Cabozantinib + Nivolumab + Ipilimumab for Thyroid Cancer

Recruiting at 35 trial locations

Overseen By Prakash C. Neupane

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Oral anticoagulants, Immunosuppressants

Disqualifiers: Other malignancy, 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: 14

Duration: 6 months

11 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with certain types of thyroid cancer that resist standard radioactive iodine therapy. It combines three medications: cabozantinib (also known as Cabometyx or Cometriq), which may slow tumor growth, and nivolumab and ipilimumab, immunotherapy drugs designed to enhance the body's immune response against cancer. The goal is to determine if this combination outperforms typical chemotherapy treatments. This trial may suit those with differentiated thyroid cancer that has worsened after VEGFR-targeted treatment and does not absorb radioactive iodine. As a Phase 2 trial, the research focuses on evaluating 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 must stop taking your current medications. However, you cannot take certain medications like strong CYP3A4 inducers or require systemic corticosteroids above a certain dose. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

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

Research has shown that the combination of cabozantinib, nivolumab, and ipilimumab has been tested for safety in people. Some side effects have occurred. For instance, about 11% of patients taking cabozantinib and nivolumab experienced significant increases in liver enzymes, indicating liver stress.

This combination treatment may also cause the immune system to mistakenly attack normal organs, affecting their function. However, studies suggest that careful management can address these side effects, possibly through dose adjustments or additional treatments.

Overall, while risks exist, the safety of this combination is considered manageable with proper monitoring and care. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cabozantinib, nivolumab, and ipilimumab for thyroid cancer because it offers a unique multi-targeted approach. Unlike standard treatments like radioactive iodine or surgery, this combination includes a tyrosine kinase inhibitor (cabozantinib), which can block signals that promote cancer growth, alongside two immune checkpoint inhibitors (nivolumab and ipilimumab) that help the immune system recognize and attack cancer cells. This powerful trio not only targets cancer cells directly but also boosts the body's immune response, potentially leading to better outcomes for patients.

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

Research has shown that the combination of cabozantinib, nivolumab, and ipilimumab, which participants in this trial will receive, may help treat thyroid cancer unresponsive to other treatments. Studies have found that cabozantinib stops tumor growth by blocking certain proteins. Nivolumab and ipilimumab enhance the immune system's ability to attack cancer cells. Additionally, research found that patients with specific markers, such as high levels of PD-L1, had better survival rates with these treatments. This combination could offer hope when other therapies have failed. ^{2 3 6 7 8}

Who Is on the Research Team?

Bhavana Konda

Principal Investigator

Ohio State University Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced differentiated thyroid cancer that's resistant to radioactive iodine and has worsened after VEGFR-targeted therapy. They must have measurable disease, not be pregnant, agree to use contraception, and be able to swallow pills. Excludes those with certain other cancers within the last 2 years or specific health conditions.

Inclusion Criteria

I have someone legally authorized to make decisions for me due to my impaired decision-making capacity.

I have HIV, am on treatment, and my viral load is undetectable.

My thyroid cancer does not respond to radioactive iodine treatment.

Exclusion Criteria

I am not on any medications that are not allowed in the study.

My cancer has not spread to major blood vessels or the GI tract.

I do not have untreated brain or spinal cord cancer spread.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Pre-Treatment

Patients receive cabozantinib S-malate orally once daily on days -14 to -1 prior to cycle 1

2 weeks

1 visit (in-person)

Treatment

Patients receive cabozantinib S-malate, nivolumab, and ipilimumab. Treatment repeats every 42 days for cycles 1-4 and every 28 days for subsequent cycles.

6 months

Multiple visits (in-person and virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib S-malate
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing a combination of three drugs: Cabozantinib (blocks enzymes for cell growth), Nivolumab, and Ipilimumab (both boost the immune system against cancer). It aims to see if this trio is more effective than standard chemotherapy treatments for this type of thyroid cancer.

How Is the Trial Designed?

Group I: Treatment (cabozantinib S-malate, nivolumab, ipilimumab) Experimental Treatment 6 Interventions

Patients receive cabozantinib S-malate PO QD on days -14 to -1 prior to cycle 1, days 1-42 of cycles 1-4 and days 1-28 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on days 1, 15, and 29 of cycles 1-4 and day 1 of subsequent cycles and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Treatment repeats every 42 days for cycles 1-4 and every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI during screening, and blood sample collection throughout the study.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39133806/

Cabozantinib Plus Ipilimumab/Nivolumab in Patients With ... This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0305737225001641

Effectiveness of immune checkpoint inhibitor therapy in ... Biomarker analysis from 3 studies revealed improved survival outcomes in patients with high PD-L1 expression, TMB-H and cytotoxic T-cell markers ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03914300?cond=%22Papillary%20Carcinoma%22&intr=%22immunoglobulins%22&viewType=Table&rank=2

Testing the Combination of Cabozantinib, Nivolumab, and ... This phase II trial studies how well cabozantinib, nivolumab, and ipilimumab work in treating patients with differentiated thyroid cancer that does not ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11834700/

Cabozantinib Plus Ipilimumab/Nivolumab in Patients With ... This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in ...

5. opdivohcp.com opdivohcp.com/efficacy/rcc/opdivo-cabometyx

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib ... Nivolumab plus cabozantinib versus sunitinib for previously untreated advanced renal cell carcinoma: results from 55-month followup of the CheckMate 9ER trial.

6. opdivohcp.com opdivohcp.com/safety/rcc/opdivo-cabometyx

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib) Safety ... In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Immune-Mediated Endocrinopathies. OPDIVO and ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S030573722100181X

Management of adverse events associated with ... The safety profile was manageable with prophylaxis, supportive care, dose holds and reductions for cabozantinib, and dose holds and immunosuppressive therapy ...

8. opdivo.com opdivo.com/side-effects

What you should know about side effects OPDIVO and OPDIVO Qvantig can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work.