FMT to Convert Response to Immunotherapy

Official title

Conversion of Unresponsiveness to Immunotherapy by Fecal Microbiota Transplantation in Patients With Metastatic Melanoma: a Randomized Phase Ib/IIa Trial

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.

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.

Primary outcome measures

• Efficacy, defined as clinical benefit (stable disease (SD), partial response (PR), complete response (CR) [Time frame: At 12 weeks after FMT]

Secondary outcome measures (5)

• Safety, measured as the occurrence of toxicity of grade 3 or higher [Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT]
• Progression free survival (PFS) [Time frame: Up to one year post-FMT]
• The change in gut microbiome following FMT and the duration and stability over time [Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT]
• The change in metabolome following FMT and the duration and stability over time [Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT]
• The immune changes; changes in cell populations (absolute, relative, phenotypical), in chemokine/cytokine levels and in the tumor-microenvironment [Time frame: At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT]

Eligibility 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• Antoni van Leeuwenhoek — Amsterdam

Publications

• Borgers JSW, Burgers FH, Terveer EM, van Leerdam ME, Korse CM, Kessels R, Flohil CC, Blank CU, Schumacher TN, van Dijk M, Henderickx JGE, Keller JJ, Verspaget HW, Kuijper EJ, Haanen JBAG. Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial. BMC Cancer. 2022 Dec 30 PMID 36585700

Identifiers

NCT: NCT05251389 · N21FMT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗