Gut microbiota restoration with oral pooled fecal microbiotherapy after intensive chemotherapy: the phase 1b CIMON trial.

abstractIntensive induction chemotherapy (IC) combined with broad-spectrum antibiotics for acute myeloid leukemia (AML) leads to gut microbiota dysbiosis, promoting pathological conditions and an increased incidence of complications, possibly limiting eligibility to allogeneic hematopoietic cell transplantation (alloHCT). The purpose of this dose-ranging phase 1 study (CIMON) was to evaluate the first-in-man use of MaaT033, a pooled, allogeneic, lyophilized, and standardized fecal microbiotherapeutic product, formulated as a delayed-release capsule for oral administration. Primary objectives of the study were to evaluate the maximum tolerable dose of MaaT033 in 21 patients with AML having undergone IC and antibiotics. Secondary objectives were to assess MaaT033 safety, its efficacy in restoring the patients' gut microbiome using shotgun sequencing to evaluate the recommended dose regimen, and patient compliance. MaaT033 was shown to be safe and effective for gut microbiota restoration in patients with AML receiving IC and antibiotics, with an excellent gut microbiota reconstruction based on diversity indices at the species level and restoration of microbial communities close to the composition of the drug product. The maximum tolerable dose of MaaT033 was not determined because the interim results suggested adequate efficacy as measured by engraftment at lower doses (3 capsules per day). Moreover, inflammatory markers (C-reactive protein, interleukin-6) decrease with treatment, whereas short-chain fatty acids increase over time. A randomized, placebo-controlled phase 2b trial, in recipients of alloHCT patients is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT04150393.