The gut microbiome plays an important role in immune modulation. Specifically, the presence and function of certain gut microbial taxa has been associated with better anti-tumor immune responses. In clinical trials using fecal microbiota transplantation (FMT) to treat immune checkpoint inhibitor (ICI) refractory metastatic melanoma patients, complete responses (CR), partial responses (PR) and durable stable disease (SD) have been observed, with prolonged overall survival. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, is not fully elucidated. Furthermore, it is unknown whether a change in microbiome irrespective of the origin of the FMT (from ICI-responding (R) or non-responding (NR) metastatic melanoma donors) is able to revert ICI unresponsiveness. To address this, we will transfer the microbiota of either ICI-R or ICI-NR melanoma patients via FMT.
In this randomized, double-blinded phase Ib/IIa trial 24 αPD1-refractory patients with advanced stage cutaneous melanoma, will receive an FMT of ICI-R or ICI-NR donors. Anti-PD-1 treatment will be continued according to the patient’s regular treatment schedule. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥30% decrease within the past 24 months) and two patients with progression (≥20% increase within the past 3 months) will be selected as ICI responding or non-responding donor, respectively. The primary endpoint is to investigate the efficacy, defined as clinical benefit (SD, PR, CR) at 12 weeks, confirmed on a second scan at week 16. The secondary endpoint is safety. The study will be considered safe if less than seven patients have experienced a grade 3-4 toxicity. To assess changes in the gut microbiome and metabolome, feces samples will be collected at baseline, prior to FMT and after FMT. Tumor biopsies and blood samples will be collected to analyze local and systemic immune changes. Patient recruitment started in April 2022.
NCT05251389.
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital.
AVL Donation Investment Fund.
E.M. Terveer: Financial Interests, Personal, Advisory Board: Finch Therapeutics . E.J. Kuijper: Financial Interests, Personal, Research Grant: Vedanta Biosciences. J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Third Rock Venture, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Immunocore, Gadeta, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics, Scenic; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio; Non-Financial Interests, Personal, Member: ASCO, AACR, SITC; Other, Personal, Other, Editor-in-Chief IOTECH: ESMO; Other, Personal, Other, Editorial Board ESMO Open: ESMO; Other, Personal, Other, Editorial Board: Kidney Cancer. All other authors have declared no conflicts of interest.