Dose Optimization and Efficacy Assessment of a Fluoropyrimidine Antidote

Inclusion criteria

Presence of at least one severe toxicity or intoxication resulting from fluoropyrimidine use, defined as: receiving an overdose of medication (total dose and/or infusion rate higher than recommended in the package insert) and/or Grade 3 or 4 serious adverse events after fluoropyrimidine exposure, according to CTCAE v5.0, which may include (but are not limited to): nausea, vomiting, diarrhea, anemia, neutropenia, febrile neutropenia, thrombocytopenia, and mucositis;

Lack of access to uridine triacetate (UT) in the standard of care;

Diagnosis of an invasive solid tumor under systemic treatment with a fluoropyrimidine (5-fluorouracil or capecitabine);

Organ function considered adequate by the investigator prior to the current fluoropyrimidine intoxication episode;

Ability to take oral medication;

For men and women of reproductive potential, agreement to practice abstinence or use highly effective contraceptive methods during study participation and for at least 6 months after the last dose of IP;

Men must agree not to donate sperm for at least 6 months after the last dose of IP;

Body surface area between 1.4 and 2.4 m², calculated using the Du Bois method;

AST/ALT within normal limits for participants without liver metastases;

AST/ALT up to 3x the upper limit of normal in participants with liver metastases;

Total and fractionated bilirubin up to 2x the upper limit of normal;

Agreement to abstain from alcohol consumption during the treatment period;

As a specific inclusion criterion for participants in Phase 1 of the study: a medical indication, according to routine care, for hospitalization of at least 48 hours for the clinical management of fluoropyrimidine-related toxicity.

Exclusion criteria

Pregnant or breastfeeding women;

Known history of allergic reaction to the molecules of the copound and/or to other molecules in the same class;

Life expectancy of less than 30 days prior to hospital admission, based on underlying cancer and existing comorbidities;

Estimated creatinine clearance <70 mL/min;

Liver cirrhosis;

Known liver or kidney disease;

Individuals with acquired immunodeficiency may be included only if they have no active opportunistic infections and following careful clinical assessment by the investigator, taking into account concurrent medications;

Family history or known deficiency of the enzyme responsible for metabolizing the molecules of the copound and/or to other molecules in the same class;

Uncontrolled infection;

Hemodynamically unstable patients;

Patients under orotracheal intubation;

Patients unable to take oral medication;

Prolonged QT interval;

CNS metastases considered uncontrolled by the investigator;

History of malabsorptive or inflammatory gastrointestinal disease;

Use within the last 30 days of lactulose, protease inhibitors, amiodarone, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampin, or rifapentine;

Use within the last 5 days of dietary supplements containing the molecules of the copound;

Use within the last 30 days of drugs classified as anticonvulsants;

Personal history of seizures;

Comorbidities deemed limiting by the investigator;

History of renal or liver transplant;

Presence of intestinal obstruction.