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

NCT07456852 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: MC250411NCI-2026-0106525-011528
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Malignant Digestive System Neoplasm

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Proportion of patients with RHI decline ≥ 20%

  Up to 1 year

• Proportion of patients with absolute RHI ≤ 2.0

  Up to 1 year

• High-sensitivity troponin T (hsTnT) (indicator of myocardial ischemia)

  Up to 1 year

• Presence of Holter abnormalities (ST-segment changes, arrhythmias)

  Up to 1 year

• Presence of ischemic symptoms (angina or angina equivalents, dyspnea, claudication)

  Up to 1 year

Study Arms (4)

Phase I (EndoPAT, ECG, Holter monitoring, blood sample)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Drug: Capecitabine; Procedure: Electrocardiogram; Drug: Fluorouracil; Device: Holter Monitoring; Other: Medical Device Usage and Evaluation; Other: Questionnaire Administration

Phase II arm I (Isosorbide mononitrate)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Electrocardiogram; Device: Holter Monitoring; Drug: Isosorbide Mononitrate; Other: Medical Device Usage and Evaluation; Other: Questionnaire Administration

Phase II arm II (Diltiazem hydrochloride)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Drug: Diltiazem Hydrochloride; Procedure: Electrocardiogram; Device: Holter Monitoring; Other: Medical Device Usage and Evaluation; Other: Questionnaire Administration

Phase II arm III (Placebo administration)

PLACEBO COMPARATOR

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.

Procedure: Biospecimen Collection; Procedure: Electrocardiogram; Device: Holter Monitoring; Other: Medical Device Usage and Evaluation; Drug: Placebo Administration; Other: Questionnaire Administration

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Phase I (EndoPAT, ECG, Holter monitoring, blood sample); Phase II arm I (Isosorbide mononitrate); Phase II arm II (Diltiazem hydrochloride); Phase II arm III (Placebo administration)

Capecitabine DRUG

Given IPO

Also known as: Ro 09-1978/000, Xeloda

Phase I (EndoPAT, ECG, Holter monitoring, blood sample)

Diltiazem Hydrochloride DRUG

Given PO

Also known as: Cardizem, Diltiazem HCl

Phase II arm II (Diltiazem hydrochloride)

Electrocardiogram PROCEDURE

Undergo ECG

Also known as: ECG, EKG, Electrocardiograms

Phase I (EndoPAT, ECG, Holter monitoring, blood sample); Phase II arm I (Isosorbide mononitrate); Phase II arm II (Diltiazem hydrochloride); Phase II arm III (Placebo administration)

Fluorouracil DRUG

Given IV

Also known as: 5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757

Phase I (EndoPAT, ECG, Holter monitoring, blood sample)

Holter Monitoring DEVICE

Undergo Holter monitoring

Also known as: HOLTER CONTINUOUS ECG RECORDING, Holter Electrocardiography, Holter Monitor

Phase I (EndoPAT, ECG, Holter monitoring, blood sample); Phase II arm I (Isosorbide mononitrate); Phase II arm II (Diltiazem hydrochloride); Phase II arm III (Placebo administration)

Isosorbide Mononitrate DRUG

Given PO

Also known as: Imdur, ISMO, Monoket, Monosordil

Phase II arm I (Isosorbide mononitrate)

Medical Device Usage and Evaluation OTHER

Use EndoPAT

Phase I (EndoPAT, ECG, Holter monitoring, blood sample); Phase II arm I (Isosorbide mononitrate); Phase II arm II (Diltiazem hydrochloride); Phase II arm III (Placebo administration)

Placebo Administration DRUG

Given PO

Phase II arm III (Placebo administration)

Questionnaire Administration OTHER

Ancillary studies

Phase I (EndoPAT, ECG, Holter monitoring, blood sample); Phase II arm I (Isosorbide mononitrate); Phase II arm II (Diltiazem hydrochloride); Phase II arm III (Placebo administration)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Mayo Clinic: lead

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Gastrointestinal Neoplasms

Interventions

Specimen Handling; Capecitabine; Diltiazem; Fluorouracil; dehydroftorafur; Electrocardiography, Ambulatory; isosorbide-5-mononitrate; Isosorbide

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Electrocardiography; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Electrodiagnosis; Monitoring, Ambulatory; Monitoring, Physiologic; Sorbitol; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Study Officials

• Joerg Herrmann, MD

  Mayo Clinic in Rochester

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Clinical Trials Referral Office

CONTACT

855-776-0015; mayocliniccancerstudies@mayo.edu

Interventional & Ischemic Heart Disease Research Team

CONTACT

507-255-1724

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: In Phase II, patients, treating clinicians, and study staff are blinded to treatment assignment.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be observed during their initial cycle of standard of care 5-FU or capecitabine treatment to establish baseline condition and evaluate for abnormal vasoreactivity prior to beginning phase II. Any patients with a \>= 20% decline in RHI from baseline as measured by EndoPAT during phase I will undergo randomization and continue to phase II.

Study Record Dates

• First Submitted: March 2, 2026
• First Posted: March 9, 2026
• Study Start: April 30, 2026
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2030
• Last Updated: June 2, 2026

Record last verified: 2026-05

Locations

US (1)