Cabozantinib + Immunotherapy for Cancer

Not currently recruiting at 59 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Anticoagulants, CYP3A4 inducers

Disqualifiers: Autoimmune disease, Uncontrolled hypertension, 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: 1

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates whether a combination of three treatments—cabozantinib, nivolumab, and ipilimumab—can effectively shrink poorly differentiated neuroendocrine tumors. Cabozantinib (Cabometyx) may block enzymes that promote tumor growth, while nivolumab and ipilimumab are immunotherapies that could enable the immune system to attack the cancer. Individuals with these specific tumors who have tried only one other cancer treatment without success might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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 take certain medications like strong CYP3A4 inducers or systemic corticosteroids above a certain dose. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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 in patients with various cancers, including advanced kidney cancer. Studies have found these treatments to be generally well-tolerated.

One study found this combination to be safe and effective for several cancer types, with a 38% response rate in some rare tumors. Additionally, using nivolumab and ipilimumab together has been linked to a 28% reduction in the risk of death for patients with advanced kidney cancer.

However, these treatments can have side effects. They boost the immune system to attack cancer cells, which can sometimes cause the immune system to attack healthy cells as well. Participants in these studies have experienced various side effects, but these treatments have been approved for certain cancers, indicating their safety when used under medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cabozantinib, ipilimumab, and nivolumab because it offers a unique approach to cancer treatment that could enhance effectiveness against tumors. Unlike many standard cancer treatments that focus solely on one mechanism, this combo utilizes a multi-pronged attack: cabozantinib inhibits tumor growth by blocking certain proteins, while ipilimumab and nivolumab are immunotherapy drugs that help the immune system better recognize and fight cancer cells. This synergistic effect has the potential to improve patient outcomes by not only targeting the cancer directly but also empowering the body's own defenses to join the fight more effectively.

What evidence suggests that this combination treatment could be effective for neuroendocrine tumors?

Research has shown that a combination of three drugs—cabozantinib, nivolumab, and ipilimumab—may effectively treat various types of cancer. In this trial, participants will receive this combination treatment. Studies have found that this combination can help patients live longer without their cancer worsening, particularly in kidney cancer. Specifically, patients taking cabozantinib and nivolumab had a 49% lower chance of their cancer spreading or growing compared to those taking another drug called sunitinib. This combination works because cabozantinib inhibits enzymes that promote tumor growth, while nivolumab and ipilimumab enhance the immune system to attack cancer cells. Although data for poorly differentiated neuroendocrine tumors is limited, the mechanism of these drugs and early results in other cancers suggest potential effectiveness. ^{1 3 5 6 7}

Who Is on the Research Team?

Anteneh A Tesfaye

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with poorly differentiated neuroendocrine tumors, excluding small cell lung cancer and merkel cell carcinoma. Participants must have only failed one prior treatment, have measurable disease, and be able to perform daily activities (ECOG <=2). They should not be pregnant or breastfeeding and must agree to use contraception. People who've had major surgery recently, those with active autoimmune diseases or a history of severe allergies to similar drugs are excluded.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

Your hemoglobin level must be at least 9 grams per deciliter.

PT/INR and PTT test < 1.3 x ULN

Exclusion Criteria

I have previously been treated with cabozantinib or other MET-targeting therapies.

I need treatment with strong medications that change how my body processes drugs.

I haven't had chemotherapy or certain drugs within the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib s-malate orally once daily, nivolumab intravenously over 30 minutes, and ipilimumab intravenously over 90 minutes. Treatment repeats every 21 days for 4 cycles, then every 28 days for subsequent cycles.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4 weeks

1 visit (in-person) at 4 weeks, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab
• Nivolumab

Trial Overview The study tests the effectiveness of combining XL184 (cabozantinib), nivolumab, and ipilimumab in treating certain neuroendocrine tumors. Cabozantinib may block enzymes needed for tumor growth while nivolumab and ipilimumab could help the immune system fight cancer by interfering with tumor growth.

How Is the Trial Designed?

Group I: Treatment (cabozantinib s-malate, nivolumab, ipilimumab) Experimental Treatment 3 Interventions

Patients receive cabozantinib s-malate PO QD on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Cabozantinib combined with nivolumab (CaboNivo) and with ipilimumab (CaboNivoIpi) showed manageable safety profiles, with 75% and 87% of patients experiencing grade 3 or 4 treatment-related adverse events, respectively, including fatigue and hypertension.

The treatment demonstrated promising efficacy, with an overall response rate of 30.6% and a median overall survival of 12.6 months for all patients, while patients with metastatic urothelial carcinoma had even better outcomes, with a median overall survival of 25.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. Apolo, AB., Nadal, R., Girardi, DM., et al.[2023]

In a phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

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]

Cabozantinib (CAB) has shown significant improvements in overall survival and progression-free survival in phase-III studies for patients with advanced renal cell carcinoma and hepatocellular carcinoma, leading to its approval in Japan for these conditions.

CAB may enhance antitumor immunity and, when combined with PD-1 checkpoint inhibitors like nivolumab, has demonstrated increased progression-free survival compared to standard treatments, indicating a potential synergistic effect in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX&#174;)]. Osaka, T., Yamaguchi, N., Hara, T.[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]

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]

Cabozantinib combined with nivolumab is shown to be superior in terms of progression-free survival (PFS) compared to axitinib + pembrolizumab and nivolumab + ipilimumab for the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC), based on a systematic review of four randomized controlled trials involving treatment-naïve patients.

While cabozantinib + nivolumab demonstrated effectiveness, the combination of lenvatinib + pembrolizumab showed numerical superiority in overall survival, indicating that while cabozantinib + nivolumab is a strong option, other combinations may also be effective and warrant consideration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab. Niewada, M., Macioch, T., Konarska, M., 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]

In a review of 129 oncology patients treated with immune checkpoint inhibitors, 51.9% experienced at least one immune-related adverse event (irAE), highlighting the common occurrence of these side effects.

Nearly half of the irAEs were managed according to established guidelines, but there was significant variability in documentation and management practices, indicating a need for improved adherence as immunotherapy use increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Adherence to Toxicity Management Guidelines for Immune-Related Adverse Events. Teimouri, A., Minard, LV., Scott, SN., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4539

Analysis of phase II study of cabozantinib (Cabo) with ... Reduction of the starting dose of Cabo to 20 mg/d in combination with Nivo/Ipi results in numerically lower ≥ grade 3 TrAEs than starting at 40 mg/d.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38954785/

Final Results From a Phase I Trial and Expansion Cohorts of ... CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, ...

3. opdivo.com opdivo.com/advanced-kidney-cancer/clinical-trial-results/opdivo-cabometyx-immunotherapy-combination

Clinical trial results for advanced kidney cancer (renal cell ... People given OPDIVO + CABOMETYX had a 49% lower risk of their cancer spreading, growing, or getting worse than those given SUTENT. More people given OPDIVO + ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212851

Cabozantinib plus Nivolumab and Ipilimumab in Renal- ... Treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03866382

Study Details | NCT03866382 | Testing the Effectiveness of ... This phase II trial studies how well cabozantinib works in combination with nivolumab and ipilimumab in treating patients with rare genitourinary (GU) tumors.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02233

Final Results From a Phase I Trial and Expansion Cohorts ... We report an overall response rate of 38%, with notable efficacy in rare tumor types, such as penile carcinoma, bladder adenocarcinoma, and ...

7. news.bms.com news.bms.com/news/details/2024/Eight-Year-Data-for-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Continue-to-Demonstrate-Longest-Survival-Benefit-vs.-Sunitinib-Reported-in-Patients-with-Previously-Untreated-Advanced-or-Metastatic-Renal-Cell-Carcinoma/default.aspx

Eight-Year Data for Opdivo (nivolumab) Plus Yervoy ... Patients with previously untreated advanced or metastatic renal cell carcinoma treated with Opdivo plus Yervoy experienced a 28% reduction in the risk of death ...