Ropidoxuridine in Treating Patients With Advanced Gastrointestinal Cancer Undergoing Radiation Therapy

PRIMARY OBJECTIVES:

I. To conduct a phase I dose escalation trial, to determine the safety and the maximum
tolerated dose (MTD), of oral (po) IPdR (ropidoxuridine) given daily for 28 consecutive days
with concurrent intensity-modulated radiation therapy (IMRT) in patients with advanced
gastrointestinal cancers treated with palliative radiation.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To establish the pharmacokinetics of daily
po dosing of IPdR x 28 days. III. To assess, for patients treated at the MTD, for biochemical
evidence of IPdR effect in normal tissue (circulating granulocytes) and tumor tissue (in
patients with accessible tumor tissue) by measuring %iododeoxyuridine (IUdR)-deoxyribonucleic
acid (DNA) cellular incorporation by flow cytometry and high-pressure liquid chromatography
(HPLC) analyses.

IV. To assess the use of %IUdR-DNA cellular incorporation (measured by the investigational
laboratory assays of flow cytometry and HPLC) as an exploratory biomarker of IPdR for the
following effects: the %IUdR-DNA tumor cell incorporation from day 8 tumor biopsies in
gastrointestinal (GI) cancer patients receiving MTD doses of IPdR as an exploratory biomarker
of tumor radiosensitization using Response Evaluation Criteria in Solid Tumors (RECIST)
criteria.

V. To assess the use of %IUdR-DNA cellular incorporation (measured by the investigational
laboratory assays of flow cytometry and HPLC) as an exploratory biomarker of IPdR for the
following effects: the %IUdR-DNA cellular incorporation in patients' circulating granulocytes
taken weekly during the 28-day IPdR MTD dose, on day 29, and week 8 as an exploratory
biomarker of IPdR systemic toxicities to bone marrow as measured by complete blood count
(CBC)/differential values.

OUTLINE: This is a dose-escalation study of ropidoxuridine.

Beginning 30 minutes to 2 hours before radiation therapy, patients receive ropidoxuridine PO
once daily (QD) on days 1-28 in the absence of disease progression or unacceptable toxicity.
Beginning on day 8, patients undergo IMRT 5 days a week for 3 weeks in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed advanced, incurable
cancers of the esophagus, liver, stomach, small bowel, pancreas, bile duct, colon or
rectum and be eligible to receive chest, abdominal and/or pelvic radiation therapy
(RT) for palliation; documentation of this is required in physician note; concomitant
systemic therapy is not allowed during administration of palliative RT; palliative RT
can be considered for advanced primary tumors or metastatic disease as above

- Patients must not have received systemic chemotherapy for at least 4 weeks, and must
not have received prior radiation therapy to the tumor site being irradiated on this
study

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately; men and women treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of IPdR administration

- Ability to understand and the willingness to sign a written informed consent document

- Human immunodeficiency virus (HIV) positive (+) patients with cluster of
differentiation 4 (CD4) counts >= 250 cells/mm^3 on anti-viral therapy

- Women of child-bearing potential must have a negative pregnancy test

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to IPdR

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with IPdR