Lenvatinib Plus Pembrolizumab In Patients With Immune Checkpoint Inhibitor Naïve Metastatic Uveal Melanoma

A Phase II Clinical Trial Evaluating The Combination Of Lenvatinib Plus Pembrolizumab In Patients With Treatment Naive Metastatic Uveal Melanoma

The purpose of this study is to evaluate the efficacy of lenvatinib and pembrolizumab to treat metastatic uveal melanoma.

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma, Uveal
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Lenvatinib

Detailed Description

This is a phase II, single arm, single institution clinical trial. Adults (age≥18 years-old) with immune checkpoint inhibitor naïve metastatic uveal melanoma will be evaluated for eligibility. Eligible participants will be treated with the combination of Lenvatinib 20 mg daily + pembrolizumab 200 mg IV every 3 weeks for a maximum of 2 years.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic uveal melanoma will be enrolled in this study.
• Male participants must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of Lenvatinib and refrain from donating sperm during this period.

• Female participants are eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:

  1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
  2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days post pembrolizumab or post Lenvatinib whichever occurs last.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Have measurable disease based on iRECIST. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. If slides are only available, ten slides would be required. Newly obtained biopsies are preferred to archived tissue.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
• Have adequate organ function as defined in the following table (Table 2). Specimens must be collected within 7 days prior to the start of study intervention.
• Subjects must agree to undergo paired fresh tumor biopsy specimens (to be collected pre-treatment and day #15). Subjects with tumor metastases that are not amenable to image guided biopsies or who have a contraindication to biopsy (including but not limited to anticoagulation therapy that cannot be interrupted for a biopsy) are still eligible for participation in the clinical trial without undergoing biopsies.

Exclusion Criteria:

• A WOCBP who has a positive serum pregnancy test within 24 hours prior to the first dose of study intervention (see Appendix 3).
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Prior therapy with Tebentafusp is permitted. Prior liver directed therapy is permitted (including but not limited to radioembolization, chemoembolization, immunoembolization, radio-frequency ablation, external beam radiation and resection).
• Participants previously treated with radiation therapy must have recovered from all radiation-related toxicities and not require corticosteroids.
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed-virus vaccines and mRNA vaccines are allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early stage bladder cancer, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has had an allogenic tissue/solid organ transplant.
• Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.
• Electrolyte abnormalities that have not been corrected
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.
• Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• Subjects having ≥2+ proteinuria on urine dipstick testing. However, subjects with ≥2+ proteinuria on urine dipstick testing may undergo a 24-hour urine collection for quantitative assessment of proteinuria. Subjects with <1 g/24-hour proteinuria are eligible for participation.
• Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy. Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.
• Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).
• Females of child-bearing potential must be willing to use effective contraception during study and for 120 days after the last dose
• The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its excipients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Lenvatinib; Lenvatinib 20 mg daily plus pembrolizumab 200 mg IV every 3 weeks.	Drug: Pembrolizumab; 200 mg IV every 3 weeks for a maximum of 2 years.; Other Names: Keytruda; Drug: Lenvatinib; 20 mg daily for a maximum of 2 years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the Effect of Lenvatinib Plus Pembrolizumab on Progression Free Survival	Progression free survival, defined as the time from enrollment to the first documented evidence of disease progression or death.	An average of 6 months and 7 days from the time of enrollment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab	Objective response rate (complete and partial responses assessed by iRECIST)	6 weeks after treatment discontinuation
Evaluate the Effect of Treatment With Lenvatinib Plus Pembrolizumab on Overall Survival	Overall survival, defined as the time from enrollment to death (resulting from any cause).	12 weeks post treatment discontinuation
Evaluate the Safety and Tolerability of Treatment With Lenvatinib Plus Pembrolizumab in Patients With Metastatic Uveal Melanoma	Number of participants who experienced dose reduction or treatment discontinuation due to treatment related adverse events (TRAE).	30 days after last treatment dose, on average 5 months from the start of treatment.

Collaborators and Investigators

• Sponsor: Providence Health & Services
• Collaborators: Merck Sharp & Dohme LLC; Eisai Inc.
• Investigators: Principal Investigator: Matthew Taylor, MD, Providence Health & Services

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2022
• Primary Completion (Actual): December 3, 2024
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: January 11, 2022
• First Submitted That Met QC Criteria: March 24, 2022
• First Posted (Actual): April 4, 2022

Study Record Updates

• Last Update Posted (Actual): July 25, 2025
• Last Update Submitted That Met QC Criteria: July 7, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Pembrolizumab; Lenvatinib; Melanoma; Phase 2; Uveal
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: 2021000802

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No