Malignant Digestive System Neoplasm
Conditions
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.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGCapecitabine
Given IPO
Given PO
PROCEDUREElectrocardiogram
Undergo ECG
DRUGFluorouracil
Given IV
DEVICEHolter Monitoring
Undergo Holter monitoring
Given PO
OTHERMedical Device Usage and Evaluation
Use EndoPAT
DRUGPlacebo Administration
Given PO
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
In Phase II, patients, treating clinicians, and study staff are blinded to treatment assignment.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in reactive hyperemia index (RHI) | Baseline (up to 3 days before start of infusion); during infusion; 12-36 hours post-infusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with RHI decline ≥ 20% | Up to 1 year | 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. |
| Proportion of patients with absolute RHI ≤ 2.0 | Up to 1 year | 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. |
| High-sensitivity troponin T (hsTnT) (indicator of myocardial ischemia) | Up to 1 year | Will be compared between patients with and without a decline in RHI ≥20% from baseline. |
| Presence of Holter abnormalities (ST-segment changes, arrhythmias) | Up to 1 year | Assessed using 48-hour continuous Holter monitoring. Will be compared between patients with and without a decline in RHI ≥20% from baseline. |
| Presence of ischemic symptoms (angina or angina equivalents, dyspnea, claudication) | Up to 1 year | Will be compared between patients with and without a decline in RHI ≥20% from baseline. |
| Seattle Angina Questionnaire (SAQ) | Baseline (up to 3 days before start of infusion); during infusion; 12-36 hours post-infusion | 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). |
Countries
United States
Contacts
CONTACTClinical Trials Referral Office
CONTACTInterventional & Ischemic Heart Disease Research Team
PRINCIPAL_INVESTIGATORJoerg Herrmann, MD
Mayo Clinic in Rochester
Outcome results
None listed