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

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

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.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Nitroglycerin 0.2 MG/HR; Drug: Nitroglycerin 0.4 MG/HR; Drug: Nitroglycerin 0.6 MG/HR

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75216
      • Dallas Veterans Affairs Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Nitroglycerin; Dose escalation trial of Nitroglycerin

Drug: Nitroglycerin 0.2 MG/HR; 0.2mg/hr nitroglycerin transdermal patch daily. The first 3 patients will have a low dose patch applied (0.2 mg/hr).; Drug: Nitroglycerin 0.4 MG/HR; 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.; Drug: Nitroglycerin 0.6 MG/HR; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: US Department of Veterans Affairs
• Investigators: Principal Investigator: Jonathan Dowell, MD, UT Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2016

Study Registration Dates

• First Submitted: July 29, 2011
• First Submitted That Met QC Criteria: July 29, 2011
• First Posted (ESTIMATE): August 1, 2011

Study Record Updates

• Last Update Posted (ACTUAL): January 14, 2021
• Last Update Submitted That Met QC Criteria: December 21, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: radiation therapy; nitroglycerin; 5-flourouracil; neo-adjuvant treatment
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Vasodilator Agents; Nitroglycerin
• Other Study ID Numbers: STU 122010-172