Immune + Targeted Therapies for Renal Cell Carcinoma

Recruiting at 51 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Immunosuppressants, Pembrolizumab, Lenvatinib, Belzutifan

Disqualifiers: Cardiovascular disease, Lung disease, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

370 Participants Needed

Trial Summary

What is the purpose of this trial?

Substudy 03B is part of a larger research study that is testing experimental treatments for renal cell carcinoma (RCC). The larger study is the umbrella study (U03). The goal of substudy 03B is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced second line plus (2L+) clear cell renal cell carcinoma (ccRCC). This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to demonstrate a tolerable safety profile for the combination of investigational agents. There will be no hypothesis testing in this study.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy, you must stop it at least 7 days before starting the trial.

What data supports the effectiveness of the drug combination including Favezelimab, MK-4830, Pembrolizumab, KEYTRUDA, MK-3475, and Quavonlimab for renal cell carcinoma?

Research shows that pembrolizumab, a component of the treatment, when combined with axitinib, significantly improves survival rates and response in patients with advanced renal cell carcinoma compared to sunitinib, a standard treatment. ^{1 2 3 4 5}

What safety data exists for pembrolizumab in treating renal cell carcinoma?

Pembrolizumab has been studied in various trials for renal cell carcinoma, showing it can cause adverse reactions (side effects) when used alone or in combination with other drugs like lenvatinib and cabozantinib. Common side effects include fatigue, diarrhea, and high blood pressure, but these can often be managed with appropriate care. ^{3 6 7 8 9}

What makes the drug combination of Favezelimab, MK-4830, Pembrolizumab, and Quavonlimab unique for treating renal cell carcinoma?

This drug combination is unique because it combines multiple immune checkpoint inhibitors, like pembrolizumab and quavonlimab, which target different pathways to enhance the immune system's ability to fight renal cell carcinoma. This approach aims to improve outcomes by leveraging the body's immune response more effectively than single-agent therapies. ^{2 3 4 10 11}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with advanced renal cell carcinoma who've seen their cancer progress after treatment with specific systemic therapies. They must be able to take oral meds, have good organ function, controlled blood pressure, and no recent major surgery or active infections. Women of childbearing potential must use contraception and not be pregnant or breastfeeding.

Inclusion Criteria

I am not pregnant, breastfeeding, and if able to bear children, I am using contraception or abstaining from sex.

My kidney cancer worsened after treatment with specific immune or targeted therapies.

I can take pills by mouth.

Exclusion Criteria

I have an autoimmune disease but haven't needed systemic treatment in the last 2 years.

I have been treated with belzutifan before.

I have a preexisting abnormal connection between two parts inside my body.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Demonstrate a tolerable safety profile for the combination of investigational agents

3 weeks

1 visit (in-person)

Efficacy

Evaluate the efficacy of experimental combinations of investigational agents

Up to 56 months

Regular visits (in-person) every 3-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Favezelimab
• MK-4830
• Pembrolizumab
• Quavonlimab

Trial Overview The study tests combinations of experimental drugs (MK-4830, Pembrolizumab/Quavonlimab, Favezelimab/Pembrolizumab) in two phases: first ensuring safety (no severe reactions), then checking if they work against kidney cancer that's worsened despite previous treatments.

Participant Groups

Group I: Pembrolizumab + MK-4830 Experimental Treatment 2 Interventions

Participants will receive pembrolizumab 200 mg PLUS MK-4830 800 mg. Both pembrolizumab and MK-4830 will be administered IV Q3W for up to 35 administrations (up to \~2 years).

Group II: Pembrolizumab + Lenvatinib Experimental Treatment 2 Interventions

Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to \~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.

Group III: Pembrolizumab + Belzutifan Experimental Treatment 2 Interventions

Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to \~ 2 years). Belzutifan will be administered orally once-daily (QD) until progressive disease or discontinuation.

Group IV: Coformulation Pembrolizumab/Quavonlimab Experimental Treatment 1 Intervention

Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg). Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to \~2 years).

Group V: Coformulation Favezelimab/Pembrolizumab Experimental Treatment 1 Intervention

Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg). Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to \~2 years).

Group VI: Belzutifan + Lenvatinib Experimental Treatment 2 Interventions

Participants will receive Belzutifan 120 mg PLUS lenvatinib 20 mg. Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

Engineering degree from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

J.D. from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a subgroup analysis of 94 Japanese patients with metastatic renal cell carcinoma, the combination of pembrolizumab and axitinib showed improved overall survival and progression-free survival compared to sunitinib, consistent with results from the larger global study.

The safety profile was also favorable, with fewer grade ≥3 treatment-related adverse events in the pembrolizumab-axitinib group (70%) compared to sunitinib (78%), and no deaths from treatment-related adverse events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study. Tamada, S., Kondoh, C., Matsubara, N., et al.[2022]

The combination of axitinib and pembrolizumab shows a high response rate of 73% in patients with previously untreated advanced renal cell carcinoma, indicating strong efficacy for this treatment regimen.

This finding suggests that the dual approach of targeting both tumor growth and immune response may be effective in managing advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

Adjuvant pembrolizumab significantly improves disease-free survival in patients with high-risk renal cell carcinoma (RCC) after surgery, as shown in the KEYNOTE 564 trial.

Pembrolizumab is an effective and well-tolerated treatment option for patients with surgically resected RCC, paving the way for future research on patient selection and biomarkers for therapy response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for patients with renal cell carcinoma following surgery: a focus on pembrolizumab. Serzan, M., Atkins, MB.[2022]

Targeted therapies and immunotherapies, including checkpoint inhibitors like anti-CTLA-4 and anti-PD-1, are showing promise in treating kidney cancer, particularly in metastatic clear cell renal carcinoma.

Recent clinical trials, such as CheckMate-025 and AGS-003, are exploring the effectiveness of these therapies, indicating a shift towards combination treatments that may enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy of renal cell cancer]. Géczi, L., Nagyiványi, K., Maráz, A.[2019]

In the phase 3 KEYNOTE-426 trial involving 861 patients, the combination of pembrolizumab and axitinib significantly improved overall survival and progression-free survival compared to sunitinib for advanced renal cell carcinoma.

While both treatment groups showed similar health-related quality of life outcomes, the time to confirmed deterioration favored sunitinib, indicating that while pembrolizumab + axitinib is more effective in extending survival, it does not significantly enhance quality of life compared to sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. Bedke, J., Rini, BI., Plimack, ER., et al.[2022]

In a phase II study involving 110 patients with advanced clear cell renal cell carcinoma (ccRCC), pembrolizumab demonstrated a 36.4% objective response rate, indicating significant antitumor activity as a first-line treatment.

The treatment was generally well-tolerated, with 30% of patients experiencing grade 3-5 adverse events, primarily colitis and diarrhea, which aligns with safety profiles observed in other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. McDermott, DF., Lee, JL., Bjarnason, GA., et al.[2022]

In the KEYNOTE-B61 trial involving 158 patients with advanced non-clear-cell renal cell carcinoma, the combination of pembrolizumab and lenvatinib demonstrated a 49% objective response rate, indicating significant antitumor activity as a first-line treatment.

The safety profile was consistent with previous studies, with 51% of patients experiencing grade 3-4 treatment-related adverse events, primarily hypertension, but no deaths were attributed to the treatment itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Albiges, L., Gurney, H., Atduev, V., et al.[2023]

In the CLEAR study involving 352 patients, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common adverse reactions including fatigue (63.1%), diarrhea (61.9%), and hypertension (56.3%).

Most adverse reactions occurred within approximately 5 months of starting treatment, and effective management strategies such as monitoring and dose modifications were identified to ensure patient safety and support ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. Motzer, R., George, S., Merchan, JR., et al.[2023]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study. [2022]

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

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

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

Adjuvant therapy for patients with renal cell carcinoma following surgery: a focus on pembrolizumab. [2022]

4. Hungary pubmed.ncbi.nlm.nih.gov

[Immunotherapy of renal cell cancer]. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. [2022]

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

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. [2022]

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

Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. [2023]

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

A Phase I/II Clinical Trial of Pembrolizumab and Cabozantinib in Metastatic Renal Cell Carcinoma. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Emerging monoclonal antibodies for the treatment of renal cell carcinoma (RCC). [2019]

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

Immune Checkpoint Therapy in Renal Cell Carcinoma. [2022]