Ropidoxuridine for Gastrointestinal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Brain metastases, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ropidoxuridine to enhance the effectiveness of radiation therapy for individuals with certain advanced gastrointestinal cancers that have spread and are incurable. The main goal is to determine the optimal dose and monitor any side effects when combined with radiation. It suits those with advanced cancer in the esophagus, stomach, or colon who have not received radiation or chemotherapy in the past four weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does state that you cannot receive any systemic therapy during the radiation treatment. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that ropidoxuridine is likely to be safe for humans?

Research has shown that ropidoxuridine is generally safe for people. One study found that participants who took higher doses of ropidoxuridine experienced only minor side effects, such as slight weight loss. It also caused less harm to normal tissues compared to similar drugs. However, some individuals experienced serious side effects at 1,800 mg per day, which prevented further use. Consequently, the recommended dose for future studies is 1,200 mg per day.

These findings suggest that ropidoxuridine is relatively safe, with manageable side effects when used with radiation therapy. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Ropidoxuridine is unique because it combines with radiation therapy to potentially enhance cancer cell sensitivity to treatment. Unlike standard chemotherapy drugs that attack rapidly dividing cells, ropidoxuridine is a radiosensitizer, meaning it specifically makes cancer cells more vulnerable to radiation. This targeted approach could improve the effectiveness of radiation therapy for gastrointestinal cancer while possibly reducing the side effects associated with traditional chemotherapy. Researchers are excited about this treatment because it represents a novel way to boost the impact of radiation, offering hope for better outcomes in patients with this challenging condition.

What evidence suggests that ropidoxuridine might be an effective treatment for gastrointestinal cancer?

In this trial, participants will receive ropidoxuridine combined with radiation therapy. Studies have shown that ropidoxuridine can increase cancer cells' sensitivity to radiation, potentially leading to more effective tumor shrinkage. Research indicates that ropidoxuridine reaches blood levels that enhance radiation treatment effects. In earlier studies, combining ropidoxuridine with radiation resulted in a noticeable reduction in tumor growth. While these findings are promising, further research is needed to confirm its effectiveness in treating metastatic gastrointestinal cancers. ^{1 2 5 6 7}

Who Is on the Research Team?

Timothy J Kinsella

Principal Investigator

Rhode Island Hospital

Are You a Good Fit for This Trial?

This trial is for adults with advanced, incurable gastrointestinal cancers such as esophageal, liver, stomach, small bowel, pancreas, bile duct, colon or rectum cancer. They must not have had chemotherapy or radiation at the tumor site within 4 weeks and should have a life expectancy over 12 weeks. Participants need normal blood counts and organ function tests and agree to use contraception.

Inclusion Criteria

Your bilirubin levels are within the normal range for the hospital or clinic where you are being treated.

I can take care of myself but might not be able to do heavy physical work.

Your white blood cell count is at least 3,000 per microliter.

Exclusion Criteria

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with IPdR

I do not have brain metastases.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ropidoxuridine orally once daily for 28 days with concurrent intensity-modulated radiation therapy (IMRT) starting on day 8 for 3 weeks

4 weeks

Daily visits for radiation therapy, weekly monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Weekly visits

What Are the Treatments Tested in This Trial?

Interventions

• Ropidoxuridine

Trial Overview The study is testing ropidoxuridine's safety and optimal dosage in combination with radiation therapy to see if it makes cancer cells more sensitive to treatment. It's a phase I trial which means it's early in the testing process focusing on finding the right dose that’s safe.

How Is the Trial Designed?

Group I: Treatment (ropidoxuridine, IMRT) Experimental Treatment 4 Interventions

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase I clinical trial involving 19 patients with advanced metastatic gastrointestinal cancers, the oral prodrug IPdR was found to be feasible and tolerable when administered daily for 28 days alongside radiation therapy, with a recommended dose of 1,200 mg per day.

Pharmacokinetic studies showed that IPdR achieved plasma levels of IUdR that are effective for radiosensitization, leading to significant treatment responses, including 2 complete responses and 3 partial responses in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation. Kinsella, T., Safran, H., Wiersma, S., et al.[2023]

Orally administered 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is efficiently converted to 5-iodo-2'-deoxyuridine (IUdR) in athymic mice, showing minimal toxicity even at high doses (up to 2 g/kg) over 6 days, which is a significant improvement over continuous infusion of IUdR that caused over 20% body weight loss.

IPdR not only enhances the incorporation of IUdR into DNA of tumor cells but also improves the radiation response of human colon cancer xenografts, suggesting its potential as a prodrug for radiosensitization in resistant cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine-mediated radiosensitization in mouse and human tissues. Kinsella, TJ., Kunugi, KA., Vielhuber, KA., et al.[2020]

Oral administration of the prodrug IPdR significantly increased the incorporation of IUdR into DNA in MMR-deficient colon cancer xenografts compared to MMR-proficient ones, indicating a potential mechanism for enhanced radiosensitization.

IPdR treatment led to substantial radiosensitization in both MMR-deficient and MMR-proficient tumors, with a greater sensitization effect observed in MMR-deficient tumors, while showing no significant systemic toxicity during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2'-deoxyribose. Seo, Y., Yan, T., Schupp, JE., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02381561?intr=ROPIDOXURIDINE&aggFilters=studyType:int&viewType=Table&rank=3

Ropidoxuridine in Treating Patients With Advanced ... This phase I trial studies the side effects and best dose of ropidoxuridine in treating patients with gastrointestinal cancer that has ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6801071/

Phase I and Pharmacology study of Ropidoxuridine (IPdR) ... We report the clinical and pharmacologic results of a first-in-human phase I dose escalation study of IPdR + concurrent radiation therapy (RT)

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2128756/

5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR)-mediated ... IPdR alone at doses of ≥500 mg/kg/d results in moderate inhibition of tumor growth. The combination of IPdR + RT results in a significant IPdR dose-dependent ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/6/4/1468/288141/Preclinical-Toxicity-and-Efficacy-Study-of-a-14

Preclinical Toxicity and Efficacy Study of a 14-day Schedule of ... We also found an improvement in the therapeutic gain with p.o. IPdR for 14 days compared to continuous infusion IUdR for 14 days with a≥2-fold increase in the ...

5. withpower.com withpower.com/trial/phase-1-stomach-neoplasms-1-2016-fa28e

Ropidoxuridine for Gastrointestinal Cancer Pharmacokinetic studies showed that IPdR achieved plasma levels of IUdR that are effective for radiosensitization, leading to significant treatment responses, ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-19-0862/339281/p/Phase-I-and-Pharmacology-Study-of-Ropidoxuridine

Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as ... Results: Nineteen patients were entered on study. Dose-limiting toxicity was encountered at 1,800 mg every day, and the recommended phase II dose is 1,200 mg ...

7. clinicaltrial.be clinicaltrial.be/en/details/76905?per_page=100&only_recruiting=0&only_eligible=0

Ropidoxuridine in Treating Patients With Advanced Gastroi... 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 ...