Melanoma (Stage III and IV cutaneous and stage IV uveal melanoma)
Conditions
Interventions
Group 1: Fecal Microbiota Transplantation (FMT), once
Sponsors
Universitätsspital Zürich
Eligibility
Sex/Gender
All
Age
18 Years to 80 Years
Inclusion criteria
Inclusion criteria: General inclusion criteria for all participants: • Individuals must be at least 18 years of age and can be male or female • Able to understand and sign the informed consent, obtained from subject according to local regulations. Patients/individuals can be included if fulfilling inclusion criteria for one of the following groups: 1. Patients with stage III and IV cutaneous, and stage IV uveal melanoma cancer, planned for first-line CI standard of care therapy, defined by the Department of Dermatology (anti-PD1 based mono- or combination therapy: anti-PD1+CTLA4 or antiPD1+antiLag3, or tebentafusp) - FMT-Recipients. 2. Patients with melanoma in durable remission after CI therapy and healthy subjects - FMT-Donors. We will recruit patients willing to donate stool samples for the study, on a "first come first serve basis". Inclusion criteria FMT-Recipients: 1. Patients, at minimum 18 years of age and maximum of 75 years of age 2. Male or female 3. Pathologically confirmed diagnosis of stage III or IV cutaneous or stage IV uveal melanoma. 4. Radiologically measurable disease 5. ECOG performance status of 0-1 6. Currently planned or ongoing first-line CI therapy, as per standard of care. 7. Willingness to receive FMT administered via colonoscopy and undergo necessary bowel preparation pre-procedure. 8. Adequate organ function as determined by standard-of-care lab and according to the investigator’s discretion. 9. Following laboratory parameters need to be met: a. Platelet count = 50 x 109 / L b. Lymphocyte count = 0.8 x 109 / L c. Neutrophil count = 0.5 x 109 / L d. Hemoglobin = 8.5 g/dL e. Prothrombin time (PT)-international normalized ration (INR) = 1.5 f. ALT/AST < 3 × the upper limit of normal (ULN)serum g. Serum creatinine clearance (eGFR) = 50 mL/min h. Total bilirubin = 20 µmol/L, except in patients with Gilbert’s Syndrome who must have a total bilirubin < 50 µmol/L i. LDH level of = 1 × ULN 10. BMI <35 kg/m2 11. Willingness to complete recipient-specific questionnaires. 12. Female subjects of childbearing potential must be willing to use highly effective method of birth control (for both genders) before the FMT procedure. 13. Female subject of childbearing potential should have a negative urine pregnancy test within minimum 8 hours prior to receiving the study intervention (FMT), performed on site. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Inclusion criteria FMT-Donors: Melanoma patients CI Responders: 1. Patients, at minimum 18 years of age and maximum of 80 at screening time 2. Documented history of stage IV cutaneous or uveal melanoma treated with anti-PD1 based CI therapy. 3. Featuring partial or complete response of the melanoma as assessed by radiologic examination and judged by the investigator with a minimum duration of respective response lasting =12 months measured since initiation of cancer immunotherapy. 4. ECOG score at the time of study enrolment 0-1 Healthy subjects: - Voluntary individuals, at minimum 18 years of age and maximum of 60 years of age Melanoma patients CI Responders and Healthy subjects: 1. Male or female 2. Willingness to complete donor-specific questionnaires. 3. Willingness to complete donor-specific blood and stool testing to evaluate infectious agents. 4. Tested negatively for all infectious agents specified. 5. Willingness to provide multiple stool samples, until total am
Exclusion criteria
Exclusion criteria: The presence of any of the following exclusion criteria will lead to the disqualification of the participant: Exclusion criteria FMT Recipients: 1. Acral or mucosal melanoma or an unknown primary tumor 2. Presence of absolute contra-indications to colonoscopy and/or FMT administration: a. Toxic megacolon b. Anatomic contra-indications to colonoscopy c. Colectomy 3. Patient is currently participating and receiving other study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of this study intervention. 4. Currently under any form of systemic antibiotics. 5. Is receiving systemic steroid therapy (> 20 mg prednisone daily or equivalent) two weeks prior to trial treatment. Patients receiving systemic steroids at physiologic doses are permitted to enroll assuming steroid dose is not above the acceptable threshold (> 20 mg prednisone daily or equivalent). 6. Any grade 3 or 4 irAE still requiring active immunosuppressive medication, apart from endocrinopathies that are stable under hormone replacement therapy or patients with ir-enterocolitis under immunosuppressive therapy. Patients who have developed grade 3–4 irAEs, which have reverted to grade 1 or 2 with immunosuppressive drugs and who are off immunosuppression or receive utmost 20 mg prednisone or equivalent at least two weeks prior to enrollment are eligible. Patients who present ir-enterocolitis Grade 1-3 or patients having recovered from ir-enterocolitis Grade 4 (now grade 1-3), taking utmost 20 mg prednisone can be included (according to current guidelines, FMT is regarded as therapy for corticosteroid refractory ir-enterocolitis). 7. Severe cardiac or pulmonary comorbidities (per judgement of the investigator), e.g.: - diagnosed heart failure with NYHA (New York Heart Association) classification > 2 - severe cardia arrhythmias, e.g. AV-block grade 3 - Unstable angina pectoris - COPD or other Pneumopathy with ventilation disorder; 8. Uncontrolled/untreated epilepsia 9. Obesity = Grade 2 (BMI of 35 kg/m2 or above) 10. Functional or anatomic stenosis in the lower gastrointestinal tract 11. Severe sleep apnea syndrome (OSAS) (as per judgement of the investigator) 12. Had a severe hypersensitivity reaction to propofol. 13. Severe anaphylactic reaction to any food (food allergies, e.g. soya, chicken egg white). 14. Has serious concomitant illnesses. The eligibility can be granted by the treating investigator on individual bases. 15. Active systemic infections, coagulation disorders or other active major medical illnesses (per judgement of the investigator) 16. Other malignancies, except adequately treated and with a cancer related life expectancy of > 5 years 17. Treatment with antibiotics 4 weeks prior to study enrollment or expectation to receive antibiotics during the course of this study 18. Has history or active infection of HIV infection or AIDS-related illness. 19. Has active infection of HBV and HCV. Patients with a history of Hepatitis B/C infection who might have received anti-viral therapy and are disease free may be considered for enrollment after discussion with Principal Investigator. 20. Patient has received a live vaccine within 4 weeks prior to the first dose of treatment. Seasonal influenza vaccines or COVID-19 vaccines for injection are generally inactivated virus vaccines and are allowed. 21. Has known psychiatric or substance abuse disorde
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean change in frequency of CD8+ T-cells from baseline in the peripheral blood of melanoma patients (FMT Recipients) 12 weeks after FMT as assessed by enumeration using flow cytometry. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Number of adverse events and serious adverse events related to FMT as recorded up to 12 weeks after microbiota transplantation (FMT) 2. Quality of life as assessed based on the questionnaire 12 weeks after FMT. 3. Change in number of CD8+ T- cells in the circulation depending on FMT donor (CI responder vs. healthy donor) 12 weeks post FMT as assess by cell enumeration using flow cytometry. 4. T-cell receptor (TCR) clonality: evaluate whether FMT using CI responder-derived FMT versus healthy donor-derived FMT modulates T-cell receptor (TCR) clonality 12 weeks post-FMT as assessed by TCR DNA sequencing. 5. Change in number of CD4+ T-cells and of T-cells overall in the circulation after FMT using CI responder-derived FMT versus healthy donor-derived FMT as assessed by flow cytometry 12 weeks post-FMT. 6. Change in PBMC composition as assessed by numbers of types of PBMCs in melanoma patients after FMT using CI responder-derived FMT versus healthy donor derived FMT as measured by single cell RNA sequencing and/or flow cytometry 12 weeks post FMT (and compared to control patients). 7. Composition of innate and adaptive immune cell subsets: Change in number of intestinal innate and adaptive immune cell subsets as assessed by spatial transcriptomics and/or immunostainings 12 weeks post FMT. 8. Change in the microbiome composition: Mean change from baseline of bacterial species in feces, intestinal-tissue and PBMCs after FMT using CI responder-derived FMT versus healthy donor-derived FMT as assessed by metagenomics analysis 12 weeks post FMT (and compared to control patients). 9. Change in the serum metabolome composition: Mean change from baseline of serum metabolome after FMT using CI responder-derived FMT versus healthy donor derived FMT as assessed by mass spectrometry 12 weeks post FMT (and compared to control patients). 10. Change in proteome: Numbers of the serum, intestinal tissue-derived and PBMC-derived proteins in FMT recipients after FMT | — |
Countries
Switzerland
Contacts
Public ContactMichael Scharl
Universitätsspital Zürich
Outcome results
None listed