Ropidoxuridine in Treating Patients With Advanced Gastrointestinal Cancer Undergoing Radiation Therapy

Phase 1

Active, not recruiting

• Conditions: Advanced Bile Duct Carcinoma; Stage IIB Pancreatic Cancer AJCC v6 and v7; Stage II Esophageal Cancer AJCC v7; Stage II Pancreatic Cancer AJCC v6 and v7; Stage IIA Esophageal Cancer AJCC v7; Stage IIA Pancreatic Cancer AJCC v6 and v7; Stage IIB Esophageal Cancer AJCC v7; Stage III Colon Cancer AJCC v7; Stage III Gastric Cancer AJCC v7; Stage III Liver Cancer
• Interventions: Radiation: Intensity-Modulated Radiation Therapy; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Ropidoxuridine

• Registration Number: NCT02381561
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase I trial studies the side effects and best dose of ropidoxuridine in treating patients with gastrointestinal cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment undergoing radiation therapy. Ropidoxuridine may help radiation therapy work better by making tumor cells more sensitive to the radiation therapy.

Detailed Description

PRIMARY OBJECTIVES:

I. To conduct a phase I dose escalation trial, to determine the safety and the maximum tolerated dose (MTD), of oral (po) IPdR (ropidoxuridine) given daily for 28 consecutive days with concurrent intensity-modulated radiation therapy (IMRT) in patients with advanced gastrointestinal cancers treated with palliative radiation.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To establish the pharmacokinetics of daily po dosing of IPdR x 28 days. III. To assess, for patients treated at the MTD, for biochemical evidence of IPdR effect in normal tissue (circulating granulocytes) and tumor tissue (in patients with accessible tumor tissue) by measuring %iododeoxyuridine (IUdR)-deoxyribonucleic acid (DNA) cellular incorporation by flow cytometry and high-pressure liquid chromatography (HPLC) analyses.

IV. To assess the use of %IUdR-DNA cellular incorporation (measured by the investigational laboratory assays of flow cytometry and HPLC) as an exploratory biomarker of IPdR for the following effects: the %IUdR-DNA tumor cell incorporation from day 8 tumor biopsies in gastrointestinal (GI) cancer patients receiving MTD doses of IPdR as an exploratory biomarker of tumor radiosensitization using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

V. To assess the use of %IUdR-DNA cellular incorporation (measured by the investigational laboratory assays of flow cytometry and HPLC) as an exploratory biomarker of IPdR for the following effects: 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 complete blood count (CBC)/differential values.

OUTLINE: This is a dose-escalation study of ropidoxuridine.

Beginning 30 minutes to 2 hours before radiation therapy, patients receive ropidoxuridine PO once daily (QD) on days 1-28 in the absence of disease progression or unacceptable toxicity. Beginning on day 8, patients undergo IMRT 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Study Timeline

• Study First Submitted: 2015-03-05
• Study First Submitted QC: 2015-03-05
• Study First Posted: 2015-03-06
• Study Start: 2016-02-01
• Primary Completion: 2018-11-08
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-06
• Last Update Posted: 2024-03-07
• Study Completion: 2025-03-05

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

• Patients must have histologically or cytologically confirmed advanced, incurable cancers of the esophagus, liver, stomach, small bowel, pancreas, bile duct, colon or rectum and be eligible to receive chest, abdominal and/or pelvic radiation therapy (RT) for palliation; documentation of this is required in physician note; concomitant systemic therapy is not allowed during administration of palliative RT; palliative RT can be considered for advanced primary tumors or metastatic disease as above
• Patients must not have received systemic chemotherapy for at least 4 weeks, and must not have received prior radiation therapy to the tumor site being irradiated on this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• 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
• Human immunodeficiency virus (HIV) positive (+) patients with cluster of differentiation 4 (CD4) counts >= 250 cells/mm^3 on anti-viral therapy
• Women of child-bearing potential must have a negative pregnancy test

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Exclusion Criteria

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients who are receiving any other investigational agents
• Patients with known brain metastases should be excluded from this clinical trial
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to IPdR
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ropidoxuridine, IMRT)	Intensity-Modulated Radiation Therapy	Beginning 30 minutes to 2 hours before radiation therapy, patients receive ropidoxuridine PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. Beginning on day 8, patients undergo IMRT 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (ropidoxuridine, IMRT)	Laboratory Biomarker Analysis	Beginning 30 minutes to 2 hours before radiation therapy, patients receive ropidoxuridine PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. Beginning on day 8, patients undergo IMRT 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (ropidoxuridine, IMRT)	Pharmacological Study	Beginning 30 minutes to 2 hours before radiation therapy, patients receive ropidoxuridine PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. Beginning on day 8, patients undergo IMRT 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (ropidoxuridine, IMRT)	Ropidoxuridine	Beginning 30 minutes to 2 hours before radiation therapy, patients receive ropidoxuridine PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. Beginning on day 8, patients undergo IMRT 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD) defined as the dose below which 2 or more of 6 patients experience dose-limiting toxicity	Up to 28 days

Secondary Outcome Measures

Name	Time	Method
%iododeoxyuridine (IUdR)-deoxyribonucleic acid (DNA) incorporation in tumor biopsies	Up to 2 weeks	Correlate %IUdR-DNA incorporation in human gastrointestinal (GI) tumor biopsies in the proposed phase I and pharmacokinetic (PK) clinical trial in GI cancer patients receiving palliative abdominal and/or pelvic radiation therapy (RT) by linear regression.
Pharmacokinetic (PK) incorporation in tumor biopsies	Days 1, 15 and 22 before drug administration, at 30, 60, 120, and 240 minutes (and 24 hours on day 1 only) following drug administration	Correlate %IUdR-DNA incorporation in human GI tumor biopsies in the proposed phase I and PK clinical trial in GI cancer patients receiving palliative abdominal and/or pelvic RT by linear regression.
%iododeoxyuridine (IUdR)-deoxyribonucleic acid (DNA) incorporation in peripheral (circulating) granulocytes	Up to 4 weeks after completion of study treatment	Correlate %IUdR-DNA incorporation in human GI tumor biopsies in the proposed phase I and PK clinical trial in GI cancer patients receiving palliative abdominal and/or pelvic RT by linear regression.
Pharmacokinetic (PK) incorporation in peripheral (circulating) granulocytes	Days 1, 15 and 22 before drug administration, 30, 60, 120, and 240 minutes (and 24 hours on day 1 only) following drug administration	Correlate %IUdR-DNA incorporation in human GI tumor biopsies in the proposed phase I and PK clinical trial in GI cancer patients receiving palliative abdominal and/or pelvic RT by linear regression.
Tumor response relationship to the %iododeoxyuridine (IUdR)-deoxyribonucleic acid (DNA) incorporation using Response Evaluation Criteria in Solid Tumors (RECIST) criteria based on high-pressure liquid chromatography (HPLC) and flow cytometry measurements	Day 8	Tumor response is the dependent variable and can be binomial (i.e. response versus \[vs.\] no response) or multinomial (i.e. complete response, partial response, stable disease or progressive disease) and the %IUdR-DNA incorporation is the independent variable.

Trial Locations

Locations (1)

Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States