Triple Drug Combo for Solid Cancers

Not currently recruiting at 69 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: PD-1 inhibitors

Disqualifiers: CNS metastases, Cardiovascular disease, 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

Compensation: Varies

Number of Visits: 6

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—belzutifan, pembrolizumab, and lenvatinib—to evaluate their safety and effectiveness in treating various solid cancers, including liver, colorectal, pancreatic, biliary tract, endometrial, and esophageal cancers. The trial includes two groups: one receiving all three drugs and another receiving only pembrolizumab and lenvatinib. It suits individuals whose cancer has spread or cannot be surgically removed and who have not succeeded with other treatments. Participants will help researchers determine if this drug combination can improve outcomes for these challenging cancers. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that blood pressure should be adequately controlled with or without antihypertensive medications. It's best to discuss your current medications with the trial team to get specific guidance.

Do I have to stop taking my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that blood pressure should be adequately controlled with or without medications, suggesting some medications might be allowed. It's best to discuss your specific medications with the trial team.

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

Research is examining the effectiveness of a combination of three drugs—pembrolizumab, belzutifan, and lenvatinib—for treating various solid tumors. Earlier studies with pembrolizumab and lenvatinib reported side effects similar to those previously observed. Common side effects included diarrhea, fatigue, and high blood pressure, sometimes necessitating dose adjustments.

For the combination of pembrolizumab and belzutifan, early results from other studies indicate it appears safe, but more information about side effects is still being collected. As this treatment undergoes further testing, more insights into its safety are expected.

Pembrolizumab and lenvatinib have already received approval for other uses, suggesting they are generally safe. However, their use with belzutifan for these specific cancers remains under investigation. Participants should discuss potential risks and benefits with their doctor before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they bring a fresh approach to tackling solid cancers, specifically those resistant to immune-oncology (IO) therapies. Unlike typical treatments like chemotherapy or standard immune checkpoint inhibitors, this combo uses pembrolizumab, an immune checkpoint inhibitor, along with belzutifan and lenvatinib. Belzutifan is particularly noteworthy as it targets the HIF-2α pathway, a novel mechanism that can inhibit cancer growth by affecting how cancer cells adapt to low oxygen. Lenvatinib, meanwhile, works by blocking certain proteins that promote tumor blood vessel formation. This triple action could potentially offer a more effective strategy for tumors that don't respond well to existing treatments.

What evidence suggests that this trial's treatments could be effective for solid cancers?

Research shows that the combination of belzutifan, pembrolizumab, and lenvatinib, administered to participants in one arm of this trial, holds promise for treating certain cancers. Studies indicate that this trio can be more effective than other treatments for advanced clear cell renal cell carcinoma. When used together, belzutifan, pembrolizumab, and lenvatinib have significantly extended the time patients live without disease progression, particularly for those whose cancer has advanced after previous treatments.

In another arm of this trial, participants will receive pembrolizumab and lenvatinib. Evidence shows a 16.7% survival rate at five years for patients with advanced endometrial cancer using this duo. This combination has also demonstrated lasting effectiveness in various solid tumors with specific genetic traits. These findings suggest that these treatments could effectively manage multiple types of solid tumors. ^{1 2 4 6 7}

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 solid tumors, including liver, colorectal, pancreatic, biliary tract, endometrial, and esophageal cancers. Participants must have measurable disease progression and agree to contraceptive measures. Exclusions include active second malignancies within 3 years, severe lung or liver conditions, HIV/Hepatitis infections (with some exceptions), and prior treatments with specific drugs.

Inclusion Criteria

My esophageal cancer worsened after one standard treatment.

I am not pregnant or breastfeeding.

I have not had chemotherapy for my liver cancer.

Exclusion Criteria

I cannot swallow pills or have a digestive issue affecting drug absorption.

I have a severe fistula in my GI tract or elsewhere.

My liver is not working well.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab, belzutifan, and lenvatinib for up to 2 years or until progressive disease or discontinuation

Up to 2 years

Pembrolizumab administered every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 67 months

What Are the Treatments Tested in This Trial?

Interventions

• Belzutifan
• Lenvatinib
• Pembrolizumab

Trial Overview The study tests the safety and effectiveness of combining belzutifan with pembrolizumab and lenvatinib in treating various solid tumors. It aims to see how well patients respond to this combination therapy without formal hypothesis testing.

How Is the Trial Designed?

Group I: Arm 2: Pembrolizumab + Lenvatinib Experimental Treatment 2 Interventions

Participants with IO resistant ESCC will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.

Group II: Arm 1: Pembrolizumab + Belzutifan + Lenvatinib Experimental Treatment 3 Interventions

Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg (For HCC: 8 mg \[body weight \<60kg\] or 12 mg \[body weight ≥ 60 kg\]). Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Belzutifan and lenvatinib will be administered orally 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 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]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

The LITESPARK-012 study is a phase III clinical trial designed to evaluate the safety and efficacy of combining pembrolizumab and lenvatinib with either belzutifan or quavonlimab for treating advanced clear cell renal cell carcinoma (ccRCC).

This research aims to determine if these novel triplet therapies can improve patient outcomes and potentially establish a new standard of care for advanced ccRCC, building on existing combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. Choueiri, TK., Powles, T., Voss, MH., et al.[2023]

In a phase 3 study involving 1069 patients with advanced renal cell carcinoma, the combination of lenvatinib and pembrolizumab showed similar or better health-related quality of life (HRQOL) outcomes compared to sunitinib, particularly in terms of time to definitive deterioration.

Patients receiving lenvatinib plus pembrolizumab experienced longer median times to deterioration in quality of life measures, indicating that this combination therapy not only improves survival but also maintains a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Motzer, R., Porta, C., Alekseev, B., et al.[2023]

The combination of pembrolizumab and lenvatinib demonstrated significantly higher objective response rates (ORRs) and progression-free survival (mPFS) compared to their individual therapies in solid cancers, with ORRs reaching up to 70% in renal cell carcinoma.

Despite a high incidence of adverse events (68.0% for the combination therapy), the toxicities were manageable and no unexpected safety issues were reported, indicating that the combination therapy is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. Mo, DC., Luo, PH., Huang, SX., et al.[2021]

In a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

Combination therapy with pembrolizumab and lenvatinib is effective as a first-line treatment for clear cell renal carcinoma and as a second-line option for recurrent or metastatic endometrial carcinoma, based on data from five completed clinical trials and two ongoing trials.

This non-chemotherapy regimen helps spare patients from prolonged myelosuppression and lowers the risk of infection, making it a safer alternative for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined use of pembrolizumab and lenvatinib: A review. Eisinger, C., Muluneh, B.[2023]

In a phase 1b study involving 6 Japanese patients with metastatic solid tumors, the combination of lenvatinib and pembrolizumab was well-tolerated, with no dose-limiting toxicities reported.

The treatment showed promising antitumor activity, with an objective response rate of 33.3%, particularly in patients with urothelial cancer, indicating potential efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. Kitano, S., Fujiwara, Y., Shimizu, T., et al.[2022]

The combination of lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

In a phase 3 study involving 487 patients with advanced urothelial carcinoma, the combination of pembrolizumab and lenvatinib did not show improved progression-free survival (4.5 months) or overall survival (11.8 months) compared to pembrolizumab with placebo.

The combination treatment resulted in a higher rate of severe adverse events (51%) compared to the placebo group (27%), leading to the conclusion that the benefit-to-risk ratio was not favorable for using lenvatinib with pembrolizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Matsubara, N., de Wit, R., Balar, AV., et al.[2023]

In a phase 2 study involving 38 patients with pleural mesothelioma, the combination of pembrolizumab and lenvatinib resulted in a promising objective response rate of 58%, indicating significant anti-tumor activity after prior chemotherapy.

However, the treatment was associated with considerable toxicity, with 26% of patients experiencing serious treatment-related adverse events, including one death, highlighting the need for careful monitoring and supportive care during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. Douma, LH., Lalezari, F., van der Noort, V., et al.[2023]

Citations

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Merck Announces KEYTRUDA® (pembrolizumab) Plus ... First combination regimen to demonstrate improvement in DFS compared to KEYTRUDA monotherapy for these patients in the adjuvant setting.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04976634

NCT04976634 | Pembrolizumab Plus Lenvatinib in ... The purpose of this study is to determine the safety and efficacy of belzutifan in combination with pembrolizumab and lenvatinib in multiple solid tumors.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04736706

NCT04736706 | A Study of Pembrolizumab (MK-3475) in ... The goal of this study is to evaluate the efficacy and safety of pembrolizumab plus belzutifan plus lenvatinib or pembrolizumab/quavonlimab plus lenvatinib ...

4. onclive.com onclive.com/view/belzutifan-plus-pembrolizumab-and-lenvatinib-improves-efficacy-in-advanced-clear-cell-rcc

Belzutifan Plus Pembrolizumab and Lenvatinib ... Belzutifan plus pembrolizumab and lenvatinib improved efficacy outcomes compared with multiple other pembrolizumab-based triplet regimens in ...

5. 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 ...

6. merckclinicaltrials.com merckclinicaltrials.com/trial/nct04976634/

Pembrolizumab Plus Lenvatinib in Combination With ... The purpose of this study is to determine the safety and efficacy of belzutifan in combination with pembrolizumab and lenvatinib in multiple solid tumors.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.TPS425

Phase 2 study of pembrolizumab plus lenvatinib and ... Other GI Cancer January 2022. Phase 2 open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors.