FMT to Convert Response to Immunotherapy

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FMT to Convert Response to Immunotherapy

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion 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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05251389
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1/Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	The Netherlands Cancer Institute
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	John Haanen, Prof
Principal Investigator Affiliation	Medical Oncologist
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Netherlands
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Melanoma Stage III, Melanoma Stage IV

Arms & Interventions

Arms

Experimental: A: FMT from an ICI non-responding donor

Patients will receive FMT from an ICI non-responding donor (defined as ≥20% increase according to RECIST 1.1 criteria within the past 3 months). Patients will continue their anti-PD-1 treatment.

Experimental: B: FMT from an ICI responding donor

Patients will receive FMT from an ICI responding donor (defined as ≥30% decrease or disappearance of all lesions according to RECIST 1.1 criteria within the past 24 months). Patients will continue their anti-PD-1 treatment.

Interventions

Other: - Fecal microbiota transplantation

Fecal microbiota transplantation of an ICI responding or Fecal microbiota transplantation from an ICI non-responding donor, in combination with ICI.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.