Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Metastatic Malignant Neoplasm in the Brain
Conditions
Brief 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 (brain metastases). Ropidoxuridine may help whole brain radiation therapy work better by making cancer cells more sensitive to the radiation therapy.
Detailed description
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
OTHERQuality-of-Life Assessment
Ancillary studies
DRUGRopidoxuridine
Given PO
RADIATIONWhole-Brain Radiotherapy
Undergo WBRT
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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; 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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Dose Limiting Toxicity | Up to week 8 | Dose limiting toxicities are protocol-defined, treatment-related adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Up to 2 years | 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. |
| Intracranial Disease Status | At 6 months | Intracranial disease status assessed at month 6. |
| Pharmacokinetics of Oral IPdR | At Day 8 | To establish the pharmacokinetics of daily oral dosing of IPdR for 8 days. |
| Number of Participants Experience Grade 3, 4, or 5 Adverse Events | 28 days | To establish safety and tolerability of oral IPdR for 28 days with whole brain radiation treatment. |
| Number of Participants With Delayed Neurological Toxicity | At 6 months | To estimate the incidence of delayed neurological toxicity at 2, 4, and 6 months after whole blood radiation treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1A Patients receive ropidoxuridine 150 mg by mouth on days 1-28 and undergo whole-brain radiotherapy (WBRT) daily, except weekends, for not more than 5 days per week beginning on day 8 for a total of 15 fractions. | 1 |
| Dose Level 1B Patients receive ropidoxuridine 300 mg by mouth on days 1-28 and undergo whole-brain radiotherapy (WBRT) daily, except weekends, for not more than 5 days per week beginning on day 8 for a total of 15 fractions. | 1 |
| Dose Level 2A Patients receive ropidoxuridine 1200 mg by mouth on days 1-28 and undergo whole-brain radiotherapy (WBRT) daily, except weekends, for not more than 5 days per week beginning on day 8 for a total of 15 fractions. | 7 |
| Dose Level 2B Patients receive ropidoxuridine 1800 mg by mouth on days 1-28 and undergo whole-brain radiotherapy (WBRT) daily, except weekends, for not more than 5 days per week beginning on day 8 for a total of 15 fractions. | 2 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1A | Total | Dose Level 2B | Dose Level 2A | Dose Level 1B |
|---|---|---|---|---|---|
| Age, Continuous | 48 years | 58 years | 58 years | 60 years | 50 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 11 Participants | 2 Participants | 7 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 9 Participants | 2 Participants | 7 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 11 participants | 2 participants | 7 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 7 Participants | 2 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 1 | 3 / 7 | 1 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 6 / 7 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 2 / 7 | 1 / 1 |
Outcome results
Primary
Number of Participants Experiencing a Dose Limiting Toxicity
Dose limiting toxicities are protocol-defined, treatment-related adverse events.
Time frame: Up to week 8
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1A | Number of Participants Experiencing a Dose Limiting Toxicity | Experienced a dose limiting toxicity | 0 Participants |
| Dose Level 1A | Number of Participants Experiencing a Dose Limiting Toxicity | Did not experience a dose limiting toxicity | 1 Participants |
| Dose Level 1B | Number of Participants Experiencing a Dose Limiting Toxicity | Did not experience a dose limiting toxicity | 1 Participants |
| Dose Level 1B | Number of Participants Experiencing a Dose Limiting Toxicity | Experienced a dose limiting toxicity | 0 Participants |
| Dose Level 2A | Number of Participants Experiencing a Dose Limiting Toxicity | Experienced a dose limiting toxicity | 0 Participants |
| Dose Level 2A | Number of Participants Experiencing a Dose Limiting Toxicity | Did not experience a dose limiting toxicity | 6 Participants |
| Dose Level 2B | Number of Participants Experiencing a Dose Limiting Toxicity | Experienced a dose limiting toxicity | 1 Participants |
| Dose Level 2B | Number of Participants Experiencing a Dose Limiting Toxicity | Did not experience a dose limiting toxicity | 0 Participants |
Secondary
Intracranial Disease Status
Intracranial disease status assessed at month 6.
Time frame: At 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1A | Intracranial Disease Status | Unknown | 0 Participants |
| Dose Level 1A | Intracranial Disease Status | Intracranial disease free | 0 Participants |
| Dose Level 1A | Intracranial Disease Status | Intracranial disease progression | 1 Participants |
| Dose Level 1B | Intracranial Disease Status | Intracranial disease free | 1 Participants |
| Dose Level 1B | Intracranial Disease Status | Unknown | 0 Participants |
| Dose Level 1B | Intracranial Disease Status | Intracranial disease progression | 0 Participants |
| Dose Level 2A | Intracranial Disease Status | Unknown | 4 Participants |
| Dose Level 2A | Intracranial Disease Status | Intracranial disease free | 1 Participants |
| Dose Level 2A | Intracranial Disease Status | Intracranial disease progression | 1 Participants |
| Dose Level 2B | Intracranial Disease Status | Intracranial disease progression | 1 Participants |
| Dose Level 2B | Intracranial Disease Status | Unknown | 0 Participants |
| Dose Level 2B | Intracranial Disease Status | Intracranial disease free | 0 Participants |
Secondary
Number of Participants Experience Grade 3, 4, or 5 Adverse Events
To establish safety and tolerability of oral IPdR for 28 days with whole brain radiation treatment.
Time frame: 28 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 5 adverse events | 0 Participants |
| Dose Level 1A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 4 adverse events | 0 Participants |
| Dose Level 1A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 3 adverse events | 0 Participants |
| Dose Level 1A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 1-2 adverse events | 1 Participants |
| Dose Level 1B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 4 adverse events | 0 Participants |
| Dose Level 1B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 3 adverse events | 0 Participants |
| Dose Level 1B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 1-2 adverse events | 1 Participants |
| Dose Level 1B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 5 adverse events | 0 Participants |
| Dose Level 2A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 3 adverse events | 2 Participants |
| Dose Level 2A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 4 adverse events | 0 Participants |
| Dose Level 2A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 1-2 adverse events | 4 Participants |
| Dose Level 2A | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 5 adverse events | 0 Participants |
| Dose Level 2B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 1-2 adverse events | 0 Participants |
| Dose Level 2B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 4 adverse events | 0 Participants |
| Dose Level 2B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 5 adverse events | 0 Participants |
| Dose Level 2B | Number of Participants Experience Grade 3, 4, or 5 Adverse Events | Grade 3 adverse events | 1 Participants |
Secondary
Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease.
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.
Time frame: Up to 2 years
Population: Only participants in Part 2 are included in this objective. Data was not collected for participants in Part 1 (DL 1A and 1B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Stable Disease | 0 Participants |
| Dose Level 1A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Complete Response | 0 Participants |
| Dose Level 1A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Not assessed/Unknown | 0 Participants |
| Dose Level 1A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Progressive Disease | 0 Participants |
| Dose Level 1A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Partial Response | 0 Participants |
| Dose Level 1B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Progressive Disease | 0 Participants |
| Dose Level 1B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Complete Response | 0 Participants |
| Dose Level 1B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Stable Disease | 0 Participants |
| Dose Level 1B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Not assessed/Unknown | 0 Participants |
| Dose Level 1B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Partial Response | 0 Participants |
| Dose Level 2A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Not assessed/Unknown | 3 Participants |
| Dose Level 2A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Stable Disease | 2 Participants |
| Dose Level 2A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Complete Response | 0 Participants |
| Dose Level 2A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Partial Response | 0 Participants |
| Dose Level 2A | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Progressive Disease | 1 Participants |
| Dose Level 2B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Partial Response | 0 Participants |
| Dose Level 2B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Not assessed/Unknown | 0 Participants |
| Dose Level 2B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Complete Response | 0 Participants |
| Dose Level 2B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Stable Disease | 1 Participants |
| Dose Level 2B | Number of Participants With Complete Response, Partial Response, Stable Disease or Progressive Disease. | Progressive Disease | 0 Participants |
Secondary
Number of Participants With Delayed Neurological Toxicity
To estimate the incidence of delayed neurological toxicity at 2, 4, and 6 months after whole blood radiation treatment.
Time frame: At 6 months
Population: Assessment not collected
Secondary
Pharmacokinetics of Oral IPdR
To establish the pharmacokinetics of daily oral dosing of IPdR for 8 days.
Time frame: At Day 8
Population: Collection not performed.