Neoadjuvant Pembrolizumab and Lenvatinib for Mucosal Melanoma

Study Overview
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Brief Summary
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In many cancers, early stage diagnosis and early treatment offers the best chance of a prolonged recurrence free- and overall survival. Neoadjuvant immunotherapy involves administering immune checkpoint inhibitors before surgical resection in high-risk resectable disease, such as mucosal melanoma. In resectable cancers, immune checkpoint inhibitors can enhance anti-tumour immunity by exploiting a competent immune system prior to surgery. Activating antigen-specific T cells found in the primary or baseline tumour continue to exert anti-tumour effects on remaining neoplastic cells after the resection of the original tumour, potentially preventing recurrences from occurring. In resectable mucosal melanoma, an opportunity exists to improve clinical outcomes with the addition of neoadjuvant and adjuvant systemic therapy with nivolumab and lenvatinib as an adjunct to surgery.

Official Title
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A Multicentre, Open Label, Phase II Study to Determine the Response to Neoadjuvant Pembrolizumab and Lenvatinib Followed by Adjuvant Treatment With Pembrolizumab and Lenvatinib in Mucosal Melanoma

Conditions
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Mucosal Melanoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Histologically confirmed diagnosis of fully-resectable mucosal melanoma Pathological ± clinical confirmation that the presenting lesion(s) does not represent metastasis from an unknown primary cutaneous or ocular melanoma Measurable disease per RECIST Availability of a newly obtained core or excisional biopsy of an affected lesion which has not been previously irradiated Ability to swallow and retain oral medication ECOG 0 - 1 Adequate organ function per laboratory values Adequately controlled blood pressure with or without anti-hypertensive medications, defined as ≤ 150/90 mmHg at screening Anticpated life expectabcy of > 12 months. Exclusion Criteria: A diagnosis of uveal or cutaneous melanoma A WOCBP who has a positive serum pregnancy test within 72 hours prior to starting study treatment 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 for any disease Prior systemic treatment for mucosal melanoma including investigational agents. Prior surgery is acceptable Major surgery within 3 weeks prior to first dose of lenvatinib Patients who have not recovered adequately from any toxicity from other permitted anti- cancer treatment regimens Prior radiotherapy within 2 weeks of start of study treatment Received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study treatment Patient is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment 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 14 days prior to the first dose of study treatment Active autoimmune disease that has required systemic treatment in the past 12 months Known additional malignancy that is progressing or has required active treatment within the past 3 years Has known central nervous system metastases and/or carcinomatous meningitis A history of (non-infectious) pneumonitis//interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease Active infection requiring systemic therapy Known history of Human Immunodeficiency Virus, active Hepatitis B or C Has a known history of active TB A current diagnosis of any gastrointestinal condition that might affect the absorption of lenvatinib Has a pre-existing ≥ Grade 3 gastrointestinal adverse event or a non-gastrointestinal fistula Prolonged QT interval >480 ms History of, or current cardiovascular disease Has a history of, or a current bleeding or thrombotic disorders or patients at risk for severe haemorrhage Active haemoptysis Patients with a ≥2+ (≥100 mg/dL) proteinuria on urine dipstick testing Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study Has had an allogenic tissue/solid organ transplant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Multicentre, open label, clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant and Adjuvant Therapy<br>Neoadjuvant pembrolizumab & lenvatinib for 6 weeks followed by definitive surgery then adjuvant pembrolizumab alone for 46 weeks | Drug: Pembrolizumab<br>* Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.<br>* Other names: Keytruda;Drug: Lenvatinib<br>* Lenvatinib is an oral potent multiple RTK inhibitor that selectively inhibits VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), fibroblast growth factor receptor (FGFR1-4), platelet derived growth factor (PDGFRα), stem cell factor receptor (KIT), and rearranged during transfection (RET)<br>* Other names: Lenvima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in immune cell expression of HIF1 and immune cell densities | Tumour and immune cell expression of HIF1a and immune cell densities will be compared between baseline and day 8 melanoma tissue biopsies. | Baseline, week 1 week 6 | 
| Pathological response rate | Proportion of patients with complete absence of residual melanoma cells in the the planned resected tumour site(s) at week 6 surgery | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RECIST response rate | Proportion of patients with a complete or partial RECIST response; patients with no RECIST response and patients who have RECIST confirmed disease progression in the neoadjuvant period. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, VEGF inhibitor, Neoadjuvant, Adjuvant, Pembrolizumab, Lenvatinib, Pathlogical respone