The purpose of this study is to determine the feasibility and safety of combining digoxin as a modulator of the hypoxia pathway in combination with FOLinic acid, 5-Fluorouracil, IRINotecan and OXaliplatin (FOLFIRINOX) in participants with resectable pancreatic cancer.
Participants with resectable pancreatic cancer will be treated with oxaliplatin 85 mg/m² IV over 2 hours, irinotecan 150 mg/m² given concurrently with folinic acid 400 mg/m² IV over 90 min, followed by a 46-hour infusion of 5-fluorouracil 2400 mg/m². Slow oral digitalization will be used starting with a daily dose of 0.125 (participants over age 65) or 0.25 mg (participants 65 or younger) per mouth daily. A steady-state will be achieved after five half-lives, which is about 7 to 10 days in the average participant. The initial blood level will be obtained one week after starting digoxin. Assuming the digoxin level is at steady-state and the renal function is stable, there is a linear relationship between digoxin dose and serum concentration. The target digoxin level is between 0.8 to 1.2 ng/mL. Participants will receive IV chemotherapy at 2 week intervals. Re-staging imaging will be performed after 4 doses. If the participants has stable or responsive disease, an additional 4 doses will be given followed by re-staging imaging. The participant will then undergo surgical exploration \~ 4 weeks after the last dose of chemotherapy. The primary endpoint is clinical toxicity. Other endpoints are status of pathologic margins, response rate, pathologic stage, progression-free survival, and overall survival. The correlative endpoint is baseline exome sequencing of circulating cell free tumor DNA. Measurement of quantity of circulating cell free tumor DNA at 4 week intervals while on chemotherapy and prior to surgery; resume at 3 month intervals after surgery. Genomic DNA will be collected at baseline for pharmacogenetic studies of polymorphisms that may be pertinent for the drugs used in the study. Blood will be collected for analysis of possible biomarkers of response to digoxin modulation.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
11
Tablet, Oral: Generic: 0.125 mg, 0.25 mg
5-FU will be given as a 46 hour continuous IV infusion
IV injection over 90 minutes
University of Nebraska Medical Center
Omaha, Nebraska, United States
Number of patients able to undergo resection surgery
Regimen will be considered for further investigation if 14 of the 20 patients are able to undergo resection
Time frame: 16 weeks
Percentage of subjects with grade 4 thrombocytopenia and grade 3-4 diarrhea
Continuous monitoring will be performed to monitor toxicity using Pocock stopping boundary that yields the probability of crossing the boundary at most 0.05 when the toxicity rate is equal to 0.182 or 0.28 separately.
Time frame: 16 weeks
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IV administration over 90 minutes
IV administration