NCT05462496

Modulation of the Gut Microbiome With Pembrolizumab Following Chemotherapy in Resectable Pancreatic Cancer

Pilot Study of Gut Microbiome Modulation to Enable Efficacy of Neoadjuvant Checkpoint-based Immunotherapy Following Chemotherapy in Pancreatic Adenocarcinoma

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Sponsor: Icahn School of Medicine at Mount Sinai · Academic / Other
• Sex: All
• Age: 19 Years
• Healthy volunteers: Not accepted

Summary

A multi-institutional, single arm pilot study of antibiotics and pembrolizumab, following chemotherapy for the treatment of surgically resectable pancreatic cancer.

Detailed description

Phase: Pilot Study Objectives Primary Objectives: • To determine the change in immune activation in pancreatic tumor tissue following treatment with antibiotics, pembrolizumab. Secondary Objectives: * To establish the safety and feasibility of pre-operative antibiotics in combination with pembrolizumab following chemotherapy * To describe the preliminary anti-tumor activity of pre-operative therapy with antibiotics, pembrolizumab, and chemotherapy in subjects with resectable pancreatic cancer Exploratory Objectives: * To determine immunophenotypic changes in the pancreatic tumor microenvironment following depletion of the microbiome using antibiotics and inhibition of PD-1 with pembrolizumab and to correlate these changes with tumor response as measured by histologic regression. * To determine changes in systemic immunogenicity as measured in PBMCs harvested from blood following depletion of the microbiome using antibiotics and inhibition of PD-1 with pembrolizumab and to correlate these changes with tumor response as measured by histologic regression. * To determine changes in the microbiome as measured in tumor and stool following treatment with chemotherapy, antibiotics, and pembrolizumab and to correlate these changes with tumor response as measured by histologic regression. * To correlate changes in immune activation with changes in microbiome abundance and composition. Methodology: Multi-center, open label, single arm pilot study Endpoint Primary endpoint: • Achievement of immune response, defined as activation of one or more of the following T cell markers: HLA-DR, CD38, CD25, KI67, and CD69; activation is defined as an increase of 20% or more over baseline in percentage of T cells expressing the marker. Secondary Endpoints: * Adverse events graded according to the NCI's Common Terminology Criteria for Adverse Events (CTCAE v5.0). * R0 resection rate and histologic regression score * Histologic regression score * Overall response rate (ORR) * Overall survival rate (OS) Exploratory Endpoints: * Immune changes within blood and tissue following treatment and correlate with clinical endpoints * Microbiome changes in tissue and stool following treatment and correlate with clinical and immunologic endpoints Study Duration 5 years Participant Duration 6 months Enrollment Period 2 years Duration of IP administration 1 week Study Centers/Sites Multicenter: 1. Mount Sinai Health System, Tisch Cancer Institute 2. TBD 3. TBD Number of participants: 25 participants with 11 accrued at Mount Sinai Health over 2 years Description of Study Agent/Procedure: Ciprofloxacin 500 mg PO BID days 63-84. Metronidazole 500 mg PO TID days 63-84. Pembrolizumab 200 mg IV day 70. 5-Fluorouracil 2400 mg/m2 IV 46-48 hours infusion days 1, 15, 28, 42, 56. Leucovorin 400 mg/m2IV days 1, 15, 28, 42, 56. Irinotecan 150 mg/m2IV days 1, 15, 28, 42, 56. Oxaliplatin 85mg/m2IV days 1, 15, 28, 42, 56. Key Procedures: Tumor biopsy, surgical resection, blood draws, and stool collection. Statistical Analysis: The primary efficacy endpoint is the achievement of immune response, defined as activation of one or more of the following markers: HLA-DR, CD38, CD25, KI67, and CD69; activation is defined as an increase of 20% or more over baseline in percentage of cells expressing the marker. With 25 patients, a 95% exact confidence interval around the immune response rate will be no more than 0.46 units wide.

Conditions

• Pancreatic Cancer

Interventions

Type	Name	Description
PROCEDURE	Biopsy	Pre-treatment tumor biopsy
DRUG	FOLFIRINOX	Patients will receive FOLFIRINOX chemotherapy every 2 weeks for 5 cycles. One cycle of mFOLFIRINOX = 14 days. Cycles of mFOLFIRINOX are delivered as follows\*: * Oxaliplatin: 85 mg/m2 IV over 2 hours on Day 1, followed by, * Irinotecan: 150 mg/m2 IV over 90 minutes on Day 1, followed by, * Leucovorin\*\*: 400 mg/m2 IV over 2 hours on Day 1, followed by, * 5FU: 2400 mg/m2 IV over 46-48 hours on Days 1-3
DRUG	Ciprofloxacin	Ciprofloxacin and metronidazole will be initiated 7 days following 5th dose of FOLFIRINOX. Subjects will self-administer ciprofloxacin 500mg PO BID on days 1-21. Participants will be instructed to take the antibiotics with food to minimize stomach upset and to administer at the same time each day. Treatment with antibiotics will continue for 21 days unless there is unacceptable toxicity or disease progression. Subjects will record date, time and number of tablets they take on provided drug diaries.
DRUG	Metronidazole	Ciprofloxacin and metronidazole will be initiated 7 days following 5th dose of FOLFIRINOX. Subjects will self-administer metronidazole 500mg PO every 8 hours on days 1-21. Participants will be instructed to take the antibiotics with food to minimize stomach upset and to administer at the same time each day. Treatment with antibiotics will continue for 21 days unless there is unacceptable toxicity or disease progression. Subjects will record date, time and number of tablets they take on provided drug diaries.
DRUG	Pembrolizumab	Pembrolizumab will be initiated 7 days post initiation of antibiotics. Subjects will receive a flat dose of pembrolizumab 200mg IV over 30 minutes.
PROCEDURE	Surgical Resection	Following completion of 21 days of antibiotics, participant will undergo repeat imaging studies. If there is no progressive disease which renders participant surgically unresectable (based on NCCN guidelines 2.2021), subject will undergo definitive surgical resection.

Timeline

• Start date: 2023-03-16
• Primary completion: 2027-08-01
• Completion: 2028-04-01
• First posted: 2022-07-18
• Last updated: 2024-10-15

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study