Cabozantinib + Nivolumab for Colorectal Cancer

Recruiting at 4 trial locations

Overseen By Matt Lee

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: MSI-H, Brain metastases, Autoimmune, 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: up to 24 months

48 Participants Needed

Trial Summary

What is the purpose of this trial?

Data from a prior phase II study of single agent cabozantinib in metastatic, refractory colorectal cancer (NCT03542877) combined with the compelling preclinical data in colorectal mouse models utilizing cabozantinib combined with nivolumab have led to this concept for a clinical trial to combine cabozantinib and nivolumab in patients with metastatic MSS CRC in the third line setting and beyond.

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 have received certain treatments like chemotherapy or biologic agents within a few weeks before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Cabozantinib and Nivolumab for colorectal cancer?

Research shows that Cabozantinib can make certain colorectal cancers more responsive to Nivolumab, a type of immune therapy, by changing how the immune system interacts with the cancer. In studies with mice, this combination slowed tumor growth more effectively than Nivolumab alone, suggesting potential benefits for patients with specific types of colorectal cancer. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Nivolumab safe for humans?

The combination of Cabozantinib and Nivolumab has been studied for safety in conditions like advanced renal cell carcinoma and hepatocellular carcinoma. Common side effects reported include fatigue, diarrhea, high blood pressure, and skin reactions on the hands and feet. These findings suggest that while the combination is generally safe, it can cause some significant side effects. ^{1 2 6 7 8}

How is the drug combination of Cabozantinib and Nivolumab unique for colorectal cancer?

The combination of Cabozantinib and Nivolumab is unique for treating microsatellite stable colorectal cancer, which typically does not respond to immune checkpoint inhibitors alone. Cabozantinib helps make these tumors more responsive to Nivolumab by modulating the immune system, potentially leading to better outcomes compared to other treatments. ^{1 9 10 11 12}

Research Team

Alexis Leal, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

This trial is for adults with metastatic or unresectable colorectal adenocarcinoma that's microsatellite stable (MSS) or has proficient mismatch repair. They must have tried certain cancer treatments without success and be in good health otherwise. Women of childbearing potential and sexually active men must agree to use contraception during the study.

Inclusion Criteria

I can have a biopsy on my cancer before starting the study drug.

I am fully active or restricted in physically strenuous activity but can do light work.

I understand the study requirements and have signed the consent form.

Exclusion Criteria

My tumor is growing into or around major blood vessels.

I have lung disease that causes symptoms or could affect lung-related side effects from treatment.

I haven't taken high-dose steroids or immunosuppressants in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib 40 mg orally daily in combination with nivolumab 480 mg IV every 28 days

up to 24 months

1 visit every 28 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cabozantinib
• Nivolumab

Trial Overview The trial tests a combination of Cabozantinib, a drug targeting cancer growth pathways, and Nivolumab, an immunotherapy drug, in patients who've had at least two other types of treatment for colorectal cancer. It aims to see if this combo is effective when others aren't.

Participant Groups

Group I: Cabozantinib 40 mg orally daily in combination with nivolumab 480 mg IV every 28 days. Experimental Treatment 2 Interventions

Cabozantinib is supplied as 20-mg tablets and will be administered orally at a dose of 40 mg/day. Nivolumab is supplied in 100 mg/Vial (10 mg/mL) vials and will be administered IV at a dose of 480 mg every 28 days.

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 Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

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

Criterium, Inc.

Industry Sponsor

Trials

18

Recruited

730+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

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 phase II trial involving 47 patients with advanced non-clear-cell renal cell carcinoma, the combination of cabozantinib and nivolumab showed a promising objective response rate of 47.5% in patients with papillary, unclassified, or translocation-associated RCC, along with a median progression-free survival of 12.5 months.

The treatment was less effective in chromophobe RCC, with no objective responses observed, highlighting the need for further research into genomic predictors of response, particularly mutations like NF2 and FH that were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Lee, CH., Voss, MH., Carlo, MI., et al.[2023]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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]

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]

In a phase Ib trial involving 35 patients with advanced gastrointestinal cancers, the combination of cabozantinib and durvalumab showed a tolerable safety profile with no dose-limiting toxicities and a 34% rate of grade 3/4 treatment-related adverse events.

The treatment demonstrated potential efficacy, with an objective response rate of 30% and a disease control rate of 83.3%, particularly in patients with a PD-L1 combined positive score (CPS) ≥5, who experienced better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. Saeed, A., Park, R., Dai, J., et al.[2023]

Nivolumab, a PD-1 inhibitor, is approved for treating various cancers, including metastatic colorectal cancer with specific genetic markers (deficient mismatch repair or microsatellite-instability high).

The FDA granted accelerated approval for nivolumab in July 2017 for patients with this type of colorectal cancer who have not responded to standard chemotherapy, highlighting its potential efficacy in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. Mehrvarz Sarshekeh, A., Overman, MJ., Kopetz, S.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint blockade by immune modulation in human immune system mouse models. [2022]

2. 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]

3. 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]

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

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. [2023]

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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

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

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

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

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

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. [2022]

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

Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer. [2023]

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

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of microsatellite instability high metastatic colorectal cancer. [2022]

12. England pubmed.ncbi.nlm.nih.gov

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer. [2023]