fmt to convert response to immunotherapy

Conditions: Melanoma Stage III; Melanoma Stage IV

Summary: 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.


Eligibility criteria:
inclusion criteria: * patients should be 18 years or older * patients have pathologically confirmed advanced stage cutaneous melanoma (stage iii or iv) requiring systemic treatment with anti-pd-1 * in case of stage iv disease, only patients with m1a or m1b disease are eligible. * patients have confirmed disease progression (≥20% increase according to recist1.1) on two consecutive scans with a four week interval while on anti-pd-1 treatment, of which the second scan has to be performed within 3 weeks prior to signing informed consent. * patients must have measurable disease per recist 1.1 criteria * patients have an ecog performance status of 0-1 (appendix d) * patients have a life expectancy of \>3 months * patients have adequate organ function as determined by standard-of-care pre-checkpoint inhibitor infusion lab (including serum alat/asat less than three times the upper limit of normal (uln); serum creatinine clearance 50ml/min or higher; total bilirubin less than or equal to 20 micromol/l, except in patients with gilbert's syndrome who must have a total bilirubin less than 50 micromol/l) * patients have an ldh level of ≤1 times uln * patients of both genders must be willing to use a highly effective method of birth control during treatment * patients must be able to understand and sign the informed consent document exclusion criteria: * patients with acral, uveal or mucosal melanoma, or patients with an unknown primary * patients who have received treatment for their melanoma other than anti-pd-1 treatment. * stage iv patients with m1c or m1d disease. * patients with autoimmune diseases: patients with a history of inflammatory bowel disease, including ulcerative colitis and crohn's disease, are excluded from this study (except hashimoto thyroiditis, vitiligo, history of psoriasis, but no active disease) * patients with any grade 3 or 4 immune-related adverse events still requiring active immunosuppressive medication, apart from endocrinopathies that are stable under hormone replacement therapy. patients who had developed grade 3-4 immune related toxicity, which has reverted to grade i with immunosuppressive drugs and who are off immunosuppression at least two weeks prior to enrollment are eligible * patients with brain or lm metastasis. * patients with an elevated ldh level * patients that have undergone major gastric/esophageal/bowel surgery (like wipple, subtotal colectomy) * severe food allergy (e.g. nuts, shellfish) * patients with a swallowing disorder or expected bowel passage problems (ileus, fistulas, perforation) * severe dysphagia with incapability of swallowing 2 liters of bowel lavage * patients with a life expectancy of less than three months * patients with severe cardiac or pulmonary comorbidities (per judgement of the investigator) * women who are pregnant or breastfeeding * patients with any active systemic infections, coagulation disorders or other active major medical illnesses * patients with other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years * patients who received treatment with antibiotics in the three months prior to study enrolment, or patients we are expected to receive systemic antibiotics during the course of this study