Immunotherapy Adjuvant Trial in Patients With Stage I-III Merkel Cell Carcinoma

Study Overview
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Brief Summary
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The I-MAT trial is a randomised, placebo-controlled, phase II trial of adjuvant Avelumab in patients with stage I-III Merkel cell carcinoma aiming to explore the efficacy of avelumab as adjuvant immunotherapy.

Detailed Description
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The I-MAT trial is a phase II, prospective, randomised, placebo-controlled, multi-institutional trial for patients with stage I-III Merkel cell carcinoma (MCC). Participants on the trial will receive either avelumab or placebo for 6 months. The primary aim of the I-MAT trial is to develop an effective, well-tolerated adjuvant immunotherapy regimen for patients with stage I-III MCC, post a range of definitive loco-regional treatment options.

Official Title
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A Randomised, Placebo-controlled, Phase II Trial of Adjuvant Avelumab in Patients With Stage I-III Merkel Cell Carcinoma

Conditions
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Merkel Cell Carcinoma, Merkel Cell Carcinoma, Stage I, Merkel Cell Carcinoma, Stage II, Merkel Cell Carcinoma, Stage III, Neuroendocrine Tumors, Carcinoma Neuroendocrine Skin

Intervention / Treatment
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* Drug: Avelumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed Merkel cell carcinoma (MCC) which is either: clinical stage I; pathological stage I with positive LVSI only; clinical or pathological stage II (including IIA and IIB); clinical or pathological stage III (including IIIA and IIIB). Absence of distant metastatic disease on baseline 18-Fludeoxyglucose (18FDG) - Positron Emission Tomography (PET) / Computed Tomography (CT) scan. 18 years of age or older. Eastern Cooperative Oncology Group (ECOG) of 0 - 2. Willing and able to provide written informed consent and comply with all study requirements. Adequate haematological, liver and renal function as determined by the screening laboratory values outlined in the protocol obtained within 14 days prior to randomisation. Agreeable to collection of archival tumour material. Where possible, the most recently acquired tumour specimen should be provided. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 72 hours prior to the start of treatment. Exclusion Criteria: Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest significant risk for immune-related adverse events. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway. Previous cancer immunotherapy, specifically interferon, anti-CD137, or anti-CTLA-4 antibody or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways are not permitted. Prior treatment with other immune-modulating agents that was within fewer than 28 days prior to the first dose of Avelumab. Active infection requiring antibiotics within 7 days of study entry. Active tuberculosis. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Uncontrolled infection with hepatitis B or hepatitis C virus (HBV or HCV) infection; Patients with previously successfully treated HCV, with positive anti-HCV antibody but undetectable (HCV) ribonucleic acid (RNA) levels are allowed on trial. Current use of immunosuppressive medication, except for the following: a. intranasal, inhaled, topical steroids, or local steroid injection ; b. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions Any systemic anti-cancer treatment (chemotherapy, targeted systemic therapy) investigational or standard of care, within 28 days of the first dose of Avelumab or planned to occur during the study period. Patients receiving bisphosphonates or denosumab will not be excluded. Pregnant or breastfeeding. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia (i.e., bronchiolitis obliterans, cryptogenic organising pneumonia), or evidence of active pneumonitis on screening chest CT scan). Uncontrolled cardiac disease including not limited to symptomatic congestive heart failure, unstable angina pectoris, life-threatening cardiac arrhythmia Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5 Grade 3). Use of live attenuated vaccines within 28 days of first dose of Avelumab. Any acute or chronic psychiatric problems that, in the opinion of the Investigator, make the patient ineligible for participation due to compliance concerns. Patients with prior allogeneic stem cell or solid organ transplantation. Patients who are involuntarily incarcerated. No evidence of other malignancy in the past 3 years, with exception of tumours with negligible risk of metastasis or death.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab<br>6 months of Avelumab at a dose of 800mg as a 60-minute intravenous (IV) infusion once every 2 weeks (13 doses) | Drug: Avelumab<br>* Avelumab IV infusion<br>* Other names: Bavencio;|
| Placebo Comparator: Placebo<br>6 months of Placebo as a 60-minute intravenous (IV) infusion once every 2 weeks (13 doses) | Drug: Placebo<br>* Placebo IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) | Recurrence-free survival (RFS) as the primary endpoint, is anticipated to be analysed over an average planned follow-up of 3.5 years. An analysis of RFS at the 24 month time point of follow-up will also be conducted as it is anticipated that the minimum follow-up for participants will be 24 months and the sample size rationale utilises RFS rates at 24 months in historical controls. RFS is defined as the time from treatment initiation until the first date of any signs or symptoms of recurrence of tumour. | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival rates at 12 and 24 months. Overall survival is defined as the time from treatment initiation to the date of death due to any cause. | 24 Months | 
| Disease-specific survival (DSS) | Disease-specific survival at 24 months from treatment initiation. Disease-specific survival is the percentage of participants who have not died from Merkel Cell Carcinoma | 24 Months | 
| Rate of loco-regional failure free survival (LRFFS) | Rate of loco-regional failure free survival (LRFFS) is defined as the time from treatment initiation to the first recurrence of the loco-regional tumour. | 24 Months | 
| Distant metastasis-free survival (DMFS) | DMFS is defined as the time from treatment initiation to the first evidence of distant metastatic disease. | 24 Months | 
| Treatment toxicity and tolerability as assessed by NCI CTCAE v5.0 | Rate of treatment-related adverse events (AEs). Safety will be measured by serious adverse events (SAEs) and AEs assessed as per NCI CTCAE v5.0, including immune-related adverse events. | 24 Months | 
| Patient-reported quality of life (QoL) as assessed by FACT-M questionnaire | FACT-M form (version 4) will be utilised. This will include patient-reported questions relating to physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing and additional patient concerns which are measured from 0-4 (Not at all - Very Much). | 24 Months |