Neoadjuvant Nivolumab and Relatlimab in Merkel Cell Carcinoma

Study Overview
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Brief Summary
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The goal of this clinical trial is to test neoadjuvant dual immunotherapy in Merkel cell carcinoma with the aim to improve recurrence-free survival

Detailed Description
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This is a phase 2, open label, single cohort, single centre, clinical trial of neoadjuvant immunotherapy with dual inhibition of PD-1 and LAG-3 immune checkpoint pathways. The hypothesis is that neoadjuvant therapy produces a higher pathological response rate (pCR) and a longer recurrence-free survival in a cohort of treatment-naïve patients with resectable stage I (≥10 mm) to stage III Merkel cell carcinoma compared to neoadjuvant nivolumab monotherapy in Checkmate 358 (n=123, NCT02488759, historical control).

Official Title
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A Phase 2, Open Label, Single Arm Clinical Trial of Neoadjuvant Nivolumab and Relatlimab in Stage I To III Resectable Merkel Cell Carcinoma

Conditions
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Merkel Cell Carcinoma

Intervention / Treatment
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* Drug: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years Written consent Histologically confirmed, resectable Merkel cell carcinoma with AJCC (8th ed) clinical stage I (≥ 10 mm), II, or III In-transit metastases are permitted if they are completely resectable Measurable disease according to RECIST 1.1 criteria Tumour amenable to core biopsy Previous radiotherapy permitted if there is RECIST-measurable progression of disease since the completion of radiotherapy ECOG 0-1 Adequate organ function on blood pathology Life expectancy >12 months Female patients to use effective contraception during study treatment and for 5 months after last dose. Exclusion Criteria: Clinical or radiographic evidence of distant metastases Contraindication to nivolumab and / or relatlimab Prior anti-PD-1, CTLA-4, PDL-1 or LAG 3 antibody exposure, or an agent directed to another stimulatory or co-inhibitory T-cell receptor for any disease or any chemotherapy or experimental local or systemic drug treatment Active autoimmune disease or requirement for chronic steroid therapy other than hormone replacement therapy A diagnosis of immunodeficiency or chronic steroid therapy >10 mg OD prednisone or equivalent Additional malignancy active within past 3 years; patients with chronic lymphocytic leukaemia can be included in this study. Uncontrolled cardiovascular disease or history of myocarditis - Has had an allogenic tissue/solid organ transplant Active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Known HIV Pregnant or breast feeding females Concurrent medical or social conditions that may prevent the patient attending assessments or procedures per schedule

Ages Eligible for Study
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Minimum Age: 18 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: Open label, single centre clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant Treatment<br>Nivolumab and relatlimab will be administered in a fixed dose combination (FDC). The FDC product contains nivolumab and relatlimab in a protein-mass ratio of 3:1 (nivolumab 240 mg and relatlimab 80 mg): in a 20 mL concentrate solution per single vial. The dose and dosing regimen for this study is nivolumab 480 mg and relatlimab 160 mg - 2 vials per infusion. This was primarily based on the observed benefit/risk profile observed in metastatic melanoma patients from Study CA224-020 pharmacokinetics (PK), pharmacodynamics, and extensive nivolumab monotherapy clinical experience. In addition, the Phase 2/3 Study CA224-047 established this dose as active in unresectable and metastatic melanoma. This study is open label and single arm, with all patients scheduled to receive two doses of nivolumab and relatlimab FDC prior to surgery on days 1 and 29. | Drug: Nivolumab 240 mg / Relatlimab 80 mg in a fixed dose combination<br>* Dual inhibition of the distinct LAG3 and PD-1 checkpoint pathways<br>* Other names: Opdualag;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate | Proportion of patients with a pathological complete response, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium: Complete pathological response (pCR) = 0% viable tumour cells in the surgical specimen | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological non-complete response rate to neoadjuvant immunotherapy | Proportion of patients with each non-pCR response category, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium: Near complete pathological response - (near pCR) - >0% - ≤10% viable tumour Partial pathological response (pPR) - >10 - ≤50% viable tumour Non pathological response (pNR) - >50% viable tumour | Week 6 | 
| Toxicity and tolerability of neoadjuvant immunotherapy and surgery | The proportion of patients with adverse events (AE) as described in CTCAE version 5.0, from the initiation of study treatment until at least 135 days after the end of treatment. Outcome measures include the proportion of patients with: An AE by CTCAE term and grade and duration AEs attributable to neoadjuvant study treatment Grade 3/4/5 AEs by AE term A requirement to interrupt study treatment and/or delay surgery within time limit due to an AE A requirement to discontinue study treatment early due to an AE A requirement for oral or parenteral steroid treatment for immune-related adverse events. Post-operative complications (e.g. seroma formation, wound infection or lymphoedema) and duration of events. and the Surgeon's assessment of 'operability' from baseline and at surgery. | Week 24 | 
| Objective response rate to neoadjuvant immunotherapy | The proportion of patients within each response category, as assessed using RECIST version 1.1, comparing week 6 to baseline CT and MRI. Objective response rate= CR and PR | Week 6 | 
| Metabolic response rate to neoadjuvant immunotherapy | The proportion of patients within each response category, as assessed using PERCIST (standardised uptake value [SUV]) comparing week 6 to baseline PET. Metabolic response rate = CMR and PMR. | Week 6 | 
| Recurrence-free survival | The proportion of patients alive and disease free from the time of surgery | 10 years | 
| Disease progression rate | The proportion of patients alive and with RECIST-defined progression of disease from the date of consent to the first radiographical evidence of local, regional or distant progression. Disease progression which leads to unresectable MCC. | Week 6 | 
| Event-free survival rate | The proportion of patients alive and disease free from the date of consent to the first radiographical evidence of local, regional or distant progression | 10 years | 
| Overall survival rate | The proportion of patients alive at years 1, 2, 5 and 10, and to actual date of death (in months), from the initiation of study treatment. | 10 years | 
| Patient reported quality of life | Changes in patient rated quality of life scores using QLQ-C30 and EQ-5D-5L from date of consent to 6 -12 weekly intervals until the end of year 1. The correlation of patient-rated quality of life scores with adverse events. | 1 year | 
| Study treatment completion rate | Proportion of patients receiving full neoadjuvant drug treatment per schedule and number of treatments missed. Proportion of patients undergoing planned surgery at week 6. Reasons for incomplete study treatment e.g. adverse event, withdrawn consent, , disease progression, patient lost to follow-up. | Week 8 |