The IRMI-FMT Trial

INDUCING REMISSION IN MELANOMA PATIENTS WITH CHECKPOINT INHIBITOR THERAPY USING FECAL MICROBIOTA TRANSPLANTATION.

Aim of the study is to investigate the effect of Fecal Microbiota Transplantation (FMT) and Checkpoint Inhibitor (CI) re-challenge in prior CI refractory patients on Progression free survival (PFS) and tumor using donor stool of former malignant melanoma patients, who have been in remission due to CI treatment for at least 1 year.

Inclusion Criteria:

1. Patients with histologically confirmed malignant melanoma

   • Age > 18 years
   • Written consent of the participant after being informed
   • Contraception as described in protocol appendix section VI

2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): PS 0 to 1.

3. Previously treated, unresectable stage III or stage IV melanoma as per the American Joint Committee on Cancer 2017 Guidelines (8th Edition) regardless of BRAF mutation status.

4. Patients must have experienced disease progression or recurrence during treatment with an anti-PD-1 monoclonal antibody, not having OR not willing to accept other approved systemic treatment options (like: BRAF and MEK inhibitors in BRAF V600 mutated melanoma).

5. Patients with CNS (central nervous system) metastases:

   • Patients are eligible if CNS metastases are treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks Prior to enrolment. In addition, patients must be either off corticosteroids or on a stable or decreasing dose <10 mg daily prednisone (or equivalent) OR
   • Patients are eligible if they have previously untreated CNS metastases and are neurologically asymptomatic. In addition, patients must be either off corticosteroids or on a stable or decreasing dose of <10 mg daily prednisone (or equivalent) OR
   • Patients with additional leptomeningeal metastases are eligible if they are treated and neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrolment and have an estimated life expectancy of at least 3 months. In addition, subjects must be either off corticosteroids or on a stable or decreasing dose of <10 mg daily prednisone (or equivalent)

6. Patients must have evaluable disease by CT (computer tomography) or MRI (magnet resonance imaging) per RECIST 1.1 criteria (Appendix 3) (radiographic tumor assessment performed before as well as after 10 weeks of first dose of study drug) or clinically apparent disease that the investigator can follow for response.

Exclusion Criteria:

1. Active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 2 weeks after treatment is complete and within 28 days prior to first dose of study treatment administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study treatment administration. Stable dose of anticonvulsants is allowed. Treatment for CNS metastases may include stereotactic radiosurgery (e.g. GammaKnife, CyberKnife, or equivalent) or neurosurgical resection. Patients who received whole brain radiation therapy are not eligible.
2. Prior treatment with chemotherapy, interferon (adjuvant setting), IL-2 (Interleukin-2), BRAF/MEK Inhibitors (v-Raf murine sarcoma viral oncogene homolog B/Mitogen-Activated Protein Kinase) for subjects with known BRAF V600 mutations, MEK inhibitors for NRAS (N-Rat sarcoma) mutations, and cKIT (Tyrosinkinase) Inhibitor subjects with known cKIT mutations is NOT allowed.
3. Uveal melanoma is excluded.
4. Coexisting severe chronic diseases other than melanoma (other neoplasias, autoimmune diseases,…).
5. Secondary gastrointestinal motility disorders.
6. Pregnancy and breast feeding.
7. Large abdominal surgery in medical history.
8. Intake of any medication introduced by another clinical study.
9. Any conditions (e.g. allergies), that do not allow the administration or intake of any of the substances used in this study (Nivolumab, Vancomycin, colonic lavage fluid).