Ropidoxuridine in Treating Patients With Advanced Gastrointestinal Cancer Undergoing Radiation Therapy

Stage IV Pancreatic Cancer AJCC v6 and v7 Clinical Trial

Official title:

Phase I and Pharmacology Study of Oral 5-Iodo-2-Pyrimidinone-2'- Deoxyribose (IPdR) as a Prodrug for IUdR-Mediated Tumor Radiosensitization in Gastrointestinal Cancers

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02381561
• Other study ID #: NCI-2015-00258
• Secondary ID: NCI-2015-00258BR
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: February 1, 2016
• Est. completion date: March 5, 2025

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 19
• Est. completion date: March 5, 2025
• Est. primary completion date: November 8, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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

Related Conditions & MeSH terms

• Advanced Bile Duct Carcinoma
• Colonic Neoplasms
• Esophageal Neoplasms
• Gastrointestinal Neoplasms
• Intestinal Neoplasms
• Liver Neoplasms
• Pancreatic Neoplasms
• Rectal Neoplasms
• 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 IIB Pancreatic Cancer AJCC v6 and v7
• Stage III Colon Cancer AJCC v7
• Stage III Esophageal Cancer AJCC v7
• Stage III Gastric Cancer AJCC v7
• Stage III Liver Cancer
• Stage III Pancreatic Cancer AJCC v6 and v7
• Stage III Rectal Cancer AJCC v7
• Stage III Small Intestinal Cancer AJCC v7
• Stage IIIA Colon Cancer AJCC v7
• Stage IIIA Esophageal Cancer AJCC v7
• Stage IIIA Gastric Cancer AJCC v7
• Stage IIIA Rectal Cancer AJCC v7
• Stage IIIA Small Intestinal Cancer AJCC v7
• Stage IIIB Colon Cancer AJCC v7
• Stage IIIB Esophageal Cancer AJCC v7
• Stage IIIB Gastric Cancer AJCC v7
• Stage IIIB Rectal Cancer AJCC v7
• Stage IIIB Small Intestinal Cancer AJCC v7
• Stage IIIC Colon Cancer AJCC v7
• Stage IIIC Esophageal Cancer AJCC v7
• Stage IIIC Gastric Cancer AJCC v7
• Stage IIIC Rectal Cancer AJCC v7
• Stage IV Colon Cancer AJCC v7
• Stage IV Esophageal Cancer AJCC v7
• Stage IV Gastric Cancer AJCC v7
• Stage IV Liver Cancer
• Stage IV Pancreatic Cancer AJCC v6 and v7
• Stage IV Rectal Cancer AJCC v7
• Stage IV Small Intestinal Cancer AJCC v7
• Stage IVA Colon Cancer AJCC v7
• Stage IVA Liver Cancer
• Stage IVA Rectal Cancer AJCC v7
• Stage IVB Colon Cancer AJCC v7
• Stage IVB Liver Cancer
• Stage IVB Rectal Cancer AJCC v7
• Stomach Neoplasms

Intervention

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo IMRT

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Drug:
• Ropidoxuridine
Given PO

Locations

Country	Name	City	State
United States	Rhode Island Hospital	Providence	Rhode Island

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	%iododeoxyuridine (IUdR)-deoxyribonucleic acid (DNA) incorporation in tumor biopsies	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.	Up to 2 weeks
Secondary	Pharmacokinetic (PK) incorporation in tumor biopsies	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.	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
Secondary	%iododeoxyuridine (IUdR)-deoxyribonucleic acid (DNA) incorporation in peripheral (circulating) granulocytes	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.	Up to 4 weeks after completion of study treatment
Secondary	Pharmacokinetic (PK) incorporation in peripheral (circulating) granulocytes	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.	Days 1, 15 and 22 before drug administration, 30, 60, 120, and 240 minutes (and 24 hours on day 1 only) following drug administration
Secondary	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	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.	Day 8