Microbiota Transplant to Cancer Patients Who Have Failed Immunotherapy Using Faeces From Clinical Responders

Inclusion Criteria:

1. Participant must be 18 years of age, at the time of signing the informed consent

2. Histologically confirmed malignant melanoma, NSCLC, CSCC, HNSCC, renal clear cellcarcinoma or MSI+ solid cancer

3. Metastatic disease or local recurrence not curable by standard therapy

4. PD-L1 positivity is required for subjects with HNSCC (>20% combined positive score)and NSCLC (>20% PD-L1 expression)

5. Measurable disease according to iRECIST

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

7. Progressive disease, as considered by the treating physician, on therapy withPD1/PD-L1 blockers and/or CTLA4-blockers and/or LAG-3 blockers, or combinationsregimes comprising any of these agents. Further treatment with ICI is considered tobe within standard practice.

8. Patients without any response to ICI at any time point during their disease historyare eligible, without a need for re-introduction of ICI before enrollment, even ifsubsequent lines of anti-cancer therapy have been given. For patients with priorresponse to ICI, the criteria depend on the cancer form:

9. Malignant melanoma, NSCLC and MSI-H/dMMR solid cancers: Prior response to ICIis allowed only if PD under ICI has been documented <9 months before enrolmentand without subsequent lines of anti-cancer therapy. For patients with priorresponse to ICI followed by subsequent lines of anti-cancer therapy, andpatients that have not received ICI the last 9 months, ICI has to bere-introduced, and these patients have to again show progressive disease whileon ICI therapy.

10. CSCC, HNSCC and renal clear cell carcinoma: Prior response to ICI is allowed,without a need for re-introduction, even if subsequent lines of anti-cancertherapy have been given, provided that disease progression has been documentedunder ICI therapy the last 12 months.

11. Mandatory pre-FMT biopsy and lesion accessible for further biopsies

12. Life expectancy >3 months

13. Adequate organ function as defined below:

14. Hemoglobin > 9 g/dL

15. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L

16. Platelet count ≥80 x 109/L

17. INR≤1.2

18. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).

19. AST and ALT ≤2.5 x ULN unless liver metastases are present, in which case itmust be ≤5x ULN

20. Albumin >25 g/L

21. Serum creatinine ≤1.5 X ULN OR measured creatinine clearance (CL) >40 mL/min orCalculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroftand Gault 1976) or by 24-hour urine collection for determination of creatinineclearance.

22. Capable of giving signed informed consent

Exclusion Criteria:

1. Other cancer within 3 years prior to study entry, with the exception of those with anegligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamouscell skin cancer)

2. Spinal cord compression not definitively treated with surgery and/or radiation, orpreviously diagnosed and treated spinal cord compression without evidence thatdisease has been clinically stable for > 2 weeks prior to first FMT

3. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients withindwelling catheters are allowed

4. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must beon a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases ormetastases causing nerve impingement) amenable to palliative radiotherapy should betreated prior to enrolment. Asymptomatic metastatic lesions whose further growthwould likely cause functional deficits or intractable pain (e.g., epiduralmetastasis that is not presently associated with spinal cord compression) should beconsidered for loco-regional therapy if appropriate prior to enrolment.

5. Significant cardiovascular disease, such as New York Heart Association (NYHA)cardiac disease (Class II or greater), myocardial infarction within 3 months priorto study entry, unstable arrhythmias, or unstable angina. Patients with a known leftventricular ejection fraction (LVEF) < 40% will be excluded. Patients with knowncoronary artery disease, congestive heart failure not meeting the above criteria, orLVEF < 50% must be on a stable medical regimen that is optimized in the opinion ofthe treating physician, in consultation with a cardiologist if appropriate

6. Undergone allogeneic stem cell or solid organ transplantation

7. A positive test for HIV

8. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV)infection or resolved HBV infection (defined as having a negative HbsAg test and apositive antibody to hepatitis B core antigen [anti-HBc] antibody test) areeligible. Patients positive for hepatitis C virus (HCV) antibody are eligible onlyif polymerase chain reaction (PCR) is negative for HCV RNA.

9. Active tuberculosis

10. Ongoing immune-related adverse effects from immunotherapy treatments that are ofGrade ≥2, excluding endocrine adverse effects. An ongoing grade 2 cutaneous reactionis allowed.

11. Severe infection within 14 days prior to first FMT, requiring hospitalization.

12. Any condition that significantly increases the risk of perforation during endoscopyfor FMT.

13. A history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the subject'sparticipation for the full duration of the trial, or is not in the best interest ofthe subject to participate, in the opinion of the treating Investigator.

14. Known psychiatric or substance abuse disorders that would interfere with cooperationand the requirements of the trial

15. A requirement of systemic antibiotics at the time of study entry.

16. Received oral or IV antibiotics within 5 days prior to first FMT.

17. Currently receiving other study therapy that may interfere with the interpretationof data in this study.

18. Received treatment with systemic corticosteroids or other systemic immunosuppressivemedications (including but not limited to prednisone, dexamethasone,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosisfactor [TNF] agents) within 10 days prior to first FMT, or anticipated requirementfor systemic immunosuppressive medications during the trial. A daily dose equivalentto ≤10mg prednisolone is allowed.

19. Patients who have received acute, low-dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea) may be enrolledin the study.

20. Patients with a history of allergic reaction to IV contrast requiring steroidpre-treatment should have baseline and subsequent tumor assessments performedusing MRI.

21. The use of inhaled corticosteroids for chronic obstructive pulmonary disease,mineralocorticoids (e.g., fludrocortisone) for patients with orthostatichypotension, and low-dose supplemental corticosteroids for adrenocorticalinsufficiency are allowed.

22. Pregnant or breastfeeding

23. Any reason why, in the opinion of the investigator, the patient should notparticipate