In this study the aim is to investigate whether transfer of the microbiota of either responder or non-responder patients via fecal microbiotica transplantation (FMT) can convert the response to immunotherapy in immune checkpoint inhibitors (ICI) refractory metastatic melanoma patients. This is a randomized double-blind intervention phase Ib/IIa trial in ICI refractory metastatic melanoma patients receiving either FMT of an ICI responding or FMT from an ICI non-responding donor, in combination with ICI. Following randomization, patients will receive vancomycin 250 mg, four times daily for 4 days (day -5 up until day -2), and undergo bowel clearance on day -1 (in total 1L MoviPrep). The FMT, either derived from donor group R (who showed a good response on anti-PD-1 therapy) or donor group NR (who showed progression on anti-PD-1 therapy), will be performed by a gastroenterologist using esophagogastroduodenoscopy. A total amount of 198mL (containing a total of 60 gram feces) will be used for transplantation. Anti-PD-1 treatment will be continued according to the patient's regular treatment schedule. Evaluation of safety and response to treatment will be performed.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
24
Fecal microbiota transplantation of an ICI responding or Fecal microbiota transplantation from an ICI non-responding donor, in combination with ICI.
Antoni van Leeuwenhoek
Amsterdam, Netherlands
RECRUITINGEfficacy, defined as clinical benefit (stable disease (SD), partial response (PR), complete response (CR)
Time frame: At 12 weeks after FMT
Safety, measured as the occurrence of toxicity of grade 3 or higher
Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT
Progression free survival (PFS)
PFS will be calculated from the date of registration to the date of progression or death, whichever occurs first, censoring patients without progression and who are still alive at last follow-up
Time frame: Up to one year post-FMT
The change in gut microbiome following FMT and the duration and stability over time
To assess the fecal microbiome (which includes bacteria, archaea, viruses, parasites and fungi), nucleotides will be isolated for next generation sequencing and molecular methodologies (e.g. PCR, qPCR). Initially, whole genomic DNA (metagenomics) and the ITS2 region or the rRNA gene will be will be sequenced, giving insights in the overall microbiota's structural and functional features and in the structural features of the fungal microbiota, respectively, which both will be associated to clinical variables.
Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT
The change in metabolome following FMT and the duration and stability over time
To assess the metabolome in feces (which includes amino acids, short lipids, sugars and nucleotides), samples will be processed and analyzed by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) or Nuclear magnetic resonance (NMR). The identified metabolic profile will be associated with the microbiome data and clinical variables.
Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT
The immune changes; changes in cell populations (absolute, relative, phenotypical), in chemokine/cytokine levels and in the tumor-microenvironment
Tumor biopsies and blood samples will be analyzed to investigator the local and systemic immune changes: changes in cell populations (absolute, relative, phenotypical), in chemokine/cytokine levels and in the tumor-microenvironment (TME). If possible, results will be linked to response.
Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT
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