Rectal Cancer
Conditions
Keywords
nitroglycerin, 5-flourouracil, radiation therapy, neo-adjuvant treatment
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.
Interventions
DRUGNitroglycerin 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).
DRUGNitroglycerin 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.
DRUGNitroglycerin 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.
Sponsors
US Department of Veterans Affairs
University of Texas Southwestern Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Adult men and women otherwise eligible for medical care at Dallas VA Medical center were identified as they presented for consideration of standard therapy.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Dose escalation trial of Nitroglycerin: 0.2mg/hr nitroglycerin transdermal patch daily | 7 |
| Cohort 2 nitroglycerin: 0.4 mg/hr nitroglycerin transdermal patch daily | 3 |
| Cohort 3 nitroglycerin: 0.6 mg/hr nitroglycerin transdermal patch daily | 3 |
| Total | 13 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 1 Participants | 2 Participants | 8 Participants |
| Region of Enrollment United States | 7 participants | 3 participants | 3 participants | 13 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 3 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 7 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 7 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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
Time frame: Up to 4-6 weeks for each dosing cohort
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | The Number of Participants Experiencing Dose Limiting Toxicities (DLT) | 0 Participants |
| Cohort 2 | The Number of Participants Experiencing Dose Limiting Toxicities (DLT) | 0 Participants |
| Cohort 3 | The Number of Participants Experiencing Dose Limiting Toxicities (DLT) | 0 Participants |
Secondary
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 frame: Time of surgery (~ 6-9 wks) following the completion of neoadjuvant therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With a Pathological Complete Response (pCR) | 1 Participants |
| Cohort 2 | Number of Participants With a Pathological Complete Response (pCR) | 0 Participants |
| Cohort 3 | Number of Participants With a Pathological Complete Response (pCR) | 1 Participants |