Pembrolizumab Combo for Melanoma

No longer recruiting at 42 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme Corp.

Must be taking: Pembrolizumab, ATRA

Must not be taking: Immunosuppressants

Disqualifiers: CNS metastases, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 104 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for melanoma, a serious type of skin cancer, particularly for those whose cancer has not responded to previous PD-1 treatments. The researchers aim to determine if these combinations can outperform current options. One new option under investigation is the combination of pembrolizumab (an immunotherapy drug) and all-trans retinoic acid (ATRA). Suitable candidates have melanoma that cannot be surgically removed and has worsened after previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have received prior systemic anticancer therapy within 4 weeks before randomization or if you are on immunosuppressive therapy within 7 days before the first dose.

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

A previous study found that the combination of pembrolizumab, quavonlimab, and vibostolimab had a safety profile similar to pembrolizumab and vibostolimab alone, with expected and similar side effects. Common side effects included tiredness and some skin reactions, which were generally manageable.

Another study examined pembrolizumab, quavonlimab, and lenvatinib together. The safety was considered manageable, with most side effects being mild to moderate. Some patients experienced more serious effects, but these were less common.

Research on pembrolizumab with all-trans retinoic acid (ATRA) has shown that this combination is well tolerated, with most patients not experiencing severe side effects. The treatment aims to help the immune system fight melanoma more effectively.

In summary, while these treatments have some side effects, they are generally manageable and expected. ^{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 innovative combinations that target the cancer in multiple ways. Pembrolizumab, a well-known checkpoint inhibitor, is being paired with quavonlimab and vibostolimab, both of which further enhance the immune system's ability to attack cancer cells, using different pathways. Another promising combination involves pembrolizumab with lenvatinib, an oral drug that disrupts tumor blood supply, potentially enhancing pembrolizumab's effectiveness. Additionally, pairing pembrolizumab with all-trans retinoic acid (ATRA) introduces a unique approach by using ATRA to modulate immune responses and potentially increase the treatment's impact. This multi-pronged strategy could lead to more effective and durable responses compared to current standard treatments.

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

Research has shown that combining pembrolizumab with quavonlimab and vibostolimab, one of the treatment arms in this trial, may help treat melanoma. Early results from studies like KEYVIBE-001 suggest this combination can shrink tumors in patients whose cancer does not respond to PD-1 inhibitors, a type of cancer treatment.

Another treatment arm in this trial involves the combination of pembrolizumab, quavonlimab, and lenvatinib. Studies such as LEAP-004 indicate this combination might help when other immunotherapies have failed, offering a new option for those who haven't responded to previous treatments.

Finally, the trial also includes an arm studying the combination of pembrolizumab with all-trans retinoic acid (ATRA). Early research suggests this combination could provide long-term benefits for some patients, helping them live longer and delaying cancer progression. These findings offer hope for better outcomes in treating melanoma. ^{1 2 3 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 that has worsened despite treatment with PD-1 inhibitors. Participants must have adequate organ function, not be pregnant or breastfeeding, and agree to use contraception if necessary. They should not have had more than three prior treatments for their melanoma and must have recovered from the major side effects of previous therapies.

Inclusion Criteria

My melanoma diagnosis was confirmed through lab tests.

I have had 3 or fewer treatments for my advanced melanoma.

I am a male willing to use contraception if I take lenvatinib or ATRA.

Exclusion Criteria

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

I have a history of hepatitis B.

I have an autoimmune disease treated with medication 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 investigational treatments in different arms, including pembrolizumab with quavonlimab, vibostolimab, lenvatinib, or ATRA, for up to approximately 2 years

Up to 104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 28 months

What Are the Treatments Tested in This Trial?

Interventions

• ATRA
• Lenvatinib
• Pembrolizumab
• Quavonlimab
• Vibostolimab

Trial Overview The study tests the safety and effectiveness of combining Pembrolizumab with other investigational drugs (Lenvatinib, ATRA, Quavonlimab, Vibostolimab) in treating melanoma resistant to standard PD-1 inhibitor therapy. It aims to find better options than current treatments by comparing different drug combinations.

How Is the Trial Designed?

Group I: Pembrolizumab + all-trans retinoic acid (ATRA) Experimental Treatment 1 Intervention

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

Group II: Pembrolizumab + Quavonlimab + Vibostolimab Experimental Treatment 3 Interventions

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

Group III: Pembrolizumab + Quavonlimab + Lenvatinib Experimental Treatment 3 Interventions

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

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

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 a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

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]

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 (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]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

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]

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]

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, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36378549/

A Phase I/II Clinical Trial Combining Pembrolizumab and All ... With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12198584/

Pembrolizumab and all-trans retinoic acid combination ... Immune checkpoint inhibitors have dramatically improved outcomes for a subgroup of patients with melanoma; however, the majority do not respond ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03200847

NCT03200847 | Pembrolizumab and All-Trans Retinoic ... To determine the clinical outcomes with tumor-specific T cell responses. Official Title. Pembrolizumab and All-Trans Retinoic Acid in Combination Treatment of ...

4. jitc.bmj.com jitc.bmj.com/content/12/Suppl_2/A713.full

619 Pembrolizumab and all-trans retinoic acid combination ... Conclusions Updated OS and PFS data from this trial underscore the long-term clinical benefit of combining anti-PD-1 with ATRA, with survival ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.9536

Pembrolizumab and all-trans retinoic acid combination ... This analysis seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in advanced melanoma patients. Methods: This ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/29/7/1209/718765/Targeting-MDSC-Differentiation-Using-ATRA-A-Phase

Targeting MDSC Differentiation Using ATRA: A Phase I/II ... A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in ...

7. jitc.bmj.com jitc.bmj.com/content/12/Suppl_2/A713.full.pdf

pembrolizumab and all-trans retinoic acid combination ... Here, we report 5-year OS and PFS rates for all patients included in this trial. Methods A total of 24 patients with metastatic melanoma were enrolled in this ...