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

19 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Ropidoxuridine for gastrointestinal cancer?

Research shows that Ropidoxuridine, as a prodrug (a substance that converts into an active drug in the body) for Iododeoxyuridine, enhances the effectiveness of radiation therapy in treating gastrointestinal cancers by making cancer cells more sensitive to radiation. This combination has been shown to be less toxic and easier to administer than previous treatments, with promising results in both preclinical and early human studies. ^{1 2 3 4 5}

Is Ropidoxuridine (IPdR) safe for human use?

Ropidoxuridine (IPdR) has been studied as a treatment for advanced gastrointestinal cancer and is generally considered less toxic than its predecessor, Iododeoxyuridine (IUdR), with fewer side effects in preclinical and early human trials. In studies, it was tolerated at higher doses with minimal weight loss and less impact on normal tissues compared to IUdR, suggesting it is relatively safe for human use. ^{1 4 6 7 8}

How does the drug ropidoxuridine differ from other treatments for gastrointestinal cancer?

Ropidoxuridine is unique because it is an oral prodrug that converts into iododeoxyuridine (IUdR), a compound that makes cancer cells more sensitive to radiation, but with less toxicity and easier administration compared to IUdR itself. This makes it a promising option for enhancing the effectiveness of radiation therapy in gastrointestinal cancers. ^{1 2 4 5 9}

Research Team

Timothy J Kinsella

Principal Investigator

Rhode Island Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. United States 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. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Current status of radiation sensitization by fluoropyrimidines. [2013]

3. United States 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. [2020]

4. United States 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Intraarterial iododeoxyuridine infusion combined with irradiation. A pilot study. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

An in vivo comparison of oral 5-iodo-2'-deoxyuridine and 5-iodo-2-pyrimidinone-2'-deoxyribose toxicity, pharmacokinetics, and DNA incorporation in athymic mouse tissues and the human colon cancer xenograft, HCT-116. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

First-in-human phase 0 trial of oral 5-iodo-2-pyrimidinone-2'-deoxyribose in patients with advanced malignancies. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

A case report of typhlitis during novel use of ropidoxuridine-capecitabine-radiotherapy for treatment-naïve rectal cancer. [2023]