Ropidoxuridine and Whole Brain Radiation Therapy in Treating Patients With Brain Metastases

PRIMARY OBJECTIVES:

I. To conduct a phase 1 dose escalation trial in patients with brain metastases to determine
the maximum tolerated dose (MTD) of ropidoxuridine (5-iodo-2-pyrimidinone-2'-deoxyribose
[IPdR]) when administered alone orally once daily for 7 consecutive days and then
concurrently with conventionally fractionated whole brain radiation therapy (WBRT) for
additional 21 days.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity to IPdR-mediated radiosensitization.

II. To estimate 6 month intracranial progression-free survival (PFS) in brain metastasis
cancer patients who receive daily oral IPdR x 28 days and WBRT.

III. To establish the pharmacokinetics of daily oral dosing of IPdR times 8 days.

IV. To evaluate safety and tolerability of oral IPdR x 28 days and WBRT. V. To estimate the
incidence of delayed neurological toxicity at 2, 4, and 6 months (+/-1 week) post-completion
of WBRT (for patients without intracranial progression) including delayed-recall through
Hopkins Verbal Learning Test Revised (HVLT-R) and quality of life as measured by the
Functional Assessment of Cancer Therapy-Brain (FACT-BR).

TERTIARY OBJECTIVES:

I. To assess for biochemical evidence of IPdR effect in normal tissues (circulating
granulocytes) by measuring %IUdR-deoxyribonucleic acid (DNA) cellular incorporation by flow
cytometry and high-pressure liquid chromatography (HPLC) analyses as an exploratory biomarker
for the %IUdR-DNA tumor cell incorporation from day 8 extracranial tumor biopsies in brain
metastasis cancer patients receiving MTD doses of IPdR as an exploratory biomarker of tumor
radiosensitization using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

II. To assess for biochemical evidence of IPdR effect in normal tissues (circulating
granulocytes) by measuring %IUdR-deoxyribonucleic acid (DNA) cellular incorporation by flow
cytometry and high-pressure liquid chromatography (HPLC) analyses as an exploratory biomarker
for 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 serial complete blood count
(CBC)/differential values.

OUTLINE: This is a dose escalation study of ropidoxuridine.

Patients receive ropidoxuridine orally (PO) once daily (QD) on days 1-28 and undergo WBRT
daily for not more than 5 days per week beginning on day 8 for a total of 15 fractions.

After completion of study treatment, patients are followed up every 2 months for 6 months,
every 3-4 months for 6 months, and every 6 months for 1 year.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy with brain metastases and are
being recommended palliative WBRT

- Life expectancy of greater than 2 months to allow completion of study treatment and
assessment of dose-limiting toxicity

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

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 100,000/mcL

- Calculated creatinine clearance >= 45 mL/min/1.73 m^2

- Total bilirubin:

- If no known liver metastases: total bilirubin < 1.5 x institutional upper limit
of normal (ULN)

- If known liver metastases, then: total bilirubin < 2.5 x ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]):

- If no known liver metastases: AST/SGOT and ALT/SGPT both < 2 x ULN

- If known liver metastases, then: AST/SGOT and ALT/SGPT both < 5 x ULN

- Human immunodeficiency virus (HIV) positive (+) patients with CD4 counts >= 250
cells/mm^3 on anti-viral therapy are eligible for the study

- Negative urine or serum pregnancy test result for females of child bearing potential
only; 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

Exclusion Criteria:

- Presence of diffuse lepto or pachy meningeal carcinomatosis (focal/localized
involvement from limited meningeal based metastases acceptable), greater than 1 cm
mid-line shift, uncal herniation, or severe hemorrhage/hydrocephalous (small
intra-lesional hemorrhage or anticipated surgical cavity is acceptable); patients with
seizure at presentation who have been started on levetiracetam and have been stable
for 48 hours prior to study registration are eligible at the discretion of treating
physician

- Patients who have received systemic cytotoxic chemotherapy or approved oral targeted
therapy or immunotherapy for 2 weeks, or other investigational agents for 3 weeks (4
half-lives for any oral targeted agents), or radiotherapy to a non-brain site for 2
weeks before initiation of IPdR therapy; patients who have recovered from serious
(Common Terminology Criteria for Adverse Events [CTCAE] grade 3 or more higher) to
grade 1 or less adverse events from the previous therapies are eligible;
prior/current/future hormonal therapy and/or bisphosphonates are permitted with no
minimum interval to initiation of study therapy; if indicated, patients can receive
palliative radiation therapy to a non-brain site concurrent or immediately post-study
treatment with no minimum interval to initiation of study therapy

- Patients must not have received prior whole brain radiation therapy; previous SRS/SRT
done at least 3 weeks from the planned start of IPdR therapy is acceptable;
SRS/SRT/fractionated boosts or neurosurgery can be performed once the dose limiting
toxicity (DLT) assessment has been completed, if felt clinically necessary

- Patients with primary tumors including germ cell tumor, or lymphoma/leukemia

- Patients who are receiving any other investigational agent

- Patients needing more than 8 mg dexamethasone per day at the time of start of WBRT
will not be eligible to participate in the study; however, patients will be allowed
entry into the study if it is medically safe to reduce the daily dose of dexamethasone
to 8 mg or less from the day of the start of WBRT; the dexamethasone dose for such
patients may be increased beyond 8 mg per day during the course of treatment if
medically necessary; this increased need for dose should be communicated to the
study's principal investigator, Dr Mohindra at the University of Maryland

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

- Uncontrolled intercurrent illness if it would increase the risk of toxicity or limit
compliance with study requirements; this includes, but is not limited to, ongoing
uncontrolled serious infection requiring intravenous (i.v.) antibiotics, progressive
congestive heart failure, unstable angina pectoris, 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