Belzutifan for Advanced Cancers

Recruiting at 74 trial locations

Overseen By Toll Free Number

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: CNS metastases, Cardiac disease, HIV, others

No Placebo Group

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing belzutifan, a medication given alone, in patients with advanced cancers that have specific genetic changes. The drug works by blocking a protein that helps cancer cells grow. Belzutifan showed significant response rates for both Von Hippel-Lindau disease-associated kidney cancers and other types of cancers.

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.

What data supports the effectiveness of the drug Belzutifan for advanced cancers?

Belzutifan is approved for treating certain patients with von Hippel-Lindau disease-associated cancers, like renal cell carcinoma, based on its ability to inhibit a protein that helps tumors grow. This suggests it might also be effective for other advanced cancers. ^{1 2 3 4 5}

What makes the drug Belzutifan unique for treating advanced cancers?

Belzutifan is unique because it targets a specific pathway involved in cancer cell survival by inhibiting HIF-2α (hypoxia-inducible factor 2-alpha), which is different from many other cancer treatments that target more common pathways like ALK or BRAF mutations. This novel mechanism of action offers a new approach for treating advanced cancers, especially in cases where other treatments may not be effective. ^{6 7 8 9 10}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Belzutifan (HIF-2α Inhibitor)

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.

Participant Groups

Group I: Belzutifan Experimental Treatment 1 Intervention

Belzutifan, 120 mg, oral, once daily (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

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]

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]

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]

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]

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]

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 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]

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]

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]

References

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

Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling. [2023]

2. United States 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). [2022]

3. United States 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. [2021]

4. Switzerland 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. [2023]

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

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. [2022]

6. England 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. [2022]

7. Germany 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. [2018]

8. England 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. [2022]

9. France pubmed.ncbi.nlm.nih.gov

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

10. England 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. [2023]