liver Cancer

Overseen By Jennifer Knox, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Anticoagulants

Disqualifiers: Brain metastases, Cardiovascular disorders, GI disorders, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of cabozantinib (also known as Cabometyx) for individuals with liver cancer that has returned after a liver transplant. Cabozantinib targets specific proteins that promote cancer growth, potentially controlling the disease. Participants will take a pill daily until it either ceases to be beneficial or causes significant side effects. This trial may suit those with recurrent liver cancer post-transplant who are ineligible for further surgery or local treatments. 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. However, you cannot participate if you are currently receiving other investigational agents or using anticoagulants at therapeutic doses.

Is there any evidence suggesting that cabozantinib is likely to be safe for humans?

Research has shown that cabozantinib is generally safe for people with liver cancer. Studies have found it well-tolerated and effective for those with advanced liver cancer, specifically hepatocellular carcinoma (HCC). In past research, patients who had already tried other treatments for HCC experienced manageable side effects when taking cabozantinib.

Like many medications, cabozantinib can cause side effects, but they are usually not severe. Common side effects might include fatigue, diarrhea, or changes in appetite. However, a doctor can often help manage these.

Overall, cabozantinib has a history of safety in treating liver cancer, which can reassure those considering joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for liver cancer?

Researchers are excited about cabozantinib for liver cancer because it targets cancer differently than traditional treatments like sorafenib or lenvatinib. Unlike these treatments, which primarily focus on blocking blood vessel growth (angiogenesis), cabozantinib inhibits multiple pathways, including MET and AXL, which are involved in tumor growth and metastasis. This multi-target approach could potentially offer better outcomes by cutting off cancer's ability to spread and thrive in multiple ways. Additionally, cabozantinib is taken orally, making it a more convenient option compared to some IV treatments.

What evidence suggests that cabozantinib might be an effective treatment for liver cancer?

Research has shown that cabozantinib, which participants in this trial will receive, may effectively treat liver cancer, specifically hepatocellular carcinoma (HCC). In previous studies, patients taking cabozantinib experienced a median time of 5.2 months during which their cancer did not worsen, and they lived for an average of 11.5 months after starting treatment. Some patients saw their tumors shrink, while others experienced a halt in cancer growth. Cabozantinib blocks proteins that help cancer cells grow, making it a promising option for those whose liver cancer has returned after a liver transplant. ^{1 3 5 6 7}

Who Is on the Research Team?

Jennifer J. Knox, MD, MSc

Principal Investigator

Princess Margaret Cancer Centre

Are You a Good Fit for This Trial?

Adults who've had a liver transplant to treat hepatocellular carcinoma (liver cancer) but now have recurrence. They should not have tried cabozantinib before, may have had one prior therapy for advanced cancer, and must be able to swallow pills. Excluded are those with recent treatments, other serious health issues like infections or heart problems, pregnant women, or anyone with conditions that might interfere with the trial.

Inclusion Criteria

Have histologically or cytologically confirmed hepatocellular carcinoma that has recurred.

No prior treatment with cabozantinib. May be systemic therapy naïve or have received up to 1 line of prior therapy for advanced HCC with sorafenib or lenvatinib.

Agree to use effective contraceptive methods until at least 30 days (for women) and 3 months (for men) after the last administration of study medication. Serum pregnancy test should be negative

Exclusion Criteria

Other clinically significant disorders: Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness, Serious non-healing wound/ulcer/bone fracture, Malabsorption syndrome, Uncompensated/symptomatic hypothyroidism, Requirement for hemodialysis or peritoneal dialysis, Pregnant women

Patients with a grade >= 2 elevated liver enzymes who are suspected of cellular rejection will undergo biopsy. Patients diagnosed with cellular rejection in the biopsy sample using the Banff schema are ineligible

Active hepatitis B or C in liver graft

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Several visits (in-person)

Study Drug Period

Participants receive cabozantinib as prescribed, with weekly clinic visits for tests and assessments

Until no longer beneficial or intolerable side effects occur

Weekly visits (in-person)

End of Study Drug Visit and Follow-up

Participants have an End of Study Drug visit 30 days after the last dose, followed by follow-up visits every 8 weeks

30 days for End of Study Drug visit, then every 8 weeks for follow-up

1 visit (in-person) for End of Study Drug, then every 8 weeks (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib

Trial Overview The study is testing cabozantinib's effectiveness in controlling recurrent liver cancer after a transplant. It targets proteins involved in tumor growth. Participants will take this drug until it stops working for them or side effects become too severe.

How Is the Trial Designed?

Group I: Cabozantinib Experimental Treatment 1 Intervention

Cabozantinib, at a dose of 60 mg orally (by mouth), once a day (at bedtime), continuously.

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 Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Published Research Related to This Trial

In a study of 26 patients with unresectable hepatocellular carcinoma treated with cabozantinib, both full-dose (60 mg) and reduced-dose (40 or 20 mg) groups showed similar efficacy, with objective response rates of 6.7% and 9.1%, respectively.

The reduced-dose group experienced significantly fewer side effects, such as decreased appetite and fatigue, suggesting that lower doses of cabozantinib may be a safer treatment option without compromising effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter retrospective study of initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma. Tomonari, T., Tani, J., Ogawa, C., et al.[2023]

Cabozantinib (Cabometyx) has received approval for the treatment of locally advanced or metastatic differentiated thyroid cancer that has not responded to previous therapies targeting vascular endothelial growth factor receptors.

This approval highlights Cabozantinib's efficacy in addressing a specific type of thyroid cancer that has progressed after other treatments, providing a new option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Cabozantinib. Aschenbrenner, DS.[2023]

In the Phase III CELESTIAL trial, cabozantinib significantly improved overall survival (OS) and progression-free survival (PFS) in hepatocellular carcinoma patients compared to placebo, with the most effective dose being 60 mg daily.

While the 60 mg dose provided the best efficacy outcomes, it also increased the risk of adverse events (AEs); lower doses (20 or 40 mg) reduced the likelihood of AEs like palmar-plantar erythrodysaesthesia and diarrhea, suggesting a balance between maximizing efficacy and minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib exposure-response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma. Nguyen, L., Chapel, S., Tran, BD., et al.[2020]

Cabozantinib is a multi-inhibitor of receptor tyrosine kinases that has shown promise in treating hepatocellular carcinoma (HCC), a common and serious liver cancer, based on data from early and later phase clinical trials.

While cabozantinib has demonstrated efficacy in HCC treatment, further research is necessary to optimize treatment strategies for different patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as a second-line treatment option in hepatocellular carcinoma. D'Angelo, A., Sobhani, N., Bagby, S., et al.[2022]

Cabozantinib (Cabometyx®) is now approved as a first-line treatment for advanced renal cell carcinoma (RCC) in treatment-naïve adults, expanding its use beyond patients who have already received VEGF-targeted therapy.

In a phase 2 trial, cabozantinib significantly improved median progression-free survival and objective response rates compared to the standard treatment sunitinib, while its side effects are manageable, similar to other tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. Lyseng-Williamson, KA.[2020]

Cabozantinib significantly improves overall survival in patients with advanced hepatocellular carcinoma (HCC) who have previously been treated with sorafenib, as demonstrated in the phase III CELESTIAL trial.

While cabozantinib is effective as a second-line and the only third-line treatment for advanced HCC, common side effects include palmar-plantar erythrodysesthesia and hypertension, indicating a need for careful patient management and further research to optimize treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the treatment of hepatocellular carcinoma. Personeni, N., Rimassa, L., Pressiani, T., et al.[2020]

Cabozantinib is an effective treatment for advanced hepatocellular carcinoma in patients previously treated with sorafenib, showing improved overall survival and progression-free survival compared to placebo in the phase III CELESTIAL study.

While cabozantinib can cause common adverse events like fatigue and gastrointestinal issues, these can be managed with supportive care and dose adjustments, allowing for continued treatment with a low rate of discontinuation due to side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Events Associated with Cabozantinib Treatment in Patients with Advanced Hepatocellular Carcinoma. Schwartz, G., Darling, JO., Mindo, M., et al.[2021]

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]

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]

Cabozantinib effectively targets the c-MET/ERK/p21/PKM2 signaling pathway and inhibits angiogenesis in hepatocellular carcinoma (HCC), showing stable disease in certain mouse models, but it has limited efficacy against other tumor types like Akt/Ras and c-Myc liver tumors.

Combining cabozantinib with the mTOR inhibitor MLN0128 resulted in tumor regression in specific HCC mouse models, while combining it with the checkpoint inhibitor anti-PD-L1 did not enhance therapeutic benefits, suggesting that mTOR inhibitors may be a more effective partner for cabozantinib in HCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma. Shang, R., Song, X., Wang, P., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7395054/

Cabozantinib for the Treatment of Advanced ... The median progression-free survival (PFS) and overall survival (OS) were 5.2 and 11.5 months, respectively. The observed effects were independent of prior ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34414123/

Cabozantinib in Advanced Hepatocellular Carcinoma The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) ...

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

Cabozantinib in Patients with Advanced and Progressing ... Results. At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo.

4. cabometyxhcp.com cabometyxhcp.com/hcc-treatment

Hepatocellular Carcinoma (HCC) Treatment Option for ... The primary efficacy outcome measure was OS. Secondary endpoints were PFS and ORR. Median OS was 10.2 months with CABOMETYX (n=470) vs 8.0 months with placebo ( ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1665268125001425

Real-world efficacy of cabozantinib alone or in combination ... This real-world data demonstrated that cabozantinib is effective, well-tolerated, and feasible in patients with HCC refractory to multiple lines of systemic ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40795838/

Real-world clinical outcomes of cabozantinib as a second- ... Conclusions: Cabozantinib shows consistent effectiveness and safety in the 2L HCC setting following prior TKIs or IO-based regimens in real- ...

7. academic.oup.com academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyaf252/8229573?searchresult=1

Real-world clinical outcomes of cabozantinib as a second-line ... Clinical outcomes for 2L cabozantinib were consistent regardless of 1L therapy, with a median rwTTD of 3.2 months and rwTNTD of 7.6 months ...