FOLFIRINOX With Digoxin in Patients With Resectable Pancreatic Cancer

September 29, 2023 updated by: University of Nebraska

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • Recruiting
        • University of Nebraska Medical Center
        • Contact:
        • Principal Investigator:
          • Jean L Grem

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment
Participants start FOLFIRINOX. They will also begin digoxin and take it up to 4-5 months time period in patients with resectable pancreatic cancer. Digoxin is taken at the time of neo-adjuvant chemotherapy treatment, prior to surgery. After surgery, participants will continue with post-adjuvant chemotherapy.
Drug: Oxaliplatin
IV administration
Other Names:
  • Eloxatin
Drug: Digoxin
Tablet, Oral: Generic: 0.125 mg, 0.25 mg
Other Names:
  • Lanoxin
  • Digitek
  • Digox
Drug: 5Fluorouracil
5-FU will be given as a 46 hour continuous IV infusion
Other Names:
  • 5-FU
  • Adrucil
Drug: Calcium Leucovorin
IV injection over 90 minutes
Other Names:
  • Folinic Acid
Drug: Irinotecan
IV administration over 90 minutes
Other Names:
  • Camptosar
  • CPT-11
  • Camptothecin-11

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients able to undergo resection surgery
Time Frame: 16 weeks
Regimen will be considered for further investigation if 14 of the 20 patients are able to undergo resection
16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of subjects with grade 4 thrombocytopenia and grade 3-4 diarrhea
Time Frame: 16 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nebraska

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Jean Grem, MD, University of Nebraska

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 12, 2021

Primary Completion (Estimated)

February 1, 2025

Study Completion (Estimated)

February 1, 2025

Study Registration Dates

First Submitted

October 18, 2019

First Submitted That Met QC Criteria

October 25, 2019

First Posted (Actual)

October 28, 2019

Study Record Updates

Last Update Posted (Actual)

October 3, 2023

Last Update Submitted That Met QC Criteria

September 29, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0668-19-FB
  • 1P50CA127297-01A2 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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