Sitravatinib + Nivolumab for Advanced Kidney Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining sitravatinib and nivolumab in treating advanced kidney cancer that has spread. Sitravatinib may inhibit tumor growth by blocking certain enzymes, while nivolumab, an immunotherapy, enhances the immune system's ability to attack the cancer. Suitable patients have been diagnosed with metastatic or advanced clear cell renal cell cancer and have previously undergone 1 or 2 other treatments, including specific drugs. As a Phase 2 trial, the research focuses on assessing the treatment's efficacy in an initial, smaller group of participants.

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.

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

Research has shown that the combination of sitravatinib and nivolumab has been tested for safety in several studies. In one study, patients experienced some side effects, but these were generally manageable. Another study found that this treatment helped control cancer for an average of 10.3 months, indicating a positive effect.

However, unexpected immune system reactions occurred when sitravatinib was combined with other drugs. These side effects were more common with additional drugs, not with sitravatinib and nivolumab alone.

Overall, while some risks exist, research suggests that this treatment is generally well-tolerated when used together. Prospective trial participants should discuss possible side effects with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for kidney cancer?

Researchers are excited about sitravatinib combined with nivolumab for advanced kidney cancer because it offers a new approach to tackling the disease. Unlike many current treatments, which mainly focus on inhibiting tumor growth through blocking specific pathways alone, sitravatinib works by targeting multiple pathways and helping the immune system better recognize and attack cancer cells. When combined with nivolumab, which boosts the immune system's T-cells, this duo has the potential to enhance the body's ability to fight off cancer more effectively. This combination aims to offer a more comprehensive strategy to combat kidney cancer, potentially leading to better outcomes for patients.

What evidence suggests that sitravatinib and nivolumab might be an effective treatment for advanced kidney cancer?

Research has shown that using sitravatinib with nivolumab, the combination tested in this trial, may help treat advanced kidney cancer. In a past study, 88% of patients who received this combination showed no signs of cancer two years later, indicating that many remained cancer-free for that period. Nivolumab, a type of immunotherapy, helps the body's immune system fight cancer cells and has succeeded in other cases as well. It can slow tumor growth and help patients with advanced kidney cancer live longer. Sitravatinib may inhibit certain enzymes that aid cancer growth, and when combined with nivolumab, it can enhance its effectiveness. ^{1 2 6 7 8}

Who Is on the Research Team?

Pavlos Msaouel

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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 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]

Citations

1. nature.com nature.com/articles/s41467-023-38342-7

Phase II trial of neoadjuvant sitravatinib plus nivolumab in ... Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03015740

Sitravatinib and Nivolumab in Treating Patients With ... This phase I/II trial studies the side effects of sitravatinib and how well it works with nivolumab in treating patients with kidney cancer that has spread ...

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

Clinical trial results for advanced kidney cancer (renal cell ... In the clinical trial, people given OPDIVO + YERVOY had a 37% lower risk of dying than those given SUTENT, and more than half of the people given OPDIVO + ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8975659/

Efficacy and Safety of Nivolumab for Advanced Renal Cell ... Nivolumab plus ipilimumab has significant benefits versus sunitinib in the treatment of advanced RCC in terms of tumor progression control and prolongation of ...

5. actionkidneycancer.org actionkidneycancer.org/effectiveness-of-nivolumab-persists-long-term-in-advanced-renal-cell-carcinoma/

Effectiveness of nivolumab persists long-term in advanced ... In the phase I study, the 5-year overall survival (OS) rate was 34%. In the phase II study, 29% of patients remained alive at 4 years. In addition, further ...

6. targetedonc.com targetedonc.com/view/nivolumab-plus-sitravatinib-combo-impresses-in-renal-cell-carcinoma

Nivolumab Plus Sitravatinib Combo Impresses in Renal ... The combination resulted in a median progression-free survival (PFS) of 10.3 months.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39794332/

Sitravatinib in combination with nivolumab plus ipilimumab in ... Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events.

8. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/21/NCT03680521/Prot_000.pdf

516-002 Official Title: A Phase 2 Study of Sitravatinib in ... To evaluate the preoperative clinical activity of the combination of sitravatinib and nivolumab in patients with locally-advanced. ccRCC ...