Ropidoxuridine for Glioblastoma

Recruiting at 8 trial locations

Overseen By Tyvin Rich, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Shuttle Pharmaceuticals, Inc.

Must not be taking: Acid-reducing agents

Disqualifiers: Prior glioblastoma treatment, Second malignancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 38

Duration: 6 weeks

54 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, open-label, phase 2 study evaluating the safety and efficacy of oral ropidoxuridine as a radiation-sensitizing agent in patients with newly diagnosed wild-type isocitrate dehydrogenase glioblastoma with an unmethylated O6-methylguanine-DNA methyltransferase promoter, undergoing standard 60 Gy radiotherapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does prohibit the use of acid-reducing agents like proton pump inhibitors and histamine-2 blockers. Glucocorticoid therapy for symptom control is allowed.

What data supports the effectiveness of the drug Ropidoxuridine for treating glioblastoma?

Research shows that Ropidoxuridine, when used as a prodrug for Iododeoxyuridine (IUdR), enhances the effect of radiation therapy in glioblastoma models, leading to better tumor control compared to radiation alone. It is also easier to administer and less toxic than IUdR, making it a promising option for radiosensitization in cancer treatment. ^{1 2 3 4 5}

Is Ropidoxuridine (IPdR) safe for humans?

Ropidoxuridine (IPdR) has been studied in both animals and humans, showing it is generally well-tolerated with minimal side effects. In animal studies, high doses did not cause significant weight loss or changes in activity, and in human studies, it was found to be less toxic than similar treatments. ^{1 2 3 6 7}

How is the drug Ropidoxuridine different from other treatments for glioblastoma?

Ropidoxuridine is unique because it is an oral prodrug that converts into a radiosensitizer, making cancer cells more sensitive to radiation therapy, and it is easier to administer with fewer side effects compared to similar treatments that require continuous infusion. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for adults with a new diagnosis of IDH-wildtype glioblastoma, which is an aggressive brain cancer, and their tumors must have an unmethylated MGMT promoter. Participants should be ready to undergo standard radiotherapy.

Inclusion Criteria

My kidney, liver, and bone marrow are functioning well.

I can care for myself and am up and about more than 50% of my waking hours.

I have signed the consent form or my legal representative has.

Exclusion Criteria

Any investigational therapy within 28 days or within 5 half-lives of study entry.

I am not pregnant or breastfeeding.

Any medical condition that places the patient at an unacceptably high risk for toxicities, or makes the patient unsuitable for study participation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive ropidoxuridine for 1 week before starting radiotherapy

1 week

5 visits (in-person)

Treatment

Participants receive ropidoxuridine and 60 Gy radiotherapy over 6 weeks

6 weeks

30 visits (in-person)

Rest

Participants undergo a 4-week rest period following treatment

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with MRI at week 11 and radiographic assessments every 3 months

Ongoing

Every 3 months until disease progression

Treatment Details

Interventions

• Ropidoxuridine

Trial Overview The study tests ropidoxuridine's effectiveness in making tumor cells more sensitive to radiation therapy. It's a phase 2 trial where patients receive either the usual treatment or the same plus oral ropidoxuridine.

Participant Groups

Group I: Ropidoxuridine 960 mg Experimental Treatment 1 Intervention

Ropidoxuridine is administered orally at 960 mg, 5 days a week for a total of 7 weeks, starting 1 week before the initiation of radiotherapy.

Group II: Ropidoxuridine 1200 mg Experimental Treatment 1 Intervention

Ropidoxuridine is administered orally at 1200 mg, 5 days a week for a total of 7 weeks, starting 1 week before the initiation of radiotherapy.

Ropidoxuridine is already approved in United States for the following indications:

Approved in United States as Ropidoxuridine for:

• Glioblastoma

Who Is Running the Clinical Trial?

Shuttle Pharmaceuticals, Inc.

Lead Sponsor

Trials

1

Recruited

50+

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]

A 14-day oral administration of 5-iodo2-pyrimidinone-2'-deoxyribose (IPdR) at doses up to 1500 mg/kg/day showed no significant systemic toxicity in athymic mice, indicating its safety for further clinical trials.

IPdR significantly enhanced the incorporation of the active drug IUdR into tumor DNA and improved radiosensitization in glioblastoma xenografts compared to radiation therapy alone, suggesting its potential efficacy in treating high-grade gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine radiosensitization in U251 human glioblastoma xenografts. Kinsella, TJ., Vielhuber, KA., Kunugi, KA., 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]

In a study of 60 patients with high-grade gliomas, including glioblastoma multiforme, the combination of halogenated pyrimidines and high-dose brain irradiation resulted in a median survival of 13 months, with 24% of patients surviving 18 months.

Patients who completed the planned treatment had a better median survival of 14 months and a 30% 18-month survival rate, indicating that the treatment regimen may be effective and comparable to other therapies for glioblastoma multiforme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Halogenated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme. Jackson, D., Kinsella, T., Rowland, J., et al.[2019]

The study found that combining the radiosensitizer 5-bromo-2-doxyuridine (BrdUrd) with continuous low dose rate irradiation significantly enhances the effectiveness of treatment for malignant glioma, particularly at a dose rate of 12 cGy/hr.

The results suggest that BrdUrd can improve the efficacy of both temporary and permanent radiation implants, making it a promising option for enhancing glioma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma. McLaughlin, PW., Mancini, WR., Stetson, PL., et al.[2019]

The study found that administering the drug IPdR three times a day (t.i.d.) significantly improved its conversion to the active form IUdR, leading to better incorporation of IUdR into tumor DNA and enhanced tumor growth delay compared to a once daily (q.d.) schedule.

The every other day (q.o.d.) dosing schedule also showed improved conversion efficiency and resulted in less systemic toxicity, making it a promising option for future clinical trials in enhancing tumor radiosensitization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts. Seo, Y., Yan, T., Schupp, JE., 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]

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

Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as a prodrug for 5-iodo-2'-deoxyuridine radiosensitization in U251 human glioblastoma xenografts. [2020]

3. 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]

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

Halogenated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme. [2019]

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

Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma. [2019]

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

Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2'-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts. [2020]

7. 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]