Immune and Targeted Combination Therapies for Kidney Cancer

Recruiting at 55 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Immunosuppressants, Live vaccines

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: Unknown

400 Participants Needed

Trial Summary

What is the purpose of this trial?

Substudy 03A 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 03A is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced first line (1L) 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 information 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 study treatment.

What data supports the effectiveness of the drug combination therapies for kidney cancer?

Research shows that combinations like pembrolizumab plus lenvatinib are effective for advanced renal cell carcinoma, improving survival rates compared to other treatments. Additionally, belzutifan combined with cabozantinib has shown antitumor activity in advanced kidney cancer, suggesting potential benefits of these drug combinations. ^{1 2 3 4 5}

What safety data exists for the combination of lenvatinib and pembrolizumab in treating kidney cancer?

The combination of lenvatinib and pembrolizumab has been studied for safety in patients with advanced kidney cancer. Common side effects were identified, and strategies for managing these side effects were reviewed, indicating that while there are adverse reactions, they can be managed effectively. ^{1 2 5 6 7}

What makes the drug combination of Belzutifan, Favezelimab, Lenvatinib, Pembrolizumab, Quavonlimab, and Vibostolimab unique for kidney cancer?

This drug combination is unique because it includes novel agents like belzutifan, which targets hypoxia-inducible factor 2α, and quavonlimab, an inhibitor of cytotoxic T-lymphocyte-associated protein 4, potentially offering a new standard of care for advanced kidney cancer by improving patient outcomes compared to existing treatments. ^{2 3 5 8 9}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with advanced first line clear cell renal cell carcinoma who haven't had systemic therapy for it. They must be able to take oral meds, have good organ function, and manage contraception if needed. Excluded are those with recent vaccines, multiple cancer treatments, immunodeficiency or other cancers within 3 years.

Inclusion Criteria

My organs are functioning well.

Side effects from my last treatment are mild or gone.

My kidney cancer has spread and is confirmed by tissue analysis.

Exclusion Criteria

I have received an organ or tissue transplant from another person.

I have had serious heart problems in the last year.

You have been diagnosed with HIV.

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

Efficacy

Evaluate the safety and efficacy of experimental combinations of investigational agents

Up to 43 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Belzutifan
• Favezelimab
• Lenvatinib
• Pembrolizumab
• Quavonlimab
• Vibostolimab

Trial Overview The study tests combinations of experimental drugs like Pembrolizumab and others (Favezelimab/Pembrolizumab, Belzutifan) in two phases: a safety phase to ensure tolerability and an efficacy phase without hypothesis testing.

Participant Groups

Group I: 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 II: Pembrolizumab + Belzutifan + Lenvatinib Experimental Treatment 3 Interventions

Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to \~2 years). Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation.

Group III: Coformulation Vibostolimab/Pembrolizumab+Belzutifan Experimental Treatment 2 Interventions

Participants will receive vibostolimab/pembrolizumab (coformulation of 200 mg vibostolimab and pembrolizumab 200 mg). Vibostolimab/pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to \~2 years). Belzutifan will be administered orally QD until progressive disease or discontinuation.

Group IV: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib Experimental Treatment 2 Interventions

Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to \~2 years). Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation.

Group V: Coformulation Favezelimab/Pembrolizumab+ Lenvatinib Experimental Treatment 2 Interventions

Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) PLUS lenvatinib 20 mg. Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to \~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation.

Belzutifan is already approved in United States for the following indications:

Approved in United States as Welireg for:

• Advanced renal cell carcinoma (RCC) following a PD-1 or PD-L1 inhibitor and a VEGF TKI
• Von Hippel-Lindau disease-associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors

Who Is Running the Clinical Trial?

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

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

Findings from Research

The combination of belzutifan and cabozantinib shows promising antitumor activity in patients with advanced clear cell renal cell carcinoma who have already undergone previous treatments.

This study highlights the potential of this drug combination as a new therapeutic option for patients with this challenging form of kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belzutifan Plus Cabozantinib Is Effective in Immunotherapy-Treated Renal Cell Carcinoma. [2023]

The LITESPARK-012 study is a phase III clinical trial designed to evaluate the safety and efficacy of combining pembrolizumab and lenvatinib with either belzutifan or quavonlimab for treating advanced clear cell renal cell carcinoma (ccRCC).

This research aims to determine if these novel triplet therapies can improve patient outcomes and potentially establish a new standard of care for advanced ccRCC, building on existing combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Choueiri, TK., Powles, T., Voss, MH., et al.[2023]

The combination of lenvatinib and pembrolizumab demonstrated promising antitumor activity in patients with metastatic renal cell carcinoma (RCC), with an objective response rate of 72.7% in treatment-naive patients and 55.8% in those previously treated with immune checkpoint inhibitors, based on a study of 143 patients.

While the treatment showed efficacy, it also had a manageable safety profile, with 57% of patients experiencing grade 3 treatment-related adverse events, primarily hypertension, and 7% experiencing grade 4 events, indicating that careful monitoring is necessary during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lee, CH., Shah, AY., Rasco, D., et al.[2022]

In a subset analysis of the CLEAR study involving 73 Japanese patients with advanced renal cell carcinoma, the combination of lenvatinib and pembrolizumab showed significantly longer progression-free survival (22.1 months) compared to sunitinib (10.9 months).

The combination therapy also resulted in a higher objective response rate (69.0% vs. 45.2%) and longer median duration of response (20.3 months vs. 9.1 months), although it was associated with a higher incidence of grade ≥3 treatment-emergent adverse events (95.2% vs. 87.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab versus sunitinib for advanced renal cell carcinoma: Japanese patients from the CLEAR study. Eto, M., Takagi, T., Kimura, G., et al.[2023]

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]

In a phase 1b study involving 6 Japanese patients with metastatic solid tumors, the combination of lenvatinib and pembrolizumab was well-tolerated, with no dose-limiting toxicities reported.

The treatment showed promising antitumor activity, with an objective response rate of 33.3%, particularly in patients with urothelial cancer, indicating potential efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. Kitano, S., Fujiwara, Y., Shimizu, T., et al.[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]

A 49-year-old man with advanced metastatic renal cell carcinoma was successfully treated with a combination of lenvatinib and pembrolizumab, leading to the disappearance of lung metastases and significant shrinkage of the primary tumor.

Following this combination therapy, a robot-assisted radical nephrectomy was performed, resulting in complete surgical remission, highlighting the effectiveness of this treatment strategy for metastatic renal cell carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. Sato, H., Sazuka, T., Fujimoto, A., et al.[2023]

References

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

Belzutifan Plus Cabozantinib Is Effective in Immunotherapy-Treated Renal Cell Carcinoma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. [2023]

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

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. [2022]

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

Lenvatinib plus pembrolizumab versus sunitinib for advanced renal cell carcinoma: Japanese patients from the CLEAR study. [2023]

5. 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]

6. 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]

7. Germany pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. [2022]

8. Hungary pubmed.ncbi.nlm.nih.gov

[Immunotherapy of renal cell cancer]. [2019]

9. Australia pubmed.ncbi.nlm.nih.gov

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. [2023]