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

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ClinicalTrials.gov Identifier: NCT02993146
Recruitment Status : Recruiting
First Posted : December 15, 2016
Last Update Posted : July 3, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

December 14, 2016
December 15, 2016
July 3, 2018
December 7, 2016
August 1, 2019   (Final data collection date for primary outcome measure)
Maximum tolerated dose of ropidoxuridine 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 [ Time Frame: Up to week 8 ]
MTD of ropidoxuridine defined as the dose immediately below the lowest dose that produces DLTs in at least 2 patients assessed by National Cancer Institute's Common Toxicity Criteria version 4 [ Time Frame: Up to week 8 ]
Complete list of historical versions of study NCT02993146 on ClinicalTrials.gov Archive Site
  • Tumor response assessed by Response Evaluation Criteria in Solid Tumors 1.1 [ Time Frame: Up to 2 years ]
    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).
  • Pharmacokinetic parameters of daily oral dosing of ropidoxuridine [ Time Frame: 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 course 1 ]
    The pharmacokinetics of daily oral dosing of ropidoxuridine for 28 days will be explored.
  • Biomarkers [ Time Frame: Up to week 8 ]
    Biomarker data will be explored in a simple descriptive manner.
  • Intracranial progression free survival (icPFS) [ Time Frame: From the date of start of treatment to time of progression or death, whichever occurs first, assessed at 6 months ]
    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.
  • Overall survival [ Time Frame: Up to 2 years ]
    Will be explored using the Kaplan-Meier method.
  • 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) [ Time Frame: Up to 6 months ]
  • Biomarkers [ Time Frame: Up to 32 weeks ]
    Biomarker data will be explored in a simple descriptive manner as data are limited in this small phase 1 study.
  • Incidence of delayed neurological toxicity assessed by HVLT-R and FACT-BR [ Time Frame: Up to 32 weeks ]
  • Pharmacokinetic parameters of daily oral dosing of ropidoxuridine [ Time Frame: Up to day 28 ]
  • Time to progression [ Time Frame: From study entry until first documented evidence of progression, assessed up to 32 weeks ]
    This will be explored using the Kaplan-Meier method.
  • Tumor response assessed by RECIST 1.1 [ Time Frame: Up to 32 weeks ]
    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).
Not Provided
Not Provided
 
Ropidoxuridine and Whole Brain Radiation Therapy in Treating Patients With Brain Metastases
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
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.

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.

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Metastatic Malignant Neoplasm
  • Metastatic Malignant Neoplasm in the Brain
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Drug: Ropidoxuridine
    Given PO
    Other Names:
    • 5-Iodo-2-pyrimidinone 2' deoxyribonucleoside
    • 5-Iodo-2-pyrimidinone-2'-deoxyribose
    • IPdR
  • Radiation: Whole-Brain Radiotherapy
    Undergo WBRT
    Other Names:
    • WBRT
    • whole-brain radiation therapy
Experimental: 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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Drug: Ropidoxuridine
  • Radiation: Whole-Brain Radiotherapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
47
Same as current
Not Provided
August 1, 2019   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
United States
 
 
NCT02993146
NCI-2016-01909
NCI-2016-01909 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HP-00067789
9979 ( Other Identifier: Mayo Clinic Cancer Center LAO )
9979 ( Other Identifier: CTEP )
UM1CA186686 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Pranshu Mohindra Mayo Clinic Cancer Center LAO
National Cancer Institute (NCI)
June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP