Fecal microbiota transplantation (FMT) combined with first-line gemcitabine and nab-paclitaxel chemotherapy in patients with advanced pancreatic ductal adenocarcinoma (PDAC).

Abstract

758 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer related deaths in Canada. There has been no approval of new systemic agents applicable to the majority of PDAC patients and novel approaches are required. As in the gut, PDAC tumours have distinct resident microbes. Fecal microbiota transplantation (FMT) into murine PDAC models using healthy donor stool altered the mouse gut microbiota and tumour microbiota, identifying cross-talk between these distinct microbiomes. FMT increased CD8+ T cell infiltration into the tumour leading directly to decreased tumour volume. This has not been tested in patients with advanced PDAC. Methods: This single institution, open-labelled single arm trial combined FMT with gemcitabine and nab-paclitaxel (GnP) in patients with advanced PDAC. Patients received a single oral FMT using healthy donor stool followed by GnP the following week. The primary objective is safety, assessed using the NCI-CTCAE v5 with a safety threshold of 50% grade ≥3 toxicities. Secondary objectives include overall survival, objective response rate, and biochemical response using CA199. Blood and stool were collected at 5 key timepoints to measure changes in the gut microbiome and circulating immune cell populations. Results: To date, 10 of a planned 20 patients have completed FMT and received at least 1 dose of GnP. Median age was 72 (59-82) and 7 were male. All had an ECOG 0-2. No toxicities to FMT were observed. All 10 experienced at least one adverse event, and 60% experienced a grade 3/4 toxicity with neutropenia most common. There were no new or unexpected toxicities, and all grade 3/4 toxicities were consistent with GnP and at an equivalent incidence. Three patients discontinued due to toxicity. Five patients underwent response evaluation with 1 assessment CT scan with 1 partial response and 4 with stable disease as per RECIST 1.1. Out of 7 patients with CA199 secreting tumours, only 1 had an increase, 1 was stable, and 5 experienced a decrease of ≥50%. Conclusions: Healthy donor FMT with GnP in this small cohort of patients with advanced PDAC appears safe with no increased or unexpected grade 3/4 toxicities. Early clinical results are promising. Clinical trial information: NCT06393400 . All toxicity reported for GnP + FMT: First 10 patients as number by toxicity by organ class. Grade 1 Grade 2 Grade 3 Grade 4 Blood & Lymphatic System  Anemia 4 2 1  Neutropenia 2 3  Thrombocytopenia 6 1  Leukopenia 1 3 Gastrointestinal  Nausea 1  Diarrhea 1 1  Vomiting 1  Constipation 1  Abdominal Pain 1  Abdominal Distension 1  Mucositis 1 General  Fatigue 2 2  Weakness 1 2  Pyrexia 3  Peripheral Edema 1  Asthenia 1 Investigations  Weight Loss 1 1  Increased ALT 4 1  Increased AST 4  Increased Alkaline Phosphatase 1 1  Increased GGT 1 1  Increased Bilirubin 2  Decreased Albumin 3 Metabolism & Nutrition  Anorexia 1 1  Dehydration 1 1  Hyponatremia 2  Hypokalemia 1 1  Hypophosphatemia 1  Hypomagnesemia 1