Belzutifan for Advanced Cancers

Recruiting at 97 trial locations

Overseen By Toll Free Number

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: CNS metastases, Cardiac disease, HIV, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 5.5 years

322 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called belzutifan (also known as Welireg or MK-6482) for individuals with certain advanced cancers. It targets cancers such as pheochromocytoma/paraganglioma (rare tumors), pancreatic neuroendocrine tumors, von Hippel-Lindau disease-related tumors, and some types of gastrointestinal tumors. The trial aims to evaluate the treatment's effectiveness and safety. It may suit individuals with these advanced cancers who can take oral medication. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently taking strong inhibitors or inducers of CYP3A4 that cannot be stopped for the study duration.

Is there any evidence suggesting that belzutifan is likely to be safe for humans?

Research has shown that belzutifan is generally well-tolerated. The FDA approved it for treating von Hippel-Lindau disease and advanced kidney cancer, indicating its safety. Studies have found that patients taking belzutifan often experience fewer side effects compared to those taking everolimus, another cancer drug. Common side effects include fatigue, headache, and dizziness, which are usually mild. Belzutifan targets a specific protein involved in cancer growth, and its safety in these conditions supports its potential use in other advanced cancers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Belzutifan is unique because it targets a different pathway compared to standard cancer treatments like chemotherapy or targeted therapies that often focus on inhibiting growth signals or DNA replication. Specifically, Belzutifan inhibits hypoxia-inducible factor-2 alpha (HIF-2α), a protein that helps cancer cells survive in low oxygen environments. This mechanism is particularly promising because it can potentially disrupt the cancer cells' adaptation to hypoxic conditions, which is a common hurdle in treating advanced cancers. Researchers are excited about Belzutifan as it offers a novel approach that could complement existing therapies and possibly enhance treatment outcomes for patients with advanced cancers.

What evidence suggests that belzutifan might be an effective treatment for advanced cancers?

Research has shown that belzutifan, the treatment under study in this trial, may help treat tumors associated with von Hippel-Lindau (VHL) disease. In one study, nearly half of the patients experienced tumor shrinkage. Belzutifan also proved effective for some kidney cancers, reducing the risk of the cancer spreading or worsening by 25%. This medication targets a protein called HIF-2α, which can slow rapid tumor growth. These findings suggest belzutifan might also be effective for other advanced cancers with similar genetic changes. ^{5 6 7 8 9}

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 certain advanced cancers like pheochromocytoma, paraganglioma, pancreatic neuroendocrine tumors, VHL-associated tumors, GIST or solid tumors with HIF-2α alterations. Participants must have a specific diagnosis for each cohort, controlled blood pressure, good organ function and not be pregnant or breastfeeding. They should not have other treatments recently and no major health issues that could affect the study.

Inclusion Criteria

Has a life expectancy of at least 3 months

I am a male and agree to follow specific study conditions.

I am not pregnant or breastfeeding and meet the specific conditions.

Exclusion Criteria

I have been treated with a HIF-2α inhibitor before.

My cancer has spread to other parts of my body.

I am taking strong CYP3A4 inhibitors that I cannot stop during the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive belzutifan, 120 mg, oral, once daily until progressive disease or discontinuation

Up to approximately 5.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 5.5 years

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan

Trial Overview The trial tests belzutifan's effectiveness and safety on its own in treating various advanced cancers related to HIF-2α genetic changes. The main goal is to see how well the cancer responds to belzutifan according to standard response criteria reviewed by independent experts.

How Is the Trial Designed?

Group I: Belzutifan Experimental Treatment 1 Intervention

Belzutifan, 120 mg, oral, once daily (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 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

Published Research Related to This Trial

In a study involving 52 patients with BRAF(V600E) mutation-positive metastatic melanoma, vemurafenib showed a dose-proportional increase in plasma concentration when administered at doses ranging from 240 to 960 mg twice daily, reaching steady state by day 15.

The drug maintained relatively constant levels throughout the dosing interval, indicating effective accumulation and consistent exposure, which is important for its therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma. Grippo, JF., Zhang, W., Heinzmann, D., et al.[2018]

In a phase III trial involving 107 patients with advanced ALK-positive non-small-cell lung cancer, alectinib demonstrated a significantly longer median progression-free survival (PFS) of 9.6 months compared to just 1.4 months for standard chemotherapy, indicating its superior efficacy.

Alectinib also showed a higher objective response rate in patients with central nervous system disease (54.2% vs. 0% for chemotherapy) and had a more favorable safety profile, with fewer grade ≥3 adverse events (27.1% for alectinib vs. 41.2% for chemotherapy).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Novello, S., Mazières, J., Oh, IJ., et al.[2022]

In the final overall survival analysis of the J-ALEX study, alectinib did not show a significant survival advantage over crizotinib in patients with advanced ALK-positive non-small-cell lung cancer, with a hazard ratio of 1.03, indicating similar outcomes for both treatments.

Despite the lack of overall survival superiority, alectinib is still considered a standard treatment option for advanced ALK-positive NSCLC, as it demonstrated significantly better progression-free survival compared to crizotinib in earlier analyses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final overall survival analysis from the phase III J-ALEX study of alectinib versus crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer. Hotta, K., Hida, T., Nokihara, H., et al.[2023]

In a phase I study involving 17 patients, the combination of sorafenib and vorinostat was found to be poorly tolerated in patients with advanced renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), leading to dose reductions and interruptions due to side effects like hand-foot syndrome.

While no confirmed responses were observed, some patients with RCC experienced minor responses, suggesting that lower doses may be necessary for better tolerability and potential efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer. Dasari, A., Gore, L., Messersmith, WA., et al.[2021]

Ceritinib is an effective treatment for patients with ALK-positive advanced non-small cell lung cancer (NSCLC) who have previously been treated with crizotinib, showing a response rate of 36-56% in clinical trials and durable responses lasting up to 10 months.

The drug has a manageable safety profile, with common side effects including gastrointestinal issues, fatigue, and liver test abnormalities, making it a valuable option for patients in this specific treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceritinib: a Review in ALK-Positive Advanced NSCLC. Deeks, ED.[2020]

Belzutifan is an effective oral treatment for patients with von Hippel-Lindau disease-related renal cell carcinoma and other tumors, with a well-characterized pharmacokinetic profile based on data from multiple studies involving patients aged 19 to 84.

The drug's clearance and distribution are consistent across various demographics, and while poor metabolizers of certain enzymes may experience higher drug exposure, there are no significant safety concerns related to age, sex, or mild organ impairments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling. Marathe, DD., Jauslin, PM., Kleijn, HJ., et al.[2023]

Apatinib combined with chemotherapy showed promising efficacy in patients with pretreated metastatic breast cancer, resulting in a median progression-free survival (PFS) of 4.8 months and overall survival (OS) of 15.4 months among 52 patients studied.

The treatment was generally well tolerated, with manageable side effects such as hypertension and fatigue, making it a potential option for patients with difficult-to-treat metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of apatinib 250 mg combined with chemotherapy in patients with pretreated advanced breast cancer in a real-world setting. Zhang, R., Chen, Y., Liu, X., et al.[2023]

Alectinib significantly improved progression-free survival (PFS) compared to chemotherapy, with a median PFS of 10.9 months versus 1.4 months in patients with advanced ALK-positive non-small-cell lung cancer.

The objective response rate (ORR) was also much higher with alectinib at 50.6% compared to only 2.5% with chemotherapy, and it showed a remarkable CNS ORR of 66.7% in patients with measurable CNS metastases, indicating its efficacy in treating brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. Wolf, J., Helland, Å., Oh, IJ., et al.[2022]

In a study of 48 patients with recurrent endometrial cancer treated with pembrolizumab and lenvatinib, the best objective response rate was 23.8%, indicating a lower effectiveness compared to clinical trial results.

The treatment was associated with notable side effects, with 56.2% of patients requiring a dose reduction of lenvatinib and 16.7% discontinuing treatment due to adverse events, highlighting the importance of monitoring for safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. Kim, J., Noh, JJ., Lee, TK., et al.[2022]

In a study involving 68 patients with platinum-sensitive ovarian cancer, regorafenib did not show superior efficacy compared to tamoxifen, with similar median progression-free survival of 5.6 months for tamoxifen and 4.6 months for regorafenib.

Regorafenib had a significantly worse safety profile, with 90.9% of patients experiencing grade 3/4 adverse events, compared to 54.3% for tamoxifen, highlighting concerns about its tolerability in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib or Tamoxifen for platinum-sensitive recurrent ovarian cancer with rising CA125 and no evidence of clinical or RECIST progression: A GINECO randomized phase II trial (REGOVAR). Trédan, O., Provansal, M., Abdeddaim, C., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04846920

A Study of Belzutifan (MK-6482) in Participants With ... The goal of this study is to evaluate the safety, tolerability and pharmacokinetics of escalating doses of belzutifan as second line positive (2L+) treatment in ...

2. welireg.com welireg.com/advanced-kidney-cancer/clinical-trial-results/

Kidney cancer (advanced RCC) with a clear cell component In this study, WELIREG was proven to reduce the risk of advanced RCC spreading, growing, or getting worse by 25% compared to everolimus.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11567780/

Belzutifan for Patients with Advanced Renal Cell Carcinoma A statistically significant improvement in confirmed ORR assessed by BICR in patients with measureable disease at baseline was observed in the belzutifan arm ...

4. 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 ...

5. actionkidneycancer.org actionkidneycancer.org/updated-results-from-a-trial-with-belzutifan-for-people-with-advanced-kidney-cancer/

Updated results from a trial with belzutifan for people ... In a small phase 1/2 study, the safety and effectiveness of belzutifan was assessed in 55 patients who had taken several previous treatments for kidney cancer.

6. 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.

7. 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 ...

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

WELIREG® (belzutifan) tablets, for oral use - accessdata.fda.gov In vivo, belzutifan demonstrated anti-tumor activity in mouse xenograft models of renal cell carcinoma. ... • kidney cancer that has spread ( ...