Uridine Triacetate as an Antidote for Patients at Excess Risk of 5-Fluorouracil (5-FU) Toxicity Due to Overdosage or Impaired Elimination

The purpose of this study is to provide uridine triacetate as an antidote to treat patients at excess risk of 5-fluorouracil (5-FU) toxicity due to overdosage (defined as administration of 5-FU at a dose, or infusion rate, greater than the MTD for the patient's intended regimen) or impaired elimination. This study will evaluate survival for 30 days in patients treated with uridine triacetate, initiated between 3 and 96 hours after completion of 5-FU dosing, who are at excess risk of toxicity due to overdosage or impaired elimination. The study will also assess the occurrence, severity, and duration of toxicities known to be associated with 5-FU overdosage or impaired elimination.

Demographics, baseline disease information, prior disease-directed therapy including 5-FU, and details of the 5-FU overexposure (dose, cause, and timing) will be collected. In addition, the occurrence, severity, and duration of neutropenia, thrombocytopenia, leukopenia, mucositis, diarrhea, and skin and neurological toxicities, commonly associated with 5-FU dosing, will be assessed. Vital signs, laboratory values, and adverse events information will be collected and recorded. Systemic levels of uridine and uracil will be evaluated from the available plasma samples of treated patients. Patients will be followed for 30 days unless the patient expires or resumes chemotherapy within the 30 day period.

• Toxicity Due to Chemotherapy
• Impaired 5FU Elimination

Inclusion Criteria:

• Excess risk of toxicity due to overdosage (defined as administration of 5-FU at a dose, or infusion rate, greater than the MTD for the patient's intended regimen) of 5-FU, or impaired elimination. Impaired elimination must be documented by one of the following methods:

  • plasma 5-FU levels >10 µM more than 3 hours following cessation of 5-FU dosing
  • previous medical history from earlier 5-FU chemotherapy regimens that indicated unusual susceptibility to 5-FU toxicity, within 7-10 days of receiving 5-FU, such as Grade 3-4 diarrhea, Grade 3-4 mucositis, or Grade 4 neutropenia
  • leukocyte DPD enzyme activity <70% of that observed in the normal population (10 ± 3.4 nmol/hr)
  • presence of deleterious mutations in the DPD gene known to reflect reduced DPD activity and consequent increased risk of 5-FU toxicity
  • plasma uracil/dihydrouracil ratio greater than 2.0
• Judged by the Investigator to have the initiative and means to be compliant with the protocol
• Able to take oral medications
• Age ≥ 18 years
• Able to start treatment with uridine triacetate between 3 and 96 hours after the overdose
• Provides written informed consent (patient or legally authorized representative)

Exclusion Criteria:

• Has a known allergy to uridine triacetate or any of its excipients
• Does not have the initiative and means to be compliant with the protocol
• Unable to be compliant with taking oral medications
• More than 96 hours have elapsed since the completion of 5-FU dosing
• Unable to provide written informed consent (patient or legally authorized representative)