Summary

for people ages 18 years and up (full criteria)
at La Jolla, California and other locations
study started
David E. Piccioni

Description

Summary

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. Ropidoxuridine may help whole brain radiation therapy work better by making cancer cells more sensitive to the radiation therapy.

Official Title

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

Details

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Keywords

Metastatic Malignant Neoplasm Metastatic Malignant Neoplasm in the Brain Neoplasms Neoplasms, Second Primary Brain Neoplasms Laboratory Biomarker Analysis Pharmacological Study Quality-of-Life Assessment Ropidoxuridine Whole-Brain Radiotherapy

Eligibility

You can join if…

Open to people ages 18 years and up

  • Patients must have histologically confirmed malignancy with brain metastases and are being evaluated for 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 m2

  • 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 < 2 x ULN
  • If known liver metastases, then: AST/SGOT < 5 x ULN
  • Human immunodeficiency virus (HIV) positive (+) patients with CD4 counts >= 250 cells/mm3 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

You CAN'T join if...

  • Patients with 1-3 brain metastases, each < 3 cm by contrast magnetic resonance imaging(MRI), with stable systemic disease and ECOG score of 0-2, who would otherwise be eligible for stereotactic radiosurgery (SRS)/stereotactic radiation therapy (SRT)alone should not be enrolled into this study unless WBRT is recommended due to any medical reasons or logistic limitations as determined by the treating physician;patients who develop recurrence post-SRS/SRT or surgery alone and are recommended WBRT will be eligible for the protocol
  • Presence of diffuse leptomeningeal carcinomatosis (focal/localized involvement is acceptable), greater than 1 cm mid-line shift, uncal herniation, or significant hemorrhage/hydrocephalous (small intra-lesional hemorrhage 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 immunotherapy for 3 weeks before initiation of IPdR therapy or patients who have not recovered from serious (Common Terminology Criteria for Adverse Events [CTCAE] grade 3 or more)adverse events from the previously received agents; for oral targeted agents at least 4 half-lives of the agent should have elapsed prior to initiation of study therapy;prior hormonal therapy is permitted 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 4 weeks from the planned start of IPdR therapy is acceptable); patients planned upfront to undergo SRS/SRT/fractionated boosts or neurosurgery after WBRT are not eligible, however, these treatments/procedures 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 that 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, 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

Locations

  • UC San Diego Moores Cancer Center accepting new patients
    La Jolla California 92093 United States
  • University of California Davis Comprehensive Cancer Center accepting new patients
    Sacramento California 95817 United States
  • Huntsman Cancer Institute/University of Utah accepting new patients
    Salt Lake City Utah 84112 United States
  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center accepting new patients
    Houston Texas 77030 United States
  • Ben Taub General Hospital accepting new patients
    Houston Texas 77030 United States

Details

Status
accepting new patients
Start Date
Sponsor
National Cancer Institute (NCI)
ID
NCT02993146
Phase
Phase 1
Lead Scientist
David E. Piccioni
Study Type
Interventional
Last Updated
May 23, 2018