Pembrolizumab Combinations for Melanoma

No longer recruiting at 47 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active infection, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatment combinations for people with melanoma, a type of skin cancer that has spread to the brain. The researchers aim to determine if these combinations, including drugs like pembrolizumab (an immunotherapy drug), quavonlimab, and lenvatinib (a targeted therapy drug), are more effective and safer than current treatments. Participants should have stage IV melanoma with brain metastasis and no symptoms related to their brain metastases. As a Phase 1/Phase 2 trial, it focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received immunosuppressive therapy or systemic anticancer therapy recently, and there are restrictions on recent surgeries, radiotherapy, and certain vaccines.

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

Research has shown that the combination of pembrolizumab and lenvatinib produces side effects similar to those observed in past studies with melanoma patients. Specifically, the LEAP-003 study found side effects consistent with earlier research on these drugs.

For the combination of pembrolizumab, quavonlimab, and lenvatinib, studies indicate that the side effects are manageable, meaning they are expected and can be controlled. This combination remains under investigation, so further research is needed to confirm these findings.

Overall, these treatments have been tested for other conditions, and while they are experimental for melanoma with brain metastasis, the safety data so far appears promising. Participants should discuss potential risks with their healthcare providers before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for melanoma because they offer novel combinations that could enhance the effectiveness of current therapies. Unlike standard treatments, which often involve monotherapies like pembrolizumab, the study explores combining pembrolizumab with lenvatinib, an oral medication that targets blood vessel growth in tumors. Additionally, the coformulation of pembrolizumab with quavonlimab, another immune checkpoint inhibitor, aims to boost the immune response against cancer cells more robustly. These combinations could potentially lead to improved outcomes for patients by harnessing different mechanisms to fight melanoma.

What evidence suggests that this trial's treatments could be effective for melanoma brain metastasis?

Research shows that using pembrolizumab with lenvatinib holds promise for treating melanoma. Studies have found that this combination can combat tumors, even in patients who have tried other treatments. In advanced melanoma cases, patients who received pembrolizumab and lenvatinib achieved better results than those on standard treatments. In this trial, one group of participants will receive pembrolizumab and lenvatinib, while another group will receive a coformulation of pembrolizumab/quavonlimab with lenvatinib. Early research suggests that adding quavonlimab to pembrolizumab and lenvatinib is safe and merits further exploration. These combinations are being tested to determine if they outperform current treatments for melanoma that has spread to the brain. ^{1 3 6 7 8}

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 Stage IV melanoma that has spread to the brain, who haven't used steroids recently and aren't pregnant or breastfeeding. They must have good organ function and agree to use contraception. People with weakened immune systems, recent surgeries or therapies, active infections, other cancers within 2 years, or certain viral diseases can't join.

Inclusion Criteria

My organs are functioning well.

I agree not to breastfeed during the study.

My melanoma is at the most advanced stage, having spread to distant parts of my body.

Exclusion Criteria

I have untreated bleeding in my brain from cancer spread.

I have had pneumonitis treated with steroids or have it now.

I have been treated for an autoimmune disease in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab/quavonlimab and lenvatinib for up to approximately 2 years

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Lenvatinib
• Pembrolizumab
• Pembrolizumab/Quavonlimab

Trial Overview The study tests Pembrolizumab alone or combined with Quavonlimab in treating melanoma in the brain. The combination of Pembrolizumab and Lenvatinib was part of the study but is no longer being tested as of December 2022.

How Is the Trial Designed?

Group I: Pembrolizumab + Lenvatinib Experimental Treatment 2 Interventions

Participants will receive pembrolizumab IV plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Group II: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib Experimental Treatment 3 Interventions

Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab and quavonlimab) intravenously (IV) plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Lenvatinib is already approved in United States, European Union for the following indications:

Approved in United States as Lenvima for:

• Differentiated Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Lenvima for:

• Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Kisplyx for:

• Renal Cell Carcinoma

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

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 the phase II LEAP-004 study involving 103 patients with advanced melanoma who had disease progression on PD-1 inhibitors, the combination of lenvatinib and pembrolizumab achieved an objective response rate of 21.4%, indicating its potential effectiveness in this challenging population.

The treatment demonstrated a median progression-free survival of 4.2 months and an overall survival of 14.0 months, with a manageable safety profile, including a 45.6% incidence of grade 3-5 adverse events, primarily hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. Arance, A., de la Cruz-Merino, L., Petrella, TM., et al.[2023]

In a phase 2 trial involving 29 patients with advanced gastric cancer, the combination of lenvatinib and pembrolizumab resulted in a promising objective response rate of 69%, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with the most common grade 3 adverse events being manageable, such as hypertension and proteinuria, and no serious treatment-related complications or deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Kawazoe, A., Fukuoka, S., Nakamura, Y., et al.[2020]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

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]

The ongoing KEYNOTE-495/KeyImPaCT study is evaluating the effectiveness of pembrolizumab combined with other therapies in advanced non-small cell lung cancer (NSCLC), with results showing varying objective response rates (ORR) based on tumor characteristics, ranging from 0-12% in low T-cell-inflamed groups to 50-60% in high T-cell-inflamed groups.

The study confirms that assessing T-cell-inflamed gene expression profiles (TcellinfGEP) and tumor mutational burden (TMB) can help identify which patients are more likely to benefit from pembrolizumab-based treatments, while the safety profiles of the combinations remain consistent with previous findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. Gutierrez, M., Lam, WS., Hellmann, MD., 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]

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]

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 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 phase 2 study involving 54 patients with advanced endometrial cancer, the combination of lenvatinib and pembrolizumab resulted in a 39.6% objective response rate at week 24, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with serious adverse events occurring in 30% of patients, including one treatment-related death; however, the safety profile was consistent with previous studies of the individual drugs, except for a higher incidence of hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Makker, V., Rasco, D., Vogelzang, NJ., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40885529/

Randomized, Double-Blind, Phase III LEAP-003 Study of ... Lenvatinib plus pembrolizumab demonstrated antitumor activity in advanced melanoma after prior anti-PD-(L)1 therapy in LEAP-004. Here, we ...

2. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00928-7/fulltext

Randomized, double-blind, phase III LEAP-003 study of ... Grade 3-5 treatment-related AEs occurred in 58.7% with lenvatinib + pembrolizumab versus 29.0% with placebo + pembrolizumab. •. Lenvatinib + ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11491429/

pembrolizumab and lenvatinib versus conventional ... Grade 3–5 treatment-related adverse events were documented in 48.7% (pembrolizumab/lenvatinib) and 75.6% (CC) of patients (p=0.034), which led ...

4. targetedonc.com targetedonc.com/view/pembrolizumab-plus-lenvatinib-shows-encouraging-efficacy-in-uveal-melanoma

Pembrolizumab Plus Lenvatinib Shows Encouraging ... Key Takeaways. Pembrolizumab and lenvatinib showed promising PFS in uveal melanoma patients, with 31.8% and 60.7% rates in different cohorts.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03820986

Study Details | NCT03820986 | Safety and Efficacy ... The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combined with lenvatinib (MK-7902/E7080) compared to pembrolizumab ...

6. merck.com merck.com/news/merck-and-eisai-provide-update-on-phase-3-leap-012-trial-in-unresectable-non-metastatic-hepatocellular-carcinoma/

Merck and Eisai Provide Update on Phase 3 LEAP-012 ... The safety profile of the KEYTRUDA plus LENVIMA-based regimen was consistent with that observed in previously reported studies evaluating ...

7. merck.com merck.com/news/merck-and-eisai-provide-update-on-phase-3-trials-of-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-certain-patients-with-advanced-melanoma-leap-003-and-metastatic-colorectal-cance/

Merck and Eisai Provide Update on Phase 3 Trials of ... In both the LEAP-003 and LEAP-017 trials, the safety profile of KEYTRUDA plus LENVIMA was consistent with previously reported data on the ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10540481/

Combined use of pembrolizumab and lenvatinib: A review Data suggests that combination therapy with pembrolizumab and lenvatinib can be used first line for clear cell renal carcinoma in patients with favorable risk.