Neo PeLeMM: Neoadjuvant Pembrolizumab and Lenvatinib for Mucosal Melanoma

Sponsor

Melanoma Institute Australia (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05545969

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Mucosal Melanoma	Drug: Pembrolizumab Drug: Lenvatinib	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

44 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Multicentre, open label, clinical trialMulticentre, open label, clinical trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Oct 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neoadjuvant and Adjuvant Therapy Neoadjuvant pembrolizumab & lenvatinib for 6 weeks followed by definitive surgery then adjuvant pembrolizumab alone for 46 weeks	Drug: Pembrolizumab 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. Other Names: Keytruda Drug: Lenvatinib 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) Other Names: Lenvima

Arm

Intervention/Treatment

Experimental: Neoadjuvant and Adjuvant Therapy

Neoadjuvant pembrolizumab & lenvatinib for 6 weeks followed by definitive surgery then adjuvant pembrolizumab alone for 46 weeks

Drug: Pembrolizumab

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.

Other Names:

Keytruda

Drug: Lenvatinib

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)

Other Names:

Lenvima

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

RECIST response rate [6 weeks]
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.

Other Outcome Measures

PERCIST metabolic response rate [6 weeks]
Proportion of patients with a complete metabolic resolution (complete resolution of 18F-FDG uptake within the tumour volume); partial metabolic response (reduction of a minimum of 30% in tumour SUV normalised by lean body mass [SUL]; stable metabolic response (neither CR, PR or PD) and progressive metabolic disease (an increase of 30% in tumour SUL peak or the appearance of new lesions) in the neoadjuvant period
Immune-related response criteria [6 weeks]
Proportion of patients with a complete or partial immune related response; patients with no response and patients who have confirmed disease progression in the neoadjuvant period
Event-free survival [10 years]
Proportion of patients with either of: progression of disease prior to surgery or which precludes surgery, local or distant disease recurrence, mucosal melanoma related death and treatment related death, whichever occurs first from the first dose of neoadjuvant treatment or from surgery (disease recurrence).
Recurrence-free survival [10 years]
Proportion of patients who are recurrence-free at yearly time points from the date of definitive surgery and from the end of adjuvant treatment until the end of 5 years from C1D1. To include time to any recurrence, new primary disease, locoregional recurrence and distant recurrence.
Overall survival [10 years]
Proportion of patients alive at yearly time points from the date of first neoadjuvant study treatment (C1D1) until the end of 5 years follow up.
Incidence of any treatment-emergent adverse events [52 weeks]
Number, grade and duration of drug related adverse events across different grades, with attribution to pembrolizumab, lenvatinib or both. Number, grade and duration of drug related adverse events requiring an interruption or permanent discontinuation of pembrolizumab, lenvatinib or both. The completion rate of scheduled pembrolizumab, lenvatinib or both (administered doses / scheduled doses).
Surgical outcomes [6 weeks]
The rate of surgical complications during and following definitive surgery
Patient reported quality of life measures [52 weeks]
The change in longitudinal quality of life individual and overall scores from baseline.
Gut microbiome influence on response outcomes [52 weeks]
To correlate gastrointestinal mucosal integrity with bacterial composition in stool samples, clinical outcomes.
Concordance of INMC-rated pathological response with with RECIST response, PERCIST response and immune-related response crtieria. [6 weeks]
Concordance of pathological response with RECIST response, PERCIST response and immune-related response crtieria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.