Ropidoxuridina y radioterapia de todo el cerebro en el tratamiento de pacientes con metástasis cerebrales
Estudio de fase 1 y farmacológico de 5-yodo-2-pirimidinona-2-desoxirribosa oral (IPdR) como profármaco para la radiosensibilización tumoral mediada por IUdR en metástasis cerebrales
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.
Descripción general del estudio
Estado
Condiciones
Descripción detallada
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.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 1
Contactos y Ubicaciones
Ubicaciones de estudio
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California
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La Jolla, California, Estados Unidos, 92093
- UC San Diego Moores Cancer Center
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Sacramento, California, Estados Unidos, 95817
- University of California Davis Comprehensive Cancer Center
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Iowa
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Iowa City, Iowa, Estados Unidos, 52242
- University of Iowa/Holden Comprehensive Cancer Center
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Maryland
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Baltimore, Maryland, Estados Unidos, 21201
- University of Maryland/Greenebaum Cancer Center
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Michigan
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Ann Arbor, Michigan, Estados Unidos, 48109
- University of Michigan Rogel Cancer Center
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Detroit, Michigan, Estados Unidos, 48201
- Wayne State University/Karmanos Cancer Institute
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Farmington Hills, Michigan, Estados Unidos, 48334
- Weisberg Cancer Treatment Center
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Nebraska
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Omaha, Nebraska, Estados Unidos, 68198
- University of Nebraska Medical Center
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New York
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New York, New York, Estados Unidos, 10032
- NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
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Pennsylvania
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Philadelphia, Pennsylvania, Estados Unidos, 19111
- Fox Chase Cancer Center
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Texas
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Dallas, Texas, Estados Unidos, 75390
- UT Southwestern/Simmons Cancer Center-Dallas
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Houston, Texas, Estados Unidos, 77030
- Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
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Houston, Texas, Estados Unidos, 77030
- Ben Taub General Hospital
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Utah
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Salt Lake City, Utah, Estados Unidos, 84112
- Huntsman Cancer Institute/University of Utah
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
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Patients must have histologically confirmed malignancy with brain metastases and are being recommended palliative WBRT
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Life expectancy of greater than 2 months to allow completion of study treatment and assessment of dose-limiting toxicity
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Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
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Leukocytes >= 3,000/mcL
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Absolute neutrophil count >= 1,000/mcL
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Platelets >= 100,000/mcL
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Calculated creatinine clearance >= 45 mL/min/1.73 m^2
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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
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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
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Human immunodeficiency virus (HIV) positive (+) patients with CD4 counts >= 250 cells/mm^3 on anti-viral therapy are eligible for the study
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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
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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
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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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 in the absence of disease progression or unacceptable toxicity. |
Correlative studies Ancillary studies
Otros nombres:
Correlative studies Undergo WBRT
Otros nombres:
Given PO
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Number of Participants Experiencing a Dose Limiting Toxicity
Periodo de tiempo: Up to week 8
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Dose limiting toxicities are protocol-defined, treatment-related adverse events. |
Up to week 8
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease.
Periodo de tiempo: Up to 2 years
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To observe and record anti-tumor activity as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Complete response is no remaining tumor. Partial response is a 30% or greater decrease in overall tumor burden. Progressive disease is a 20% or greater increase in tumor burden. Stable disease is between 20% increase and 30% decrease. |
Up to 2 years
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Intracranial Disease Status
Periodo de tiempo: At 6 months
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Intracranial disease status assessed at month 6. |
At 6 months
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Pharmacokinetics of Oral IPdR
Periodo de tiempo: At Day 8
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To establish the pharmacokinetics of daily oral dosing of IPdR for 8 days. |
At Day 8
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Number of Participants Experience Grade 3, 4, or 5 Adverse Events
Periodo de tiempo: 28 days
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To establish safety and tolerability of oral IPdR for 28 days with whole brain radiation treatment. |
28 days
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Number of Participants With Delayed Neurological Toxicity
Periodo de tiempo: At 6 months
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To estimate the incidence of delayed neurological toxicity at 2, 4, and 6 months after whole blood radiation treatment. |
At 6 months
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Pranshu Mohindra, Mayo Clinic Cancer Center LAO
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Actual)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimado)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Enfermedades Cerebrales
- Enfermedades del Sistema Nervioso Central
- Enfermedades del Sistema Nervioso
- Neoplasias por sitio
- Neoplasias
- Enfermedades hematológicas
- Neoplasias del Sistema Nervioso
- Neoplasias del Sistema Nervioso Central
- Enfermedades hemic y linfáticas
- Neoplasias Hematológicas
- Neoplasias Cerebrales
- ropidoxuridina
Otros números de identificación del estudio
- NCI-2016-01909
- UM1CA186691 (Subvención/contrato del NIH de EE. UU.)
- UM1CA186686 (Subvención/contrato del NIH de EE. UU.)
- NCI-2016-01909 (Identificador de registro: CTRP (Clinical Trial Reporting Program))
- HP-00067789
- 9979 (Otro identificador: CTEP)
- 9979 (Otro identificador: JHU Sidney Kimmel Comprehensive Cancer Center LAO)
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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