Dose Escalation Trial of Nitroglycerin, 5-flourouracil and Rad Therapy for Rectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether topical nitroglycerin in addition to 5-flourouracil and radiation therapy are effective in the treatment of operable rectal cancer.

Detailed Description
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This is an open label, non-randomized, multi-cohort, dose escalation trial to evaluate the safety, tolerability, feasibility and maximum tolerated dose (MTD) of topical nitroglycerin in addition to 5-flourouracil and radiation therapy for neo-adjuvant treatment of, T3-T4 or clinically node positive, operable rectal cancer. Patients that would otherwise be eligible for concurrent neo-adjuvant chemotherapy with continuous infusion 5-FU, for locally advanced operable rectal cancer, will be assigned to 4 sequential cohorts of 3 different dose levels of nitro glycerin patches (0.2; 0.4; and 0.6 mg/hr). Each cohort will consist of 3 patients. All patients will receive radiation therapy, 45-50 Gy in 25-28 fractions to the pelvis along with continuous infusion 5-FU 225mg/M2 for the duration of the radiation therapy. The radiation therapy will be planned and delivered as per institutional standard of care for the Dallas VAMC radiation oncology department.

Official Title
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Phase I Dose Escalation Trial of Nitroglycerin in Addition to 5-flourouracil and Radiation Therapy for Neo-adjuvant Treatment of Operable Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Nitroglycerin 0.2 MG/HR
* Drug: Nitroglycerin 0.4 MG/HR
* Drug: Nitroglycerin 0.6 MG/HR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven Rectal Adenocarcinoma Histological diagnosis of operable T3-4, or T1-4 node positive, M0 rectal adenocarcinoma using endorectal ultrasound and/or MRI in addition to Computed Tomography (CT) of the chest, abdomen and pelvis for pre-study staging Acceptable alternatives for systemic staging instead of CT chest , abdomen, pelvis are CT abdomen and pelvis plus a Chest X-ray or a PET/CT Ability to give informed consent and willingness to adhere to study protocol Age ≥ 18 years and otherwise eligible to receive medical care at the Dallas VA Medical Center. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 Adequate hematological, hepatic and renal function defined as in protocol. Exclusion Criteria: Any condition that would hamper informed consent or ability to comply with the study protocol Significant history of cardiac disease, e.g. uncontrolled hypertension, unstable angina, decompensated congestive-heart failure, myocardial infarction within the last six months or ventricular arrhythmias requiring medication. Pregnant and lactating women. Patients taking Phosphodiesterase - 5 inhibitors (e.g. Sildenafil, Vardenafil or Tadalafil) and is unable to stop for the duration of the chemoradiotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitroglycerin<br>Dose escalation trial of Nitroglycerin | Drug: Nitroglycerin 0.2 MG/HR<br>* 0.2mg/hr nitroglycerin transdermal patch daily. The first 3 patients will have a low dose patch applied (0.2 mg/hr).<br>Drug: Nitroglycerin 0.4 MG/HR<br>* 0.4mg/hr nitroglycerin transdermal patch daily. The first 3 patients will have a low dose patch applied (0.2 mg/hr) if this is well tolerated a higher dose patch (0.4mg/hr) will be used for the next 3 patients.<br>Drug: Nitroglycerin 0.6 MG/HR<br>* 0.6mg/hr nitroglycerin transdermal patch daily. The first 3 patients will have a low dose patch applied (0.2 mg/hr) if this is well tolerated a higher dose patch (0.4mg/hr) will be used for the next 3 patients and if this is well tolerated an even higher dose patch (0.6mg/hr) will be used.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Experiencing Dose Limiting Toxicities (DLT) | DLT was defined as greater or equal to two instances of grade 3 toxicity, or a single event of grade 4-5 toxicity deemed probably or definitely related to the addition of transdermal neoadjuvant chemoradiation to the standard neoadjuvant chemoradiation | Up to 4-6 weeks for each dosing cohort | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Pathological Complete Response (pCR) | pathological complete response (pCR) at time of surgery following the completion of neoadjuvant therapy. This will be compared to the institutional historical pCR rate. Pathologic complete response indicates a complete absence of cancer at the time of surgical resection. | Time of surgery (  6-9 wks) following the completion of neoadjuvant therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nitroglycerin, 5-flourouracil, radiation therapy, neo-adjuvant treatment