Overview

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

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