Neoadjuvant Pembrolizumab and Lenvatinib for Mucosal Melanoma

Mucosal Melanoma Clinical Trial

— Neo PeLeMM  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05545969
• Other study ID #: MIA2022/442
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 2024
• Est. completion date: May 2036

Study information

• Verified date: January 2024
• Source: Melanoma Institute Australia
• Contact: Georgina Long, MBBS, PhD
• Phone: +612 9911 7200
• Email: ealong[@]melanoma.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 44
• Est. completion date: May 2036
• Est. primary completion date: May 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma
• Mucosal Melanoma

Intervention

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.
• 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 (PDGFRa), stem cell factor receptor (KIT), and rearranged during transfection (RET)

Locations

Country	Name	City	State
Australia	Melanoma Institute Australia	Wollstonecraft	New South Wales

Sponsors (2)

Lead Sponsor	Collaborator
Melanoma Institute Australia	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	PERCIST metabolic response rate	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	6 weeks
Other	Immune-related response criteria	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	6 weeks
Other	Event-free survival	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).	10 years
Other	Recurrence-free survival	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.	10 years
Other	Overall survival	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.	10 years
Other	Incidence of any treatment-emergent adverse events	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).	52 weeks
Other	Surgical outcomes	The rate of surgical complications during and following definitive surgery	6 weeks
Other	Patient reported quality of life measures	The change in longitudinal quality of life individual and overall scores from baseline.	52 weeks
Other	Gut microbiome influence on response outcomes	To correlate gastrointestinal mucosal integrity with bacterial composition in stool samples, clinical outcomes.	52 weeks
Other	Concordance of INMC-rated pathological response with with RECIST response, PERCIST response and immune-related response crtieria.	Concordance of pathological response with RECIST response, PERCIST response and immune-related response crtieria.	6 weeks
Primary	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
Primary	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	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