Belzutifan + Palbociclib for Kidney Cancer

Not currently recruiting at 14 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: Belzutifan, Palbociclib

Disqualifiers: Hypoxia, CNS metastases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 21

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how well two drugs, belzutifan (Welireg or MK-6482) and palbociclib (Ibrance), work alone and together to treat clear-cell renal cell carcinoma (ccRCC), a type of kidney cancer. Researchers aim to determine if these treatments can halt cancer progression in patients whose disease has advanced despite other treatments. One part of the trial will identify the best dose for the drug combination, while another will assess the effectiveness and safety of the drugs at that dose. Individuals with Stage IV ccRCC who did not respond to at least two previous treatments might be suitable candidates for this trial. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a chance to contribute to groundbreaking cancer treatment advancements.

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, it does mention that you should not have received belzutifan or palbociclib before, and you must have recovered from previous treatments.

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

Studies have shown that belzutifan, already approved for some types of kidney cancer, generally has a manageable safety profile. Most patients tolerate it well, though common side effects include fatigue, low red blood cell count (anemia), and dizziness, which are usually mild to moderate.

Palbociclib, often used with other cancer treatments, has been taken by many patients and is also considered generally safe. Common side effects include a low white blood cell count, fatigue, and nausea, which are often mild to moderate.

The combination of belzutifan and palbociclib remains under study, but early findings suggest that taking both drugs together is tolerated similarly to taking them separately. Researchers aim to find the best dose that balances effectiveness with minimal side effects. Prospective trial participants can consider these findings to understand what to expect regarding safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Belzutifan and Palbociclib for kidney cancer because they offer a novel approach compared to existing treatments like tyrosine kinase inhibitors and immunotherapy. Belzutifan targets hypoxia-inducible factor 2-alpha (HIF-2α), a protein that plays a crucial role in tumor growth, which is a different mechanism of action than many current therapies. Palbociclib is a CDK4/6 inhibitor, known for its role in halting cancer cell division, and when combined with Belzutifan, it could provide a powerful one-two punch against cancer cells. This combination potentially addresses tumor growth more directly and effectively, offering hope for improved outcomes in kidney cancer treatment.

What evidence suggests that this trial's treatments could be effective for kidney cancer?

Research has shown that belzutifan, one of the treatments in this trial, may help treat advanced kidney cancer. In earlier studies, 64% of patients taking belzutifan had their disease under control, with the cancer not worsening for about 3 months on average. In this trial, some participants will receive belzutifan alone, while others will receive a combination of belzutifan and palbociclib.

Early results regarding the combination of belzutifan and palbociclib are promising. About 50% of patients responded to this treatment, and their cancer did not worsen for an average of 11.2 months. This combination aims to effectively slow cancer growth and improve patient outcomes. ^{6 7 8 9 10}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults with advanced kidney cancer who've seen their disease get worse after at least two treatments, including anti-PD-1/L1 and VEGF-TKI therapies. They should have measurable disease, be recovered from past treatment side effects, and not need oxygen therapy or have had major surgery within the last 3 weeks.

Inclusion Criteria

My kidney cancer is at stage IV and cannot be surgically removed.

My kidney cancer has worsened after 2 treatments including PD-1/L1 and VEGF-TKI.

I have recovered from side effects of my previous treatments.

Exclusion Criteria

I have had hepatitis B or currently have hepatitis C.

My liver is not working well.

My cancer has spread to my brain or its coverings.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Establish the safety of belzutifan plus palbociclib and determine a recommended dosage of palbociclib for the combination therapy by ascending dose escalation

28 days

21 days on followed by 7 days off

Treatment Part 2

Evaluate the efficacy and safety of belzutifan plus palbociclib at the dosage level determined in Part 1

Until progressive disease or discontinuation

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan
• Palbociclib

Trial Overview The study tests belzutifan alone and combined with palbociclib in patients with advanced clear-cell renal cell carcinoma. It has two parts: first to find a safe dose of palbociclib for combination use, then to test the effectiveness and safety of this combo compared to just belzutifan.

How Is the Trial Designed?

Group I: Part 2 - Beltuzifan 120 mg + Palbociclib Experimental Treatment 2 Interventions

Participants receive beltuzifan 120 mg orally QD and palbociclib orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. Palbociclib will be administered at a dosage level determined in Part 1.

Group II: Part 2 - Beltuzifan 120 mg Experimental Treatment 1 Intervention

Participants receive beltuzifan 120 mg orally QD until progressive disease or discontinuation.

Group III: Part 1 - Beltuzifan 120 mg + Palbociclib 75 mg Experimental Treatment 2 Interventions

Participants receive beltuzifan 120 mg orally once per day (QD) and palbociclib 75 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation.

Group IV: Part 1 - Beltuzifan 120 mg + Palbociclib 125 mg Experimental Treatment 2 Interventions

Participants receive beltuzifan 120 mg orally QD and palbociclib 125 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation.

Group V: Part 1 - Beltuzifan 120 mg + Palbociclib 100 mg Experimental Treatment 2 Interventions

Participants receive beltuzifan 120 mg orally QD and palbociclib 100 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), 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

Published Research Related to This Trial

Belzutifan (MK-6482), a small-molecule HIF-2 alpha inhibitor, shows significant efficacy in treating renal cell carcinomas (RCC) associated with Von Hippel-Lindau (VHL) syndrome and in sporadic RCC that has progressed after immune checkpoint inhibitors (ICIs).

This review highlights the potential of HIF inhibitors as a new treatment option for advanced RCC patients, particularly those who have limited options after ICI therapy, aiming to delay surgery and preserve kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting hypoxia-inducible factor pathways in sporadic and Von Hippel-Lindau syndrome-related kidney cancers. Iacovelli, R., Arduini, D., Ciccarese, C., 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]

Belzutifan, a first-in-class HIF-2α inhibitor, shows promising antitumor activity in patients with clear cell renal cell carcinoma (RCC) who have previously been treated, indicating its potential as a new treatment option.

The ongoing phase III study is comparing the combination of belzutifan with lenvatinib against cabozantinib in patients with advanced RCC who have progressed after anti-PD-1/PD-L1 therapy, addressing a significant need for effective treatments in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Motzer, RJ., Schmidinger, M., Eto, M., et al.[2023]

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]

In a phase 2 study involving 52 patients with advanced clear cell renal cell carcinoma who had previously received immunotherapy, the combination of belzutifan and cabozantinib showed promising antitumour activity, with 30.8% of patients achieving a confirmed objective response, including one complete response.

The treatment was associated with manageable safety concerns, primarily hypertension (27% of patients), and serious treatment-related adverse events occurred in 29% of patients, indicating that while the combination therapy is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Choueiri, TK., McDermott, DF., Merchan, J., et al.[2023]

Combination therapies targeting immune checkpoints and vascular endothelial growth factor receptors have significantly improved outcomes for patients with metastatic renal cell carcinoma, leading to durable disease control and prolonged overall survival.

The evolving understanding of the disease at genomic and immunologic levels has resulted in marked improvements in survival rates, making combination approaches the standard of care for first-line treatment, although careful study design is essential for accurate outcome estimation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Selection in First-line Metastatic Renal Cell Carcinoma-The Contemporary Treatment Paradigm in the Age of Combination Therapy: A Review. Navani, V., Heng, DYC.[2022]

Novel targeted therapies, such as sunitinib, sorafenib, and temsirolimus, have significantly improved clinical outcomes for patients with metastatic clear cell renal cell cancer compared to traditional cytokine treatments.

The development of these therapies, which target the vascular endothelial growth factor and mTOR pathways, suggests a promising future for renal cancer treatment, with ongoing evaluations of combination therapies to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy for renal cell carcinoma: a new treatment paradigm. Hutson, TE.[2020]

Belzutifan has been approved for treating Von Hippel-Lindau disease (VHL), and experts believe it will significantly change the treatment landscape for VHL kidney cancer, reducing the need for surgery.

A survey of 60 kidney cancer specialists revealed differing opinions on when to initiate belzutifan therapy, indicating a need for collaborative efforts to develop new clinical guidelines as treatment approaches evolve.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL. Arevalo, A., Patel, N., Muraki, P., et al.[2022]

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]

Citations

1. onclive.com onclive.com/view/belzutifan-based-combinations-meet-dfs-pfs-end-points-in-renal-cell-carcinoma

Belzutifan-Based Combinations Meet DFS, PFS End Points ... LITESPARK-011 and LITESPARK-022 trials showed significant PFS and DFS improvements in RCC with belzutifan combinations, surpassing cabozantinib ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12509838/

59: Real-World efficacy and safety of belzutifan in sporadic ... The disease control rate was 64%. The median OS was 6.93 months (95% CI: 3.75-12.58). The median PFS was 3.09 months (95% CI 2.53-5.72). AEs of ...

3. merck.com merck.com/news/merck-and-eisai-announce-welireg-belzutifan-plus-lenvima-lenvatinib-met-primary-endpoint-of-progression-free-survival-pfs-in-certain-previously-treated-patients-with-advanced-renal-c/

Merck and Eisai Announce WELIREG® (belzutifan) Plus ... First treatment regimen to demonstrate a statistically significant improvement in PFS for patients whose disease progressed following anti-PD-1/L1 therapy ...

4. targetedonc.com targetedonc.com/view/interim-efficacy-data-favor-belzutifan-lenvatinib-in-advanced-rcc

Interim Efficacy Data Favor Belzutifan/Lenvatinib in ... A new trial shows that the combination of belzutifan and lenvatinib improves progression-free survival in advanced renal cell carcinoma patients ...

5. welireghcp.com welireghcp.com/von-hippel-lindau/efficacy/

Efficacy Data for WELIREG® (belzutifan) | VHL Disease Nearly half of patients achieved tumor reduction in VHL disease–associated RCC with WELIREG · MEDIAN DURATION OF RESPONSE WAS NOT REACHED · NCCN Clinical Practice ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12483163/

The safety profile of belzutifan in renal tumors - PubMed Central Belzutifan is a HIF-2ɑ inhibitor approved for the treatment of tumors in von Hippel-Lindau (VHL) syndrome and sporadic metastatic clear cell ...

7. urologytimes.com urologytimes.com/view/eric-jonasch-md-shares-pooled-safety-data-on-belzutifan-in-advanced-rcc

Eric Jonasch, MD, shares pooled safety data on belzutifan ... Belzutifan, a HIF-2α inhibitor, is approved for von Hippel-Lindau disease and advanced renal cell carcinoma, with a focus on its safety profile.

8. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/welireg

Welireg | European Medicines Agency (EMA) Welireg is a cancer medicine used to treat: adults with advanced clear cell renal cell carcinoma (a type of kidney cancer) that has worsened ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04489771

NCT04489771 | A Study of Belzutifan (MK-6482) in ... This study will compare the efficacy and safety of two doses of belzutifan in participants with advanced renal cell carcinoma (RCC) with clear cell ...

10. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/215383Orig1s007lbl.pdf

WELIREG® (belzutifan) tablets, for oral use - accessdata.fda.gov The safety of WELIREG was evaluated in an open-label clinical ... kidney cancer called renal cell carcinoma. (RCC), tumors in the brain ...