Sitravatinib + Nivolumab for Advanced Kidney Cancer

Recruiting at 1 trial location

Overseen By Pavlos Msaouel

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: PD-1, PD-L1 inhibitors

Must not be taking: Immunosuppressants, QT-prolonging drugs

Disqualifiers: Other malignancies, Autoimmune diseases, Immunocompromised, 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: 24 weeks

88 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial investigates the effect of sitravatinib and nivolumab in treating patients with clear cell renal cell cancer that has spread to other places in the body (metastatic/advanced). Sitravatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sitravatinib and nivolumab may kill more tumor cells.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but it does exclude patients currently receiving anticancer therapies or those who have received them within 2 weeks before enrollment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Sitravatinib + Nivolumab for advanced kidney cancer?

Research shows that combinations of drugs like Nivolumab with other similar drugs have been effective in treating advanced kidney cancer, improving survival and quality of life. For example, Nivolumab combined with Cabozantinib has shown better outcomes compared to other treatments, suggesting that combining Nivolumab with Sitravatinib might also be effective. ^{1 2 3 4 5}

Is the combination of Sitravatinib and Nivolumab safe for treating advanced kidney cancer?

In a study with patients having advanced kidney cancer, the combination of Sitravatinib and Nivolumab showed no severe treatment-related side effects (no grade 4/5 adverse events), indicating it is generally safe for use in humans. ^{6 7 8 9 10}

How is the drug combination of Sitravatinib and Nivolumab unique for advanced kidney cancer?

The combination of Sitravatinib and Nivolumab is unique because Sitravatinib, a tyrosine kinase inhibitor, enhances the immune response by reducing immune-suppressive cells, potentially improving the effectiveness of Nivolumab, an immune checkpoint inhibitor. This combination aims to create a more active immune environment against the cancer, which is different from other standard treatments that may not target the immune-suppressive cells in the same way. ^{2 3 6 11 12}

Research Team

Pavlos Msaouel

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced or metastatic clear cell renal cell cancer who've had 1-2 previous treatments including specific therapies like PD-1/PD-L1 CPI. They must have measurable disease, be in good physical condition, and not pregnant. Exclusions include other recent cancers, certain medical conditions, and those on conflicting medications.

Inclusion Criteria

Your hemoglobin level is at least 9 grams per deciliter.

Your total bilirubin level should be less than or equal to 1.5 mg/dL.

My kidney function is normal and I don't need dialysis.

Exclusion Criteria

Patients who cannot be compliant with the appointments required in this protocol

I have or had an autoimmune disease.

I have not had major surgery or significant injury within the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sitravatinib by mouth daily and nivolumab intravenously every 4 weeks

24 weeks

1 visit every 4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 months

Treatment Details

Interventions

• Nivolumab
• Sitravatinib

Trial Overview The trial tests sitravatinib combined with nivolumab against advanced kidney cancer. Sitravatinib may halt tumor growth by blocking enzymes needed for cell growth while nivolumab boosts the immune system to fight cancer cells.

Participant Groups

Group I: Treatment (sitravatinib, nivolumab) Experimental Treatment 4 Interventions

Patients receive sitravatinib PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

The CLEAR trial showed that the combination of lenvatinib and pembrolizumab significantly improves progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to sunitinib in treatment-naïve metastatic clear-cell renal cell carcinoma.

Combination therapies involving immune checkpoint inhibitors, such as cabozantinib plus nivolumab and axitinib plus pembrolizumab, also demonstrated similar survival benefits and improved quality of life, making them recommended first-line treatments for advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care. Bedke, J., Albiges, L., Capitanio, U., et al.[2022]

Nivolumab (Opdivo®) has been established as an effective second-line treatment for metastatic renal cell carcinoma (mRCC), showing improved overall survival (26 months vs. 19.7 months) and response rates compared to Everolimus, based on the CheckMate 025 trial with 1,080 participants.

The combination of Nivolumab and Ipilimumab has demonstrated a significantly higher objective response rate (42% vs. 27%) and better overall survival in intermediate and high-risk patients compared to Sunitinib, while also improving quality of life, despite an increase in immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for renal cell carcinoma - current status]. Grimm, MO., Foller, S.[2019]

The combination of cabozantinib (a TKI) and nivolumab (an anti-PD-1 antibody) is an effective first-line treatment for previously-untreated advanced renal cell carcinoma (RCC), showing significantly longer progression-free and overall survival compared to sunitinib monotherapy in the CheckMate 9ER trial.

Patients receiving cabozantinib plus nivolumab reported better health-related quality of life, although the combination therapy had a higher incidence of serious adverse events compared to sunitinib, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. Markham, A.[2022]

Immune checkpoint inhibitor combinations have significantly changed the treatment approach for metastatic clear-cell renal cell carcinoma, with four approved regimens for first-line therapy, including nivolumab plus ipilimumab for high-risk patients.

Choosing subsequent therapies after initial treatment is becoming complex, but there is potential for novel strategies targeting new pathways, such as hypoxia-inducible factor inhibitors, to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic sequencing in the era of first-line immune checkpoint inhibitor combinations, a novel challenge in patients with metastatic clear-cell renal cell carcinoma. Flippot, R., Gorgeu, V., Pujalte, M., et al.[2022]

Sunitinib has a similar safety profile in patients undergoing nephrectomy for kidney cancer, whether used in the adjuvant setting or for metastatic disease, based on data from phase III trials including CARMENA and SURTIME.

Effective management of sunitinib's adverse effects is crucial, particularly in the adjuvant setting, where maintaining dose intensity and exposure can impact treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of sunitinib in patients with renal cell carcinoma following nephrectomy. Heraudet, L., Domblides, C., Daste, A., et al.[2022]

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 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]

The combination of cabozantinib (a tyrosine kinase inhibitor) and nivolumab (an immune checkpoint inhibitor) significantly improved progression-free survival, overall survival, and objective response rates in patients with untreated advanced renal cell carcinoma compared to sunitinib, supporting its approval as a first-line therapy.

While the safety profile of the combination treatment is generally manageable, it requires careful monitoring and management of overlapping adverse events, such as diarrhea and hepatotoxicity, to maintain patient tolerability and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. McGregor, B., Mortazavi, A., Cordes, L., et al.[2023]

References

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

A phase II trial of nivolumab followed by ipilimumab and nivolumab in advanced non-clear-cell renal cell carcinoma. [2023]

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

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

[Immunotherapy for renal cell carcinoma - current status]. [2019]

4. France pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. [2022]

5. France pubmed.ncbi.nlm.nih.gov

Therapeutic sequencing in the era of first-line immune checkpoint inhibitor combinations, a novel challenge in patients with metastatic clear-cell renal cell carcinoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Safety of sunitinib in patients with renal cell carcinoma following nephrectomy. [2022]

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

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

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

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

10. Netherlands pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. [2023]

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

A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy. [2022]

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

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy. [2023]