Vasodilator Therapy With Isosorbide Mononitrate or Diltiazem to Reduce Vasotoxicity in Patients With Gastrointestinal Cancer Receiving Fluoropyrimidine Therapy

Vasotoxicity Surveillance Using EndoPAT: The VASA Pilot Study

This phase I/II trial compares the effect of drugs that causes widening of blood vessels as a result of smooth muscle relaxation (vasodilator therapy) with isosorbide mononitrate, diltiazem or placebo to reduce vasotoxicity in patients with gastrointestinal cancer receiving fluoropyrimidine therapy. Some patients develop chest pain (possibly even a heart attack, a drop in heart function, or a rhythm abnormality) during treatment with a class of cancer drugs known as fluoropyrimidines, which include 5-Fluorouracil (5-FU) and capecitabine. These side effects are believed to be due to the development of an abnormal reactivity of the blood vessels referred to as vasospasm. Vasotoxicity is damage or toxicity inflicted upon blood vessels (vascular system), often causing dysfunction, remodeling, or narrowing (vasoconstriction). It is a broad term used to describe the detrimental effects of certain agents, such as chemotherapy drugs. Researchers want to evaluate how often the reactivity of blood vessels becomes abnormal, during the treatment with 5-FU or capecitabine and how clinically relevant and controllable/preventable this phenomenon is in patients with gastrointestinal cancer.

Study Overview

• Status: Recruiting
• Conditions: Malignant Digestive System Neoplasm
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Biospecimen Collection; Drug: Fluorouracil; Drug: Placebo Administration; Procedure: Electrocardiogram; Drug: Capecitabine; Device: Holter Monitoring; Other: Medical Device Usage and Evaluation; Drug: Isosorbide Mononitrate; Drug: Diltiazem Hydrochloride

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
• Study Contact Backup: Name: Interventional & Ischemic Heart Disease Research Team; Phone Number: 507-255-1724

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic in Rochester
      • Principal Investigator: Joerg Herrmann, MD
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Contact: Interventional & Ischemic Heart Disease Research Team; Phone Number: 507-255-1724

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• REGISTRATION: Age ≥ 18 years
• REGISTRATION: Histologically or cytologically confirmed gastrointestinal malignancy (colon, rectal, gastric, esophageal, or other GI cancer) for which fluoropyrimidine therapy (5-FU or capecitabine) is indicated, either as single agent or in combination with other systemic therapy
• REGISTRATION: Planned initiation of 5-FU (infusional) or oral capecitabine therapy, either as standard chemotherapy or as a radiosensitizer
• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• REGISTRATION: Ability to return to Mayo Clinic for baseline and follow-up EndoPAT testing, electrocardiogram (ECG), Holter monitoring, and blood draws
• REGISTRATION: Provide written informed consent
• REGISTRATION: Adequate baseline hemodynamic status: systolic blood pressure ≥ 120 mmHg and resting heart rate ≥ 70 beats/minute (to ensure safety for potential vasodilator therapy in Phase II)
• RANDOMIZATION: Completed all phase I baseline and follow-up assessments, including EndoPAT, ECG, high-sensitivity cardiac troponin T (hs-TnT), and Holter monitoring
• RANDOMIZATION: Demonstrated a ≥ 20% decline in reactive hyperemia index (RHI) from baseline at either phase I follow-up assessment as measured by EndoPAT
• RANDOMIZATION: Adequate hemodynamic status prior to randomization: systolic blood pressure ≥ 120 mmHg and resting heart rate ≥ 70 beats/minute
• RANDOMIZATION: Ability to tolerate and comply with study medication (isosorbide mononitrate, diltiazem, or placebo) per investigator assessment
• RANDOMIZATION: Willingness to initiate study medication 5 days before and continue through the assigned fluoropyrimidine treatment cycle
• RANDOMIZATION: Provide written informed consent for randomization phase

Exclusion Criteria:

• REGISTRATION: Current or planned treatment with long-acting nitrates or calcium channel blockers at the time of fluoropyrimidine initiation
• REGISTRATION: Known hypersensitivity or contraindication to nitrates or calcium channel blockers
• REGISTRATION: Baseline systolic blood pressure < 120 mmHg or resting heart rate < 70 beats/minute
• REGISTRATION: History of myocardial infarction ≤ 6 months prior to registration, or symptomatic heart failure [decompensated or New York Heart Association (NYHA) III-IV] requiring ongoing therapy
• REGISTRATION: Recent acute coronary syndrome or coronary revascularization within 3 months of enrollment
• REGISTRATION: High-grade atrioventricular (AV) block without pacemaker
• REGISTRATION: Use of PDE-5 inhibitors [e.g. sildenafil (Viagra)] within 48 hours of enrollment
• REGISTRATION: Uncontrolled intercurrent illness including but not limited to: unstable angina, symptomatic arrhythmias, uncontrolled infection, or psychiatric/social conditions limiting compliance with study requirements
• REGISTRATION: Physical inability to undergo EndoPAT testing (e.g., digital amputation, severe hand deformity, or other limiting condition)
• REGISTRATION: Pregnant or nursing persons
• REGISTRATION: Concurrent enrollment in another interventional clinical trial that, in the opinion of the investigator, would interfere with study endpoints

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I (EndoPAT, ECG, Holter monitoring, blood sample); Patients undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection during their SOC 5-FU infusion (any time from 2 hours after start to end of infusion) and 12-36 hours post-infusion or SOC capecitabine infusion 5-8 days after starting cycle 1 and 5-8 days after completing cycle 1, before beginning the next cycle of treatment.	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Fluorouracil; Given IV; Other Names: 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5-Fu; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Procedure: Electrocardiogram; Undergo ECG; Other Names: Electrocardiograms; ECG; EKG; Drug: Capecitabine; Given IPO; Other Names: Xeloda; Ro 09-1978/000; Device: Holter Monitoring; Undergo Holter monitoring; Other Names: Holter Monitor; HOLTER CONTINUOUS ECG RECORDING; Holter Electrocardiography; Other: Medical Device Usage and Evaluation; Use EndoPAT
Experimental: Phase II arm I (Isosorbide mononitrate); Patients receive isosorbide mononitrate PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Electrocardiogram; Undergo ECG; Other Names: Electrocardiograms; ECG; EKG; Device: Holter Monitoring; Undergo Holter monitoring; Other Names: Holter Monitor; HOLTER CONTINUOUS ECG RECORDING; Holter Electrocardiography; Other: Medical Device Usage and Evaluation; Use EndoPAT; Drug: Isosorbide Mononitrate; Given PO; Other Names: Imdur; ISMO; Monoket; Monosordil
Experimental: Phase II arm II (Diltiazem hydrochloride); Patients receive diltiazem PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Electrocardiogram; Undergo ECG; Other Names: Electrocardiograms; ECG; EKG; Device: Holter Monitoring; Undergo Holter monitoring; Other Names: Holter Monitor; HOLTER CONTINUOUS ECG RECORDING; Holter Electrocardiography; Other: Medical Device Usage and Evaluation; Use EndoPAT; Drug: Diltiazem Hydrochloride; Given PO; Other Names: Cardizem; Diltiazem HCl
Placebo Comparator: Phase II arm III (Placebo administration); Patients receive placebo PO QD for 7-12 days on study. Patients also undergo EndoPat, ECG, Holter monitoring for 48 hours, and blood sample collection on study.	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Placebo Administration; Given PO; Procedure: Electrocardiogram; Undergo ECG; Other Names: Electrocardiograms; ECG; EKG; Device: Holter Monitoring; Undergo Holter monitoring; Other Names: Holter Monitor; HOLTER CONTINUOUS ECG RECORDING; Holter Electrocardiography; Other: Medical Device Usage and Evaluation; Use EndoPAT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in reactive hyperemia index (RHI)	Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value < 0.05.	Baseline (up to 3 days before start of infusion); during infusion; 12-36 hours post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with RHI decline ≥ 20%	Assessed from baseline (prechemotherapy) to follow-up assessments during and after fluoropyrimidine exposure. Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value < 0.05.	Up to 1 year
Proportion of patients with absolute RHI ≤ 2.0	Assessed from baseline (prechemotherapy) to follow-up assessments during and after fluoropyrimidine exposure. Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value < 0.05.	Up to 1 year
High-sensitivity troponin T (hsTnT) (indicator of myocardial ischemia)	Will be compared between patients with and without a decline in RHI ≥20% from baseline.	Up to 1 year
Presence of Holter abnormalities (ST-segment changes, arrhythmias)	Assessed using 48-hour continuous Holter monitoring. Will be compared between patients with and without a decline in RHI ≥20% from baseline.	Up to 1 year
Presence of ischemic symptoms (angina or angina equivalents, dyspnea, claudication)	Will be compared between patients with and without a decline in RHI ≥20% from baseline.	Up to 1 year
Seattle Angina Questionnaire (SAQ)	The Seattle Angina Questionnaire (SAQ) is a 19-item questionnaire used to assess self-reported health status and quality of life over the past 4 weeks in patients with coronary artery disease (CAD). Nine questions are answered on a 6-point scale (severely limited, moderately limited, somewhat limited, a little limited, not limited, limited, or did not do for other reasons). The remaining questions are answered using similar scales (e.g., not satisfied at all, mostly dissatisfied, somewhat satisfied, mostly satisfied, highly satisfied). Scores range from 0-100 with higher scores indicating better overall health (fewer symptoms).	Baseline (up to 3 days before start of infusion); during infusion; 12-36 hours post-infusion

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Joerg Herrmann, MD, Mayo Clinic in Rochester

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2026
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2030

Study Registration Dates

• First Submitted: March 2, 2026
• First Submitted That Met QC Criteria: March 2, 2026
• First Posted (Actual): March 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Nucleic Acids, Nucleotides, and Nucleosides; Carbohydrates; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Alcohols; Nucleosides; Uracil; Pyrimidinones; Benzazepines; Diagnostic Techniques, Cardiovascular; Deoxyribonucleosides; Heart Function Tests; Electrodiagnosis; Sugar Alcohols; Monitoring, Physiologic; Electrocardiography; Monitoring, Ambulatory; Sorbitol; Capecitabine; Fluorouracil; Diltiazem; Isosorbide; Specimen Handling; dehydroftorafur; Electrocardiography, Ambulatory; isosorbide-5-mononitrate
• Other Study ID Numbers: MC250411 (Other Identifier: Mayo Clinic); NCI-2026-01065 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 25-011528 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No