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

Phase 1

Completed

Interventions: Drug: Nitroglycerin 0.2 MG/HR
Drug: Nitroglycerin 0.4 MG/HR
Drug: Nitroglycerin 0.6 MG/HR

Brief Summary: 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: 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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Nitroglycerin	Nitroglycerin 0.2 MG/HR	Dose escalation trial of Nitroglycerin
Nitroglycerin	Nitroglycerin 0.4 MG/HR	Dose escalation trial of Nitroglycerin
Nitroglycerin	Nitroglycerin 0.6 MG/HR	Dose escalation trial of Nitroglycerin

Primary Outcome Measures

Name	Time	Method
The Number of Participants Experiencing Dose Limiting Toxicities (DLT)	Up to 4-6 weeks for each dosing cohort	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

Secondary Outcome Measures

Name	Time	Method
Number of Participants With a Pathological Complete Response (pCR)	Time of surgery (~ 6-9 wks) following the completion of neoadjuvant therapy	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.