Pembrolizumab Combinations for Melanoma

Not currently recruiting at 79 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Immunodeficiency, CNS metastases, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for advanced melanoma, a type of skin cancer that hasn't been treated before. Researchers are testing various combinations with pembrolizumab, a medication that helps the immune system fight cancer, to assess their safety and effectiveness in shrinking or eliminating the cancer. People with melanoma that can't be removed by surgery and who haven't received prior treatment for advanced disease might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative treatment.

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 be on immunosuppressive therapy or have received certain treatments like systemic anticancer therapy or radiotherapy shortly before starting the trial.

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

Research shows that patients generally tolerate the combination of pembrolizumab and quavonlimab well. Studies found this combo has a manageable safety profile, with patients experiencing only mild effects on their tumors. Similarly, early studies indicate that the combination of favezelimab and pembrolizumab has promising safety and manageable side effects, making it a potentially safe choice for patients.

Adding all-trans retinoic acid (ATRA) to the favezelimab/pembrolizumab mix for melanoma patients has demonstrated favorable tolerability, allowing patients to undergo treatment without severe side effects. Extensive studies on the combination of pembrolizumab with vibostolimab have shown it to be safe, even for patients with advanced melanoma.

Lastly, when pembrolizumab and quavonlimab are combined with lenvatinib, safety remains manageable, suggesting patients generally do not experience severe side effects with this treatment.

Overall, these treatments have consistently been well-tolerated in various studies, indicating they are relatively safe options for patients considering 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 explore novel combinations of pembrolizumab with other agents like quavonlimab and favezelimab. Unlike standard treatments, which typically involve single-agent immunotherapies, these combinations aim to enhance the immune response by targeting multiple pathways, potentially leading to more effective tumor control. For example, the coformulation of pembrolizumab and quavonlimab uniquely combines two checkpoint inhibitors, potentially improving the immune system's ability to fight cancer cells. Additionally, adding agents like ATRA and lenvatinib could further enhance these effects by modulating the tumor environment and inhibiting pathways that promote tumor growth. These innovations could provide new hope for patients with advanced melanoma by offering more powerful and comprehensive treatment options.

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

Research shows that using pembrolizumab with other treatments holds promise for advanced melanoma. In this trial, participants may receive pembrolizumab with quavonlimab, which has shown good results in shrinking tumors and is generally safe. Another trial arm involves adding favezelimab to pembrolizumab, which studies indicate can lead to better tumor shrinkage and higher response rates than pembrolizumab alone. Participants in a different arm will receive a combination of favezelimab, pembrolizumab, and all-trans retinoic acid (ATRA), which also shows high response rates, making it a promising option. Although combining pembrolizumab with vibostolimab hasn't greatly improved outcomes, some benefit exists, and this combination is being tested in another arm. Lastly, using pembrolizumab with quavonlimab and lenvatinib is under study as it may help overcome resistance to certain treatments, significantly improving the time patients live without disease progression. ^{1 2 5 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 advanced melanoma (Stage III or IV) that can't be removed by surgery and haven't been treated yet. They must have good organ function, not be pregnant or breastfeeding, agree to use contraception if applicable, and have recovered from previous treatments' side effects. People with immune deficiencies, other active cancers, brain metastases, hepatitis B/C, recent major surgeries or vaccines, certain mental disorders or infections are excluded.

Inclusion Criteria

If capable of producing sperm, male participants agree to specific conditions during the intervention period

My side effects from previous treatments are mild, except for possible hair loss or moderate nerve pain.

I am not pregnant or breastfeeding and follow the required contraceptive guidelines.

Exclusion Criteria

I have not had major surgery in the last 3 weeks.

You have been diagnosed with HIV.

I have had Hepatitis B or have Hepatitis C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Participants are monitored for dose-limiting toxicities and adverse events

3 weeks

Treatment

Participants receive various combinations of pembrolizumab and investigational agents

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ATRA
• Favezelimab/Pembrolizumab
• Lenvatinib
• Pembrolizumab
• Pembrolizumab/Quavonlimab

Trial Overview The study tests the safety and effectiveness of Pembrolizumab alone or combined with experimental drugs like Vibostolimab and Lenvatinib in treating first-line advanced melanoma. Participants are divided into different groups receiving various combinations of these medications to find the best treatment option.

How Is the Trial Designed?

Group I: Pembrolizumab + Vibostolimab Experimental Treatment 2 Interventions

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

Group III: Coformulation Pembrolizumab/Quavonlimab Experimental Treatment 2 Interventions

Participants will receive coformulation of pembrolizumab and quavonlimab (MK-1308A) IV at a specified dose on specified days for a total treatment duration of up to approximately 2 years.

Group IV: Coformulation Favezelimab/Pembrolizumab + Vibostolimab Experimental Treatment 2 Interventions

Participants will receive coformulation of favezelimab and pembrolizumab (MK-4280A) IV and vibostolimab IV at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Group V: Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA) Experimental Treatment 1 Intervention

Participants will receive coformulation of favezelimab and pembrolizumab IV Q3W for up to 35 cycles, plus ATRA orally (for 3 days surrounding each infusion of MK-4280A, including Days 1, 2, and 3 of Cycle 1 and on Days -1, 1, and 2 of all subsequent cycles).

Group VI: Coformulation Favezelimab/Pembrolizumab Experimental Treatment 1 Intervention

Participants will receive cofomulation of favezelimab + pembrolizumab (MK-4280A) IV at specified dose on specified days every 3 weeks (Q3W) for up to approximately 2 years

Group VII: Pembrolizumab Active Control 1 Intervention

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

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

Approved in United States as Tretinoin for:

• Acute promyelocytic leukemia (APL)

Approved in European Union as Tretinoin for:

• Acute promyelocytic leukemia (APL)

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

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

Published Research Related to This Trial

The combination of all-trans retinoic acid (ATRA) and pembrolizumab was well tolerated in a phase Ib/II trial with 24 patients, establishing a recommended phase II dose of 150 mg/m2 ATRA plus 200 mg pembrolizumab every three weeks.

This treatment showed a high overall response rate of 71%, with 50% of patients achieving a complete response and a median progression-free survival of 20.3 months, indicating its potential as an effective frontline therapy for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma. Tobin, RP., Cogswell, DT., Cates, VM., et al.[2023]

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]

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 study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

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]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Citations

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Estimating efficacy of favezelimab plus pembrolizumab ... Favezelimab plus pembrolizumab had a higher response rate and greater reduction in tumor burden vs pembrolizumab alone. Results suggest ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9832734/

A first-in-human study of the anti-LAG-3 antibody ... Favezelimab plus pembrolizumab vs pembrolizumab improved exploratory efficacy outcomes of survival and duration of response in MSS mCRC.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06036836

NCT06036836 | Study of Favezelimab Coformulated With ... The purpose of this study is to evaluate pathologic complete response (pCR) rate of coformulated favezelimab/pembrolizumab (MK-4280A) or pembrolizumab as ...

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Merck's favezelimab is latest Lag3 to falter | ApexOnco Expanding anti-Lag3 antibodies out of melanoma is hard, with the failure of Merck's favezelimab/Keytruda combo in colorectal cancer.

5. merck.com merck.com/news/merck-provides-update-on-phase-3-keyform-007-trial-evaluating-investigational-fixed-dose-combination-of-favezelimab-and-pembrolizumab-for-patients-with-previously-treated-pd-l1-positive-microsatellite/

Merck Provides Update on Phase 3 KEYFORM-007 Trial ... The fixed-dose combination of favezelimab and pembrolizumab (MK-4280A) is being evaluated across multiple solid tumor types and in patients ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0360301624002359

256 A Randomized, Double-Blind, Phase 2 Study of ... Early phase studies have also shown promising antitumor activity and manageable safety with favezelimab (anti–LAG3 antibody) + pembrolizumab (pembro; anti‒PD-1 ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.LBA248

The phase 3, randomized KEYFORM-007 study. The phase 3 KEYFORM-007 study (NCT05064059) evaluated the efficacy and safety of co-formulated fave/pembro vs standard-of-care (SOC) in PD-L1–positive MSS/pMMR ...