Pembrolizumab Combinations for Melanoma

Recruiting in Palo Alto (17 mi)

+50 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Immunodeficiency, CNS metastases, Autoimmune, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

Substudy 02B is part of a larger research study where researchers are looking for new ways to treat advanced melanoma that has not been treated before. The larger study is the umbrella study. Researchers want to know if adding other treatments to pembrolizumab can treat advanced melanoma. The goals of this study are to learn: * About the safety and how well people tolerate pembrolizumab given with other treatments * How many people have melanoma that responds (gets smaller or goes away) to treatment Arm 1: Pembrolizumab + Vibostolimab was added in the base protocol on 13-Nov-2019, and enrollment into this arm has been completed. Arm 2: Pembrolizumab was added in the base protocol on 13-Nov-2019, and enrollment stopped prematurely on 15-Aug-2022. Arm 3: Coformulation Pembrolizumab/Quavonlimab was added in Amendment 01 on 20-Oct-2020, and enrollment stopped prematurely on 15-Aug-2022. Arm 4: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib was added in Amendment 01 on 20-Oct-2020, and enrollment is ongoing. Arm 5: Coformulation Favezelimab/Pembrolizumab was added in Amendment 03 on 01-DEC-2022 and has paused enrollment, Arm 6: Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA) was added in Amendment 03 on 01-DEC-2022 and has paused enrollment, and Arm 7: Coformulation Favezelimab/Pembrolizumab + Vibostolimab was added in Amendment 03 on 01-DEC-2022 and enrollment was stopped prematurely on 22-SEP-2023.

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.

What data supports the effectiveness of the drug combination of pembrolizumab and other agents for melanoma?

Research shows that pembrolizumab, when combined with other agents like all-trans retinoic acid (ATRA) or lenvatinib, has been effective in treating advanced melanoma, especially in patients who have not responded to other treatments. Pembrolizumab alone has shown high response rates and is approved for treating advanced melanoma, indicating its effectiveness in this condition.

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Is pembrolizumab safe for humans?

Pembrolizumab is generally well tolerated and has a favorable safety profile in humans. Common side effects include fatigue, rash, itching, and diarrhea, while less common immune-related side effects can include thyroid issues, colitis (inflammation of the colon), hepatitis (liver inflammation), and pneumonitis (lung inflammation).

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What makes the drug combination of pembrolizumab, ATRA, favezelimab, lenvatinib, and quavonlimab unique for treating melanoma?

This drug combination is unique because it combines pembrolizumab, a PD-1 inhibitor that helps the immune system attack cancer cells, with ATRA, which targets immune cells to enhance their cancer-fighting ability, and lenvatinib, which blocks signals that tumors use to grow. This approach is particularly novel for patients whose melanoma has progressed despite previous treatments.

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Eligibility Criteria

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.

Trial Timeline

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

Participant Groups

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.

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)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Inova Schar Cancer Institute ( Site 2011) Fairfax, VA

University of Colorado, Anschutz Cancer Pavilion ( Site 2012) Aurora, CO

Mays Cancer Center ( Site 2025) San Antonio, TX

R.J. Zuckerberg Cancer Center ( Site 2032) Lake Success, NY

More Trial Locations

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC Lead Sponsor

Merck Sharp & Dohme Corp. Lead Sponsor

References

1. United States 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. [2023] 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 patients with stage IV melanoma.

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017] Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.

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

Pembrolizumab superior to ipilimumab in melanoma. [2017] In the first randomized trial to compare FDA-approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab.

4. United States 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. [2023] Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).

5. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021] Pembrolizumab [Keytruda(®) (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU. This article summarizes the milestones in the development of pembrolizumab leading to this first approval for the treatment of malignant melanoma.

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021] On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022] On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52-0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661-5. ©2017 AACR.

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

Pembrolizumab in the management of metastatic melanoma. [2020] Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that plays a major role in the treatment of advanced melanoma. Through blockade of PD-1, it leads to an increase in effector T-cell activity in the tumor microenvironment. Clinical trial outcomes for pembrolizumab in addition to pharmacokinetics, pharmacodynamics and safety of the compound are discussed in this article. Phase I trials have demonstrated safety and efficacy of pembrolizumab in advanced, pretreated melanoma patients. When compared with chemotherapy in a Phase II trial of ipilimumab-refractory patients, those treated with pembrolizumab showed superior progression-free survival. In addition, in the pivotal Phase III trial pembrolizumab improved overall survival compared with ipilimumab in patients naive to immune checkpoint inhibition. Pembrolizumab is well tolerated and has a favorable safety profile. Common adverse events are fatigue, rash, itching and diarrhea. Less frequent immune-related adverse events include hypothyroidism, colitis, hepatitis and pneumonitis.

9. England pubmed.ncbi.nlm.nih.gov

Combined use of pembrolizumab and lenvatinib: A review. [2023] The purpose of this article is to review the pharmacology, safety, evidence for current use, and potential futures uses for combination therapy with pembrolizumab and lenvatinib.

10. England 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. [2022] The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma.