This study will examine whether giving combination therapy with the drugs TNFerade plus capecitabine and radiation therapy before surgery in patients with rectal cancer is more effective than capecitabine and radiation therapy alone before surgery. TNFerade is a modified live virus that is used to insert the TNF-alpha gene into tumor cells. TNF-alpha, also known as tumor necrosis factor, is a substance produced by the immune system that has been used as an anticancer agent.

Patients 18 years of age or older with untreated rectal cancer that is confined to the primary tumor site, with or without lymph node involvement, may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, CT scans of the chest, abdomen, and pelvis, and MRI or CT scans of the brain, rectal ultrasound, colonoscopy, and review of pathological reports.

On admission to the study, participants are weighed and their heart rate, blood pressure, and temperature will be checked. A blood sample is collected for laboratory and research tests. Ten patients are treated with TNFerade, followed by chemotherapy (capecitabine) and radiation in order to gain experience with giving the TNFerade and to see if all tumor can be removed surgically. The remaining patients are then randomly assigned to receive one of two doses of TNFerade (4 X 109 pu or 4 X 1010 pu) or no TNFerade before chemotherapy and radiation. The treatment regimen is as follows:

- Radiation therapy to the tumor 5 days a week over a total of 5 weeks;

- Capecitabine, by mouth, twice a day for the 5 weeks of radiation therapy;

- TNFerade (for those assigned to receive this drug) injected into four sections of the tumor on the first day of radiation therapy and once a week thereafter for 5 weeks during radiation therapy.

Blood samples are drawn weekly to check for side effects of chemotherapy during treatment. Tumor biopsies are taken before the first dose of TNFerade or of radiation, then 3 days later, then 3 days before the third dose of TNFerade or radiation, and before the fifth dose of TNFerade or radiation. A minimum 4-week rest period follows the radiation and chemotherapy and then surgery is scheduled to remove all tumors. A temporary or permanent colostomy may be required.

Three weeks after surgery, patients return to NIH for blood tests and a CT scan to evaluate the response to treatment and to monitor side effects. Patients with no sign of tumor receive additional standard chemotherapy with 5-fluorouracil and leucovorin. Patients in whom tumor is still evident may receive additional radiation therapy or surgery.

Patients will be followed at NIH every 3 months for up to 3 years with a CT scan, physical examination, and blood tests. After this, patients will be followed by telephone or mail every year for up to 15 years to record any hospitalizations, new diagnoses, and progress.

Condition	Treatment or Intervention	Phase
Rectal Neoplasms	Drug: TNFerade	Phase II

Further Study Details: 

Expected Total Enrollment:  95

Cancers of the colon and rectum are the second leading cause of cancer death in the United States. Rectal cancers present a particular challenge for the local control given the anatomic considerations of the pelvis and their propensity to invade radially. The goal of therapy is to allow for the complete resection of these tumors while preserving sphincter function whenever possible. Combinations of pre-operative radiation and 5FU based chemotherapy followed by surgery result in complete pathologic responses in roughly 10-25% of cases. This trial is designed to determine if the local injection of a replication incompetent adenoviral vector carrying a radiation inducible TNF construct followed by radiation and chemotherapy can improve the complete pathologic response rate when compared to radiation and chemotherapy alone at the time of definitive surgical resection of locally advanced rectal cancers. Secondary endpoints will include disease free and overall survival as well as measurements of local and systemic gene product levels and determinations of changes in gene expression profiles as well as proteomic analysis of tumor tissue prior to, during and following therapy.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
All patients greater than or equal to 18 years old who have biopsy proven T3 or T4 rectal cancer which is confined to the primary tumor site with or without regional lymph node involvement. Rectal cancer will be defined as any adenocarcinoma of the rectum located below the peritoneal reflection excluding Paget's disease of the anus. The T status will be ascertained by transrectal ultrasound when possible. Patients with obstructive/circumferential lesions will be staged by CT scan and clinical exam.
Patients must be willing to return for follow-up.
Patients must be able to give and sign informed consent.
Patients must be suitable candidates for surgical resection post-chemoradiation, i.e. no history of severe congestive heart failure or severe pulmonary disease.
ECOG less than or equal to 2.
Life expectancy greater than 6 months.
EXCLUSION CRITERIA:
Patients with evidence of distant metastatic disease.
Any of the following hematologic abnormalities:
a. HGB less than 8.0 gm/dl unable to be corrected with a transfusion.
b. Absolute neutrophil count (ANC) less than 1500 cells/mm(3).
c. Platelets less than 100,000/mm(3).
d. APTT ratio or INR greater than 1.5 (except in patients who are therapeutically anticoagulated for non-related medical conditions such as atrial fibrillation and whose anti-thrombotic can not be withheld for vector injection or surgery).
A history of hepatic cirrhosis or present hepatic dysfunction with:
a. Total bilirubin greater than 2.0 mg/dl except for patients with Gilbert's syndrome who must have a direct bilirubin less than or equal to 1.0 mg/dl.
b. AST/ALT greater than or equal to 2.5 times upper limit of normal.
Renal insufficiency as determined by a serum creatinine greater than 2.0 mg/dl.
Patients may not have received prior therapy with chemotherapy, biologic therapy or radiation therapy for their rectal cancer.
Significant history of a medical problem that would preclude the patient from undergoing an operative procedure such as a history of severe congestive heart failure or active ischemic heart disease.
Concurrent second malignancy requiring systemic therapy.
Pregnant or lactating women, or men/women unable or unwilling to practice contraception.
Chronic systemic corticosteroid use.
Prior surgery for rectal cancer.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States

Study ID Numbers:  030300; 03-C-0300
Record last reviewed:  August 18, 2004
Last Updated:  March 30, 2005
Record first received:  September 15, 2003
ClinicalTrials.gov Identifier:  NCT00069147
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08