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
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 11
- 试验地点
- 14
- 主要终点
- Number of Participants Experiencing a Dose Limiting Toxicity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Treatment (ropidoxuridine, WBRT)
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.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (ropidoxuridine, WBRT)
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.
干预措施: Pharmacological Study (Other)
Treatment (ropidoxuridine, WBRT)
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.
干预措施: Quality-of-Life Assessment (Other)
Treatment (ropidoxuridine, WBRT)
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.
干预措施: Ropidoxuridine (Drug)
Treatment (ropidoxuridine, WBRT)
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.
干预措施: Whole-Brain Radiotherapy (Radiation)
结局指标
主要结局
Number of Participants Experiencing a Dose Limiting Toxicity
时间窗: Up to week 8
Dose limiting toxicities are protocol-defined, treatment-related adverse events.
次要结局
- Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease.(Up to 2 years)
- Intracranial Disease Status(At 6 months)
- Pharmacokinetics of Oral IPdR(At Day 8)
- Number of Participants Experience Grade 3, 4, or 5 Adverse Events(28 days)
- Number of Participants With Delayed Neurological Toxicity(At 6 months)