FOLFIRINOX With Digoxin in Patients With Resectable Pancreatic Cancer

Pancreas Cancer Clinical Trial

Official title:

A Phase IIa (Pilot) Study of Neoadjuvant Chemotherapy With Folinic Acid, 5-FU, Irinotecan and Oxaliplatin (FOLFIRINOX) With Digoxin in Patients With Resectable Pancreatic Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04141995
• Other study ID #: 0668-19-FB
• Secondary ID: 1P50CA127297-01A
• Status: Recruiting
• Phase: Phase 2
• Start date: February 12, 2021
• Est. completion date: February 2025

Study information

• Verified date: September 2023
• Source: University of Nebraska
• Contact: Jessi E Delaney, RN
• Phone: 402-559-1212
• Email: jessdelaney[@]unmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Purpose: 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 patients with resectable pancreatic cancer.

Description:

Methods: Patients 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 (patients over age 65) or 0.25 mg (patients 65 or younger) PO daily. A steady-state will be achieved after five half-lives, which is about 7 to 10 days in the average subject. 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. Patients will receive IV chemotherapy at 2 week intervals. Restaging imaging will be performed after 4 doses. If the patient has stable or responsive disease, an additional 4 doses will be given followed by restaging imaging. The patient will then undergo surgical exploration ~ 4 weeks after the last dose of chemotherapy.

Clinical Endpoints: Primary Endpoints: clinical toxicity. Other endpoints: status of pathologic margins, response rate, pathologic stage, progression-free survival, and overall survival.

Correlative Endpoints: 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: February 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

1. Pathologically confirmed adenocarcinoma of the pancreas. Patients must have resectable disease with no evidence of distant metastasis

2. Age: Patients must be 19 years of age or older.

3. ECOG PS of 0-1

4. Patients who received chemotherapy for malignancies other than pancreatic cancer are eligible, provided that chemotherapy was completed > 5 years ago and there is no evidence of the prior malignancy at the time of study entry.

5. All patients must have radiographically assessable disease

6. Patients must have an initial ANC greater than or equal to 1000/µL and platelet count greater than or equal to 100,000/µL

7. Patient must have normal serum potassium, magnesium and corrected calcium level

8. Patients must have a serum creatinine less than or equal to 2.0 mg/dL

9. Patients must have a total bilirubin <= 1.5 mg/dL (unless the patient has Gilbert disease with elevated non-conjugated (indirect) bilirubin; in such cases, the indirect bilirubin should be <= 1.0 mg/dL). If the patient has biliary obstruction, biliary decompression will be required. Either endoscopic placement of biliary stent or percutaneous transhepatic drainage are acceptable. Once biliary drainage has been established, institution of FOLFOX therapy may proceed when the total bilirubin falls to <= 5.0 mg/dL. The addition of irinotecan will be delayed until the total bilirubin is 1.5 mg/dL or lower.

10. The patient must be aware of the neoplastic nature of his/her disease and willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts.

11. No prior chemotherapy for pancreatic cancer

Exclusion Criteria:

1. Patients who cannot undergo staging laparoscopy. For example, this may include patients with a prior history of multiple abdominal operations in which laparoscopy may not be technically feasible or might be potentially harmful.

2. Patients with a contra-indication to receiving digoxin therapy, such as AV block, sick sinus syndrome, bradycardia, and hypersensitivity to digoxin or digitalis preparations.

3. Uncontrolled inter-current illness including, but not limited to ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might jeopardize the ability of the patient to receive the therapy program outlined in this protocol with reasonable safety.

4. Pregnant and nursing women are excluded from this study because of the risk posed by the chemotherapy agents. Female patients of childbearing potential must have a negative urine pregnancy test before receiving the first dose of study drug

5. Patients with prior malignancy will be excluded except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancers from which the patient has been disease-free for at least 5 years.

6. Patients with known HIV infection or active hepatitis B or C infection due to concern for increased toxicity

7. Patients with an active autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), ankylosing spondylitis).

8. Patients with a recognized acquired, hereditary, or congenital immunodeficiency disease including cellular immunodeficienciess, hypogammaglobulinemia, or dysgammaglobulinemia.

Related Conditions & MeSH terms

• Adenocarcinoma of the Pancreas
• Pancreas Cancer
• Pancreatic Neoplasms

Intervention

Drug:
• Digoxin
Tablet, Oral: Generic: 0.125 mg, 0.25 mg
• 5Fluorouracil
5-FU will be given as a 46 hour continuous IV infusion
• Calcium Leucovorin
IV injection over 90 minutes
• Irinotecan
IV administration over 90 minutes
• Oxaliplatin
IV administration

Locations

Country	Name	City	State
United States	University of Nebraska Medical Center	Omaha	Nebraska

Sponsors (2)

Lead Sponsor	Collaborator
University of Nebraska	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	16 weeks
Secondary	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.	16 weeks