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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. 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).
2. Absence of distant metastatic disease on baseline 18-Fludeoxyglucose (18FDG) - Positron Emission Tomography (PET) / Computed Tomography (CT) scan.
3. 18 years of age or older.
4. Eastern Cooperative Oncology Group (ECOG) of 0 - 2.
5. Willing and able to provide written informed consent and comply with all study requirements.
6. Adequate haematological, liver and renal function as determined by the screening laboratory values outlined in the protocol obtained within 14 days prior to randomisation.
7. Agreeable to collection of archival tumour material. Where possible, the most recently acquired tumour specimen should be provided.
8. 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:

1. 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.
2. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway.
3. 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.
4. Prior treatment with other immune-modulating agents that was within fewer than 28 days prior to the first dose of Avelumab.
5. Active infection requiring antibiotics within 7 days of cycle 1 day 1 of study drug dose.
6. Active tuberculosis.
7. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
8. 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.
9. 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
10. 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.
11. Pregnant or breastfeeding.
12. 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).
13. Uncontrolled cardiac disease including not limited to symptomatic congestive heart failure, unstable angina pectoris, life-threatening cardiac arrhythmia
14. 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).
15. Use of live attenuated vaccines within 28 days of first dose of Avelumab.
16. Any acute or chronic psychiatric problems that, in the opinion of the Investigator, make the patient ineligible for participation due to compliance concerns.
17. Patients with prior allogeneic stem cell or solid organ transplantation.
18. Patients who are involuntarily incarcerated.
19. Evidence of other malignancy in the past 3 years, with exception of tumours with negligible risk of metastasis or death.