Dose Optimization and Efficacy Assessment of a Fluoropyrimidine Antidote

Official title

A Phase I/II Trial to Evaluation of the Dose and Efficacy of an Antidote to Fluoropyrimidines

Overview

Fluoropyrimidines (FLU) are drugs widely used in chemotherapy for various tumors, such as breast, colon, rectal, and gastric cancers. FLU is a drug that inhibits thymine synthesis and, consequently, DNA synthesis, leading to tumor cell death. However, up to 30% of patients treated with FLU experience severe toxicities, depending on the dose and regimen received. The most common symptoms include mucositis, vomiting, nausea, diarrhea, and neutropenia. The enzyme dihydropyrimidine dehydrogenase (DPD) plays a key role in FLU metabolism. Patients with mutations in the DPYD gene (which encodes DPD) are at high risk of experiencing severe toxicities from FLU. Uridine triacetate (UT) is a drug that can be used as an antidote for 5-FU in patients who develop severe toxicities. However, despite its efficacy, it is expensive and not commercially available in Brazil. Currently, the Brazilian population has no access to an antidote for the treatment of FLU-related toxicities. This Phase I/II study will evaluate the dose, safety, and efficacy of compound the association of two molecules as an antidote for grade 3 or higher toxicities resulting from the use of FLU.

Interventions

• Drug I-01/23
  The I-01/23 will be administered over a 5-day period, with dosing adjusted according to the patient's body surface area (BSA).

Primary outcome measures

• Maximum Tolerated Dose (MTD) Determination [Time frame: 6 days]
• Survival rate [Time frame: 7 days]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 5 centers

• Instituto D'Or de Pesquisa e Ensino de Salvador — Salvador
• Instituto D'Or de Pesquisa e Ensino de Brasília — Brasília
• Instituto D'Or de Pesquisa e Ensino de Curitiba — Curitiba
• Instituto D'Or de Pesquisa e Ensino do Rio de Janeiro — Rio de Janeiro
• Instituto D'Or de Pesquisa e Ensino de São Paulo — São Paulo

Identifiers

NCT: NCT07032142 · ARCTURUS 81626124.3.1001.5249 · 81626124.3.1001.5249

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗