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

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of ropidoxuridine when given together with whole brain radiation therapy in treating patients with cancer that has spread to the brain (brain metastases). Ropidoxuridine may help whole brain radiation therapy work better by making cancer cells more sensitive to the radiation therapy.

Detailed Description
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PRIMARY OBJECTIVE: I. To conduct a phase 1 dose escalation trial in patients with brain metastases to determine the recommended phase -2 dose 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: Va. Delayed-recall through Hopkins Verbal Learning Test Revised (HVLT-R). Vb. Quality of life as measured by the Functional Assessment of Cancer Therapy-Brain (FACT-BR). CORRELATIVE 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 following: Ia. %IUdR-DNA tumor cell incorporation from day 8 extracranial tumor biopsies in brain metastasis cancer patients receiving RP2D doses of IPdR as an exploratory biomarker of tumor radiosensitization using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Ib. %IUdR-DNA cellular incorporation in patients' circulating granulocytes taken weekly during the 28-day IPdR RP2D 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 in the absence of disease progression or unacceptable toxicity. 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.

Official Title
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Phase 1 and Pharmacology Study of Oral 5-Iodo-2-Pyrimidinone-2-Deoxyribose (IPdR) as a Prodrug for IUdR-Mediated Tumor Radiosensitization in Brain Metastases

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Metastatic Malignant Neoplasm in the Brain

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Quality-of-Life Assessment
* Drug: Ropidoxuridine
* Radiation: Whole-Brain Radiotherapy


Participation Criteria
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Eligibility Criteria
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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; Note: The effects of IPdR on the developing human fetus are unknown; for this reason and because radiation therapy is known to be teratogenic, 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 because IPdR is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IPdR, breastfeeding should be discontinued if the mother is treated with IPdR

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ropidoxuridine, WBRT)<br>Patients receive ropidoxuridine PO 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 in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Ropidoxuridine<br>* Given PO<br>* Other names: IPdR;Radiation: Whole-Brain Radiotherapy<br>* Undergo WBRT<br>* Other names: whole-brain radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of ropidoxuridine | Will be defined as defined as the highest dose that has fewer than 3 (out of 6) patients experiencing dose-limiting toxicity assessed by National Cancer Institute's Common Toxicity Criteria version 4. | Up to week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response assessed by Response Evaluation Criteria in Solid Tumors 1.1 | Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group). | Up to 2 years | 
| Pharmacokinetic parameters of daily oral dosing of ropidoxuridine | The pharmacokinetics of daily oral dosing of ropidoxuridine for 28 days will be explored. | Pre-dose, 30, 60, 120, 240 minutes and 24 hours following oral dose administration on day 1 of course 1; pre-dose, 30, 60, 120, and 240 minutes following oral dose administration on days 15 and 22 of cycle 1 | 
| Biomarkers | Biomarker data will be explored in a simple descriptive manner. | Up to week 8 | 
| Intracranial progression free survival (icPFS) | This will be explored using the Kaplan-Meier method. The icPFS estimates at 6 months with their standard error of the estimate will be reported. | From the date of start of treatment to time of progression or death, whichever occurs first, assessed at 6 months | 
| Overall survival | Will be explored using the Kaplan-Meier method. | Up to 2 years | 
| Incidence of delayed neurological toxicity including delayed-recall assessed by Hopkins Verbal Learning Test Revised (HVLT-R) and quality of life assessed by Functional Assessment of Cancer Therapy-Brain (FACT-BR) |  | Up to 6 months |