Belzutifan + Palbociclib for Kidney Cancer

Recruiting at13 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Belzutifan, Palbociclib

Disqualifiers: Hypoxia, CNS metastases, Cardiac disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing belzutifan alone and with palbociclib in patients with advanced kidney cancer who haven't responded to other treatments. Belzutifan helps starve cancer cells of oxygen, and palbociclib stops them from growing. Belzutifan (Welireg™) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF)-2α, first approved in the USA for treating patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC).

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.

What evidence supports the effectiveness of the drug combination Belzutifan and Palbociclib for kidney cancer?

Research shows that Belzutifan, when combined with other drugs like cabozantinib or lenvatinib, has shown promising antitumor activity in patients with advanced kidney cancer who have been previously treated. This suggests that Belzutifan may be effective in combination with other drugs for treating kidney cancer. ^{1 2 3 4 5}

Is the combination of Belzutifan and Palbociclib safe for treating kidney cancer?

There is no specific safety data available for the combination of Belzutifan and Palbociclib in kidney cancer, but Belzutifan has been studied with other drugs like lenvatinib and cabozantinib, showing potential safety and tolerability in advanced renal cell carcinoma. ^{1 2 6 7 8}

How is the drug combination of Belzutifan and Palbociclib unique for treating kidney cancer?

The combination of Belzutifan and Palbociclib is unique because Belzutifan is a first-in-class drug that targets HIF-2α (a protein involved in tumor growth and resistance to other therapies), which is promising for kidney cancer patients who have progressed after other treatments. This approach is novel as it aims to provide an effective option for those who have limited treatment choices after standard therapies. ^{1 2 6 8 9}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Belzutifan (HIF-2 Alpha Inhibitor)
• Palbociclib (Kinase Inhibitor)

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.

Participant Groups

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.

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

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]

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]

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]

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]

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]

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]

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]

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-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. [2023]

3. United States 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. [2022]

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

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

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

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. [2023]

7. 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]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Targeting hypoxia-inducible factor pathways in sporadic and Von Hippel-Lindau syndrome-related kidney cancers. [2022]

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

Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL. [2022]