Cabozantinib + Nivolumab + Ipilimumab for Soft Tissue Sarcoma

Recruiting at 3 trial locations

Overseen By Brian A Van Tine, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Anticoagulants, Corticosteroids

Disqualifiers: Brain metastases, 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: Unknown

Duration: Up to 2 years

105 Participants Needed

Trial Summary

What is the purpose of this trial?

The hypothesis of this study is that the response rate of soft tissue sarcoma will be improved with the addition of PD-1 and CTLA-4 inhibition to cabozantinib, and that cabozantinib priming will increase the response to nivolumab and ipilimumab.

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 participate if you are currently receiving other investigational agents or certain types of anticoagulants, and there are restrictions on recent use of some cancer therapies. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug combination of Cabozantinib, Nivolumab, and Ipilimumab for treating soft tissue sarcoma?

Research shows that the combination of Nivolumab and Ipilimumab has been effective in treating soft tissue sarcoma, with some patients experiencing tumor shrinkage or stable disease. This suggests that combining these drugs with Cabozantinib might also be beneficial. ^{1 2 3 4 5}

What safety data exists for the combination of Cabozantinib, Nivolumab, and Ipilimumab?

The combination of Cabozantinib, Nivolumab, and Ipilimumab has been studied for safety in various cancers. In advanced soft tissue sarcoma, common side effects included fatigue and cough, with some patients experiencing serious side effects like high blood sugar and heart inflammation. In other cancers, safety data is still being evaluated, but these treatments are generally considered to have manageable side effects. ^{1 4 6 7 8}

What makes the drug combination of Cabozantinib, Nivolumab, and Ipilimumab unique for treating soft tissue sarcoma?

This drug combination is unique because it combines Cabozantinib, a medication that targets cancer cell growth, with Nivolumab and Ipilimumab, which are immunotherapy drugs that help the immune system attack cancer cells. This approach is novel for soft tissue sarcoma, a condition with limited treatment options, and aims to enhance the effectiveness of the immune response against the cancer. ^{1 2 3 4 6}

Research Team

Brian A Van Tine, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with advanced soft tissue sarcoma, who have tried at least one but no more than two previous treatments without success. They must be able to measure their cancer, have normal organ and bone marrow function, and not be on certain medications or have specific health conditions like brain metastases or active infections.

Inclusion Criteria

You have tumors that can be measured and are at least 10mm in size on CT scan or 20mm on chest x-ray, or can be measured using calipers during a clinical exam.

Your platelet count is at least 100,000 per cubic millimeter of blood without any transfusion.

My condition worsened after 1-2 treatments.

Exclusion Criteria

I have a history of lung scarring or inflammation not caused by infections.

I am currently being treated for an infection.

I haven't had cancer treatment in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib, nivolumab, and ipilimumab. Nivolumab and ipilimumab are given every 3 weeks for 4 doses, followed by nivolumab every 4 weeks. Cabozantinib is taken daily.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Long-term follow-up

Participants are monitored for overall survival and quality of life

Up to 5 years

Treatment Details

Interventions

• Cabozantinib
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing if combining Cabozantinib (a drug that targets tumor growth) with Nivolumab and Ipilimumab (drugs that boost the immune system) can better treat soft tissue sarcoma compared to current therapies.

Participant Groups

Group I: Crossover from Cohort A to Cohort B: Cabozantinib + Nivolumab + Ipilimumab Experimental Treatment 3 Interventions

-Participants who cross-over from Cohort A into Cohort B will initiate treatment with nivolumab at a dose of 3 mg/kg IV over approximately 30 minutes and ipilimumab at a dose of 1 mg/kg IV over approximately 30 minutes. Nivolumab and ipilimumab will be given every 3 weeks for 4 doses. Nivolumab will then be continued at a dose of 480 mg IV over approximately 30 minutes every 4 weeks, with cabozantinib to continue at 40 mg every day. Treatment may continue for up to 2 years.

Group II: Cohort B: Cabozantinib + Nivolumab + Ipilimumab Experimental Treatment 3 Interventions

-Patients randomized to Cohort B will take cabozantinib at a dose of 40 mg by mouth once each day. Nivolumab will given IV at a dose of 3 mg/kg over approximately 30 minutes every 3 weeks for 4 doses, followed by 480 mg over approximately 30 minutes every 4 weeks until treatment discontinuation. Ipilimumab will be given IV at a dose of 1 mg/kg over approximately 30 minutes every 3 weeks for 4 doses. Treatment may continue for up to 2 years.

Group III: Cohort A: Cabozantinib Experimental Treatment 1 Intervention

Patients randomized to Cohort A will take cabozantinib at a dose of 60 mg by mouth once each day of each 28-day cycle. Treatment may continue indefinitely. At time of progression, patients will continue on cabozantinib daily but will reduce their dose to 40 mg. They will cross over into Cohort B and initiate treatment.

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?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

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

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

In a study of treatment-naive patients with PD-L1 positive metastatic soft tissue sarcomas, the combination of nivolumab and ipilimumab (NPI) significantly improved overall survival (12.2 months) and progression-free survival (4.1 months) compared to nivolumab alone (NIV), which had overall survival of 9.2 months and progression-free survival of 2.2 months.

While NPI showed greater efficacy in extending survival, it was associated with a higher incidence of severe adverse events (72.9% in NPI vs. 27.1% in NIV), indicating that while it may be more effective, it is also less tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study. Chen, Y., Liu, X., Liu, J., et al.[2023]

In a study of 88 metastatic soft tissue sarcoma (STS) patients treated with checkpoint inhibitors, the therapy demonstrated notable efficacy, with 20 patients achieving a partial response and one patient achieving a complete response, particularly in undifferentiated pleomorphic sarcoma and leiomyosarcoma subtypes.

The median progression-free survival was 4.1 months and overall survival was 19.1 months, indicating that checkpoint inhibitors can be a viable treatment option for metastatic STS, although 72.2% of patients discontinued treatment due to disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas. Monga, V., Skubitz, KM., Maliske, S., et al.[2020]

In a phase 2 study involving 85 patients with metastatic sarcoma, the combination of nivolumab and ipilimumab showed a higher confirmed response rate (16%) compared to nivolumab alone (5%), indicating that the combination therapy may be more effective for certain sarcoma subtypes.

While both treatments had manageable safety profiles, serious treatment-related adverse events occurred in 19% of patients receiving nivolumab and 26% in those receiving the combination therapy, suggesting that while the combination is promising, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. D'Angelo, SP., Mahoney, MR., Van Tine, BA., et al.[2021]

In a study of patients with advanced soft tissue sarcoma treated with the combination of ipilimumab and nivolumab, the objective response rate was 15%, with one complete response and five partial responses, indicating some level of efficacy.

The treatment was generally well tolerated, with a clinical benefit rate of 34% and a median overall survival of 12 months, although 58% of patients experienced adverse events, primarily mild, with a small percentage facing more severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab for soft tissue sarcoma: a single institution retrospective review. Zhou, M., Bui, N., Bolleddu, S., et al.[2021]

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 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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A Retrospective Analysis of the Efficacy of Immunotherapy in Metastatic Soft-Tissue Sarcomas. [2020]

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

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab for soft tissue sarcoma: a single institution retrospective review. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

A comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas. [2021]

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

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

7. United States 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. [2023]

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

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