Belzutifan + Fulvestrant for Breast Cancer

Recruiting at 49 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme LLC

Must be taking: Endocrine therapy

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Curative cancer, Oral medication issues, 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: 1

Duration: Up to approximately 29 months

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for treating a specific type of breast cancer that cannot be surgically removed and has spread to other parts of the body. Researchers aim to compare the effectiveness of belzutifan (also known as Welireg or MK-6482) combined with fulvestrant against current standard treatments. The trial targets individuals with breast cancer sensitive to estrogen but not the HER2 protein, whose cancer has worsened despite previous hormone treatments. Those whose breast cancer has progressed despite hormone therapies, including a CDK4/6 inhibitor, may be suitable for this study. As a Phase 2 trial, the research focuses on evaluating 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, but you cannot participate if you are taking strong inhibitors or inducers of CYP3A4 that cannot be stopped during the study. It's best to discuss your current medications with the trial team.

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

Research shows that belzutifan, when combined with fulvestrant, is usually well-tolerated by patients. Studies have found that most side effects are mild to moderate, such as fatigue, nausea, and low red blood cell counts. Serious side effects occur less frequently, but some patients have experienced low oxygen levels in their blood.

Fulvestrant, part of this combination, is a well-known treatment for breast cancer and is generally well-tolerated. Common side effects include injection site pain and hot flashes.

The alternative treatment, everolimus with hormone therapy, can cause side effects like mouth sores, infections, and fatigue. Discuss any concerns with the healthcare team to make an informed choice. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for breast cancer, which typically involve hormone therapies like tamoxifen or aromatase inhibitors, belzutifan works by inhibiting the HIF-2α pathway, a new and promising target in cancer treatment. Researchers are excited about belzutifan because it offers a different approach by targeting the underlying hypoxia (low oxygen) conditions that cancer cells exploit to grow and survive. This unique mechanism could potentially enhance the effectiveness of hormone therapies like fulvestrant, providing a new hope for patients who may not respond well to existing options.

What evidence suggests that belzutifan plus fulvestrant might be an effective treatment for breast cancer?

This trial will compare the combination of belzutifan and fulvestrant with another treatment option. Research has shown that this combination may be promising for treating estrogen receptor-positive, HER2-negative breast cancer. Early studies suggested that belzutifan stops cancer cells from growing by blocking a survival pathway. Fulvestrant blocks estrogen, which these cancer cells need to grow. This combination aims to surpass current treatments by attacking the cancer in two ways. Initial findings in similar cancers are encouraging, but further research is needed to confirm its effectiveness specifically for breast cancer. ^{1 2 3 4 6}

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 ER+/HER2- metastatic breast cancer who've had disease progression after endocrine therapy (ET) and a CDK4/6 inhibitor. They should have an ECOG performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have recovered from major side effects of previous treatments to ≤Grade 1, except certain endocrine-related issues or ≤Grade 2 neuropathy.

Inclusion Criteria

My cancer has worsened despite hormone therapy.

My breast cancer is ER+ and HER2-, and cannot be surgically removed or cured.

My side effects from past cancer treatments are mild or gone, except for some hormone issues or slight nerve pain.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive belzutifan plus fulvestrant or everolimus plus endocrine therapy until disease progression or discontinuation

Up to approximately 29 months

IM injections on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 17 months

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan

Trial Overview The study compares the effectiveness and safety of belzutifan plus fulvestrant against everolimus combined with ET (fulvestrant or exemestane). It aims to see how well these treatments work for patients whose breast cancer has not been controlled by previous therapies. There's no formal hypothesis being tested.

How Is the Trial Designed?

Group I: Belzutifan + Fulvestrant Experimental Treatment 2 Interventions

Participants will receive belzutifan 120 mg orally once daily (QD) PLUS fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until progressive disease or discontinuation.

Group II: Everolimus + ET (fulvestrant or exemestane) Active Control 3 Interventions

Participants will receive everolimus 10 mg orally QD PLUS investigator's choice of fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter OR exemestane 25 mg 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

Published Research Related to This Trial

In a study of 138 premenopausal women with hormone receptor-positive metastatic breast cancer, the combination of fulvestrant and goserelin (F + G) showed a median time to progression of 16.3 months, which was significantly longer than goserelin alone (13.5 months), indicating improved efficacy.

While F + G was associated with some increased joint-related side effects, it demonstrated a favorable safety profile with rare severe toxicities, suggesting it could be a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant plus goserelin versus anastrozole plus goserelin versus goserelin alone for hormone receptor-positive, HER2-negative tamoxifen-pretreated premenopausal women with recurrent or metastatic breast cancer (KCSG BR10-04): a multicentre, open-label, three-arm, randomised phase II trial (FLAG study). Kim, JY., Im, SA., Jung, KH., et al.[2019]

In a study of 490 women with hormone receptor-positive metastatic breast cancer, fulvestrant 500 mg demonstrated significant effectiveness, with a median overall survival of 26.8 months, particularly better in patients receiving it as a first-line treatment (32.4 months).

The presence of liver metastasis was identified as a negative prognostic factor, impacting both progression-free survival and overall survival, highlighting the importance of disease characteristics in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of treatment and outcome with 500-mg fulvestrant in postmenopausal women with hormone receptor-positive/HER2-negative metastatic breast cancer: a real-life multicenter Italian experience. Palumbo, R., Sottotetti, F., Quaquarini, E., et al.[2022]

In a study of 86 postmenopausal patients with ER-positive metastatic breast cancer, 500 mg of fulvestrant demonstrated a clinical benefit rate of 36.0%, indicating its efficacy in managing the disease.

Patients who had not previously undergone endocrine therapy showed significantly prolonged median progression-free survival (mPFS) of 6.5 months, suggesting that fulvestrant is particularly effective when used as a first-line treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of fulvestrant in treating postmenopausal patients with estrogen receptor-positive metastatic breast cancer and prognostic analysis. Li, T., Jiao, L.[2021]

In a study involving 451 postmenopausal women with advanced breast cancer, fulvestrant was found to be as effective as anastrozole in terms of time to progression, with median times of 5.5 months for fulvestrant and 5.1 months for anastrozole.

Both treatments were well tolerated, with low withdrawal rates due to adverse events (3.2% for fulvestrant and 1.3% for anastrozole), indicating that fulvestrant is a safe and effective option for patients who have progressed on prior endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. Howell, A., Robertson, JF., Quaresma Albano, J., et al.[2022]

In a study of 54 postmenopausal women with metastatic breast cancer, fulvestrant demonstrated clinical benefit in 38.9% of patients, with a median time to progression of 6.4 months, indicating its efficacy even after multiple prior treatments.

Fulvestrant was well tolerated, with no severe toxicities (grade 3/4) reported, suggesting it is a safe option for patients with advanced breast cancer who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme. Mlineritsch, B., Psenak, O., Mayer, P., et al.[2018]

In a systematic review of four trials involving 2125 patients, fulvestrant showed no significant difference in overall survival, time to progression, clinical benefit, or objective response rate compared to standard hormonal treatments like aromatase inhibitors and tamoxifen.

Patients receiving other hormonal agents experienced a higher incidence of joint disorders, suggesting that fulvestrant may have a better tolerability profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant in the treatment of advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials. Valachis, A., Mauri, D., Polyzos, NP., et al.[2018]

Fulvestrant 500 mg significantly improves the clinical benefit rate (CBR) in postmenopausal women with hormone receptor-positive advanced breast cancer compared to other endocrine therapies, based on a meta-analysis of six randomized controlled trials involving 1588 patients.

The analysis showed that fulvestrant 500 mg was particularly effective as a first-line treatment, with a notable odds ratio of 1.33 indicating a higher proportion of patients achieving a complete or partial response or stable disease for at least 24 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A meta-analysis of clinical benefit rates for fulvestrant 500 mg vs. alternative endocrine therapies for hormone receptor-positive advanced breast cancer. Robertson, JFR., Jiang, Z., Di Leo, A., et al.[2020]

In a phase II study involving 205 postmenopausal women with advanced hormone receptor-positive breast cancer, high-dose fulvestrant (500 mg/month) showed a clinical benefit rate (CBR) similar to anastrozole (72.5% vs. 67.0%), indicating comparable effectiveness as first-line therapy.

Fulvestrant high-dose was associated with a significantly longer time to progression (TTP) compared to anastrozole, suggesting it may provide a more durable response in treatment, while both therapies had similar safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. Robertson, JF., Llombart-Cussac, A., Rolski, J., et al.[2022]

Citations

1. msdclinicaltrials.com msdclinicaltrials.com/trial/nct06428396/

Study of Belzutifan Plus Fulvestrant for ER+/HER2- Metastatic ... The purpose of this study is to assess the efficacy and safety of belzutifan (MK-6482) plus fulvestrant compared to everolimus plus endocrine therapy (ET)

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06428396

NCT06428396 | Study of Belzutifan (MK-6482) Plus ... The purpose of this study is to assess the efficacy and safety of belzutifan (MK-6482) plus fulvestrant compared to everolimus plus endocrine therapy (ET) ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS1124

LITESPARK-029: A phase 2, randomized, open-label study ... A phase 2, randomized, open-label study of belzutifan plus fulvestrant in participants with estrogen receptor–positive, HER2-negative unresectable locally ...

4. clinicaltrials.cedars-sinai.edu clinicaltrials.cedars-sinai.edu/view/MK-6482-029

Belzutifan Plus Fulvestrant in ER-Positive, HER2-Negative ... This study focuses on people who have been diagnosed with estrogen receptor-positive (ER+)/HER2-negative breast cancer that cannot be removed surgically.

5. app.trialscreen.org app.trialscreen.org/trials/phase-2-belzutifan-mk-6482-plus-fulvestrant-er-her2-metastatic-breast-trial-nct06428396

Study of Belzutifan (MK-6482) Plus Fulvestrant for ER+/HER2 A Phase 3 study of belzutifan plus fulvestrant in ER+/HER2- metastatic breast cancer. A study evaluating the efficacy and safety of belzutifan (MK-6482) plus ...

6. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/491015

Study of Belzutifan (MK-6482) Plus Fulvestrant for ER+/HER2 The purpose of this study is to assess the efficacy and safety of belzutifan (MK-6482) plus fulvestrant compared to everolimus plus endocrine therapy (ET) ...