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.
