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

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02993146
First Posted: December 15, 2016
Last Update Posted: November 7, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
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.

Condition Intervention Phase
Metastatic Malignant Neoplasm Metastatic Malignant Neoplasm in the Brain Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Quality-of-Life Assessment Drug: Ropidoxuridine Radiation: Whole-Brain Radiotherapy Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of ropidoxuridine defined as the dose immediately below the lowest dose that produces dose limiting toxicities in at least 2 patients assessed by National Cancer Institute's Common Toxicity Criteria version 4 [ Time Frame: Up to week 8 ]

Secondary Outcome Measures:
  • Biomarkers [ Time Frame: Up to week 8 ]
    Biomarker data will be explored in a simple descriptive manner.

  • 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 ]
  • 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.

  • 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.

  • 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).


Estimated Enrollment: 47
Actual Study Start Date: December 7, 2016
Estimated Primary Completion Date: August 1, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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

Detailed Description:

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 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 < 2 x ULN
    • If known liver metastases, then: AST/SGOT < 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:

  • 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02993146


Locations
United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: David E. Piccioni    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: David E. Piccioni         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Karen L. Kelly    916-734-3089      
Principal Investigator: Karen L. Kelly         
United States, Maryland
University of Maryland/Greenebaum Cancer Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Pranshu Mohindra    800-888-8823      
Principal Investigator: Pranshu Mohindra         
United States, Minnesota
Mayo Clinic Cancer Center LAO Recruiting
Rochester, Minnesota, United States, 55905
Contact: Pranshu Mohindra       pmohindra@som.umaryland.edu   
Principal Investigator: Pranshu Mohindra         
United States, New York
Columbia University/Herbert Irving Cancer Center Recruiting
New York, New York, United States, 10032
Contact: Mary R. Welch    212-305-8615      
Principal Investigator: Mary R. Welch         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Pranshu Mohindra Mayo Clinic Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02993146     History of Changes
Other Study ID Numbers: 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 )
First Submitted: December 14, 2016
First Posted: December 15, 2016
Last Update Posted: November 7, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Neoplasms
Neoplasms, Second Primary
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases