Triple Drug Combo for Solid Cancers

Recruiting at 61 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

730 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment combining three drugs to help patients with difficult-to-treat cancers. The treatment aims to stop cancer growth, help the immune system fight the cancer, and cut off the blood supply to tumors.

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.

What data supports the idea that Triple Drug Combo for Solid Cancers is an effective treatment?

The available research shows that the combination of pembrolizumab and lenvatinib, which are part of the Triple Drug Combo, has shown positive results in treating various solid cancers. For example, in patients with advanced renal cell carcinoma, this combination improved both the time patients lived without the cancer getting worse and overall survival compared to another treatment called sunitinib. Additionally, in patients with pleural mesothelioma, the combination showed promising activity after other treatments had failed. These studies suggest that the Triple Drug Combo can be an effective option for treating solid cancers. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination of Belzutifan, Welireg, MK-6482, Lenvatinib, Lenvima, Lenvatinib, Pembrolizumab, KEYTRUDA, MK-3475 for solid cancers?

Research shows that the combination of pembrolizumab and lenvatinib has demonstrated strong antitumor activity and durable responses in various solid tumors, with manageable safety, suggesting it could be an effective treatment option for solid cancers. ^{1 2 3 4 5}

What safety data is available for the triple drug combo treatment for solid cancers?

The combination of pembrolizumab and lenvatinib has been studied in various cancers, showing acceptable safety profiles. In the LEAP-011 trial for urothelial carcinoma, the combination demonstrated antitumor activity with manageable safety. The CLEAR study in renal cell carcinoma highlighted improved survival outcomes and characterized common adverse reactions, providing management strategies. In endometrial cancer, the combination's safety profile was consistent with known effects, with common adverse events including hypertension, hypothyroidism, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss. These studies suggest a consistent safety profile across different cancer types. ^{1 6 7 8 9}

What safety data exists for the triple drug combo treatment for solid cancers?

The combination of pembrolizumab and lenvatinib has shown acceptable safety in various cancers, with common side effects including high blood pressure, low thyroid function, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss. ^{1 6 7 8 9}

Is the drug combination of Belzutifan, Lenvatinib, and Pembrolizumab promising for treating solid cancers?

Yes, the combination of Belzutifan, Lenvatinib, and Pembrolizumab is promising for treating solid cancers. Research shows that these drugs work well together to fight tumors and improve patient outcomes. They have shown strong antitumor activity and can be an important new option for cancers that are hard to treat. ^{1 2 3 10 11}

What makes the triple drug combo of Belzutifan, Lenvatinib, and Pembrolizumab unique for treating solid cancers?

This triple drug combo is unique because it combines a hypoxia-inducible factor inhibitor (Belzutifan), a multikinase inhibitor (Lenvatinib), and an immune checkpoint inhibitor (Pembrolizumab), which together target different pathways to enhance immune response and inhibit tumor growth, potentially offering a new standard of care for solid cancers with limited treatment options. ^{1 2 3 10 11}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 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]

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 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]

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]

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 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]

References

1. Switzerland 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. [2023]

2. England 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]

4. England 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. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. [2021]

6. 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]

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

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Combined use of pembrolizumab and lenvatinib: A review. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

10. England pubmed.ncbi.nlm.nih.gov

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. [2023]

11. Germany pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. [2022]