Faecal Microbiota Transplantation Optimised Immune Checkpoint Inhibitor Therapy in Advanced Cutaneous Squamous Cell Carcinoma

Faecal Microbiota Transplant (FMT) Intervention Participants receive two colonoscopic Faecal Microbiota Transplant administrations of anaerobically prepared whole-stool supplied by BiomeBank (Adelaide, Australia), a Good Manufacturing Practice (GMP)-certified Therapeutic Goods Administration (TGA) -approved stool bank: Dose: 37.5g (150ml) per administration Schedule: FMT #1 within 7 days of first cemiplimab dose; FMT #2 at 6 weeks after FMT #1 Mode of administration: Colonoscopic infusion into the ileum or right colon, performed by a credentialled gastroenterologist at St Vincent's Hospital Melbourne Duration: Two administrations over 6 weeks Participants are allocated to either a single-donor (2 doses of FMT both obtained from a single individual; Cohort A) or two-donor (2 doses of FMT obtained from two different individuals; Cohort B) FMT formulation. Standard bowel preparation (Prepkit-C) is performed prior to each colonoscopy. Loperamide 4mg orally is administered 2 hours before each procedure to assist retention. FMT will be administed by study investigators, and adherence monitored. The FMT product is a biological therapeutic good holding TGA approval for recurrent Clostridioides difficile infection. Cemiplimab (International Nonproprietary Name {INN}: cemiplimab) Cemiplimab is a fully human anti-PD-1 IgG4 monoclonal antibody administered as standard-of-care PBS-reimbursed therapy concurrently with FMT: Dose: 350mg flat dose Mode of administration: Intravenous infusion over approximately 30 minutes Schedule: Every 3 weeks after first dose; with the FMT being administred within 7 days of the first dose of cemiplimab Duration: Up to 24 months, or until disease progression, unacceptable toxicity, or patient/clinician decision to cease Cemiplimab may be administered at St Vincent's Hospital Melbourne or at a local oncology service for rural and regional participants. Dietary Co-intervention All participants will be counselled to follow the same whole-food, no-food-additive diet commencing 3 weeks prior to the first FMT and continuing for the duration of the study. The diet is plant-enriched, rich in fermentable fibres and polyphenols, moderate in animal protein, and low in saturated fat. Written dietary guidelines, a sample meal plan, and verbal counselling from a clinical dietitian are provided to each participant, with the participants to self prepare their food. The dietitian may adapt recommendations to accommodate individual food intolerances while maintaining the core dietary principles. Dietician review and adherence assessment via food records will occur at 3/6/12/24 months. All participants in this study will receive the same intervention, the cohorts are assigned based on the availability of the FMT at the time of enrollment (convenience allocation).