Phase I Study of the Safety, Tolerance, and Pharmacokinetics of FK463 in Immunocompromised Children With Fever and Neutropenia
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Fever; Mycoses; Neutropenia
Intervention: FK463 (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: National Cancer Institute (NCI)
Summary
The objective of this study is to evaluate the safety, tolerance, and pharmacokinetics of
FK463, a novel echinocandin (cell wall-active antifungal lipopeptide), as early empirical
therapy for prevention of fungal infections in immunocompromised children. The study is
designed as a multicenter open label, sequential dose escalation study of intravenous FK463.
Intravenous FK463 will be administered daily as an hour infusion to patients with new onset
of fever and neutropenia (absolute neutrophil count less than or equal to 500/mm3) who will
be initiated onto broad spectrum empirical antibacterial therapy. The patient population
consists of children ages 2 to 17 years of age; two age cohorts will be studied (2-12,
13-17). Dosage levels will be 0. 5mg/kg/day (not to exceed 25 mg/day), 1. 0 mg/kg/day (not to
exceed 50 mg/day), 1. 5 mg/kg/day (not to exceed 75 mg/day) and 2. 0mg/kg/day (not to exceed
100mg/day). The planned sample size is 64 patients (a maximum of two replacement patients
may be added to a given dose level and age cohort, for a total of no more than 10 patients
per dose level and age cohort. The study will enroll no more than 80 patients). At each
dosage level, a total of 8 patients will be enrolled into each age cohort (2-12, 13-17); a
total of 16 patients will be enrolled into each dosage level. The first group of patients
will receive FK463 at 0. 5 mg/kg/day (not to exceed 25 mg/day). The second group of patients
will receive 1. 0 mg/kg/day (not to exceed 50mg/day). The third group of patients will
receive 1. 5 mg/kg/day (not to exceed 75 mg/day). The fourth group of patients will receive
2. 0mg/kg/day (not to exceed 100mg/day). Study drug will continue until recovery from
neutropenia (ANC post nadir greater than or equal 250/mm3) or until the initiation of
conventional deoxycholate amphotericin B or a lipid formulation of amphotericin B for
empirical antifungal therapy or for proven fungal infection. Patients may receive FK463 for
a maximum duration of 14 days. For any patient who meets institutional criteria to start
standard empirical antifungal therapy with conventional deoxycholate amphotericin B or a
lipid formulation of amphotericin B (greater than 96 hours on study drug) or who has a
proven breakthrough fungal infection, FK463 will be discontinued and conventional
deoxycholate amphotericin B or a lipid formulation of amphotericin B will be initiated.
Clinical Details
Official title: Phase I Study of the Safety, Tolerance, and Pharmacokinetics of FK463 in Immunocompromised Children With Fever and Neutropenia
Study design: Endpoint Classification: Safety Study, Primary Purpose: Treatment
Detailed description:
The objective of this study is to evaluate the safety, tolerance, and pharmacokinetics of
FK463, a novel echinocandin (cell wall-active antifungal lipopeptide), as early empirical
therapy for prevention of fungal infections in immunocompromised children. The study is
designed as a multicenter open label, sequential dose escalation study of intravenous FK463.
Intravenous FK463 will be administered daily as a one hour infusion to patients with new
onset of fever and neutropenia (absolute neutrophil count less than or equal to 500/mm3) who
will be initiated onto broad spectrum empirical antibacterial therapy. The patient
population consists of children ages 2 to 17 years of age; two age cohorts will be studied
(2-12, 13-17). Dosage levels will be 0. 5 mg/kg/day (not to exceed 25 mg/day), 1. 0 mg/kg/day
(not to exceed 50 mg/day), 1. 5 mg/kg/day (not to exceed 75 mg/day). 2. 0 mg/kg/day (not to
exceed 100 mg/day), 3. 0 mg/kg/day (not to exceed 150 mg/day) and 4. 0 mg/kg/day (not to
exceed 200 mg/day). The planned sample size is 96 patients (a maximum of two replacement
patients may be added to a given dose level and age cohort, for a total of no more than 10
patients per dose level and age cohort. The study will enroll no more than 120 patients).
At each dosage level, a total of 8 patients will be enrolled into each age cohort (2-12,
13-17); a total of 16 patients will be enrolled at each dosage level. The first group of
patients will receive FK463 at 0. 5 mg/kg/day (not to exceed 25 mg/day). The second group of
patients will receive 1. 0 mg/kg/day (not to exceed 50 mg/day). The third group of patients
will receive 1. 5 mg/kg/day (not to exceed 75 mg/day). The fourth group of patients will
receive 2. 0 mg/kg/day (not to exceed 100 mg/day). The fifth group of patients will receive
3. 0 mg/kg/day (not to exceed 150 mg/day). The sixth group of patients will receive 4. 0
mg/kg/day (not to exceed 200 mg/day). Study drug will continue until recovery from
neutropenia (ANC post nadir greater than or equal 250/mm3) or until the initiation of
conventional deoxycholate amphotericin B or a lipid formulation of amphotericin B for
empirical antifungal therapy or for proven fungal infection. Patients may receive FK463 for
a maximum duration of 14 days. For any patient who meets institutional criteria to start
standard empirical antifungal therapy with conventional deoxycholate amphotericin B or a
lipid formulation of amphotericin B (greater than 96 hours on study drug) or who has a
proven breakthrough fungal infection, FK463 will be discontinued and conventional
deoxycholate amphotericin B or a lipid formulation of amphotericin B will be initiated.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Children ages 2-17 with neutropenia (absolute count less than or equal 5000/mm(3)) and one
or more of the following conditions: leukemia or lymphoma, excluding those patient's on
maintenance therapy; bone marrow or peripheral stem cell transplantation; aplastic anemia;
myelodysplastic syndrome; chemotherapy anticipated to incur greater than 10 days of
neutropenia.
Patients with new onset of fever during neutropenia who will be initiated onto broad
spectrum empirical antibacterial therapy.
Patients must have sufficient venous access to permit administration of study drug,
collection of pharmacokinetic samples and monitoring of safety variables.
Concomitant therapies: Patients may have received or continue to receive antineoplastic
therapies and medications for supportive care.
Females of childbearing potential must have a negative pregnancy test and must agree to
use barrier methods of contraception throughout the study.
Informed consent of the patient, parent, or legally authorized representative obtained
prior to entry.
Verbal assent will be obtained from minors capable of understanding.
No patients with active proven deeply invasive fungal infection.
No patients with moderate or severe liver disease, as defined by: AST or ALT greater than
2. 5 times the upper limit of normal or total bilirubin greater than 2. 5 times the upper
limit of normal.
No patients who have received intravenous amphotericin B or formulations of amphotericin B
within 72 hours of entering the study or who require treatment with systemic antifungal
agents other than FK463. Patients may continue to receive fluconazole prophylactically
(no more than 400mg/day or 12mg/kg/day) while on study. All other systemic antifungals
agents must be discontinued prior to the first dose of FK463.
No patients who are on other phase I trials of investigational agents.
No patients previously enrolled into this study.
No other concomitant condition which, in the opinion of the investigator, would preclude a
patient's participation in the study.
Locations and Contacts
National Cancer Institute (NCI), Bethesda, Maryland 20892, United States
Additional Information
Related publications: Walsh TJ, Gonzalez C, Lyman CA, Chanock SJ, Pizzo PA. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis. 1996;11:187-290. Review. Berenguer J, Buck M, Witebsky F, Stock F, Pizzo PA, Walsh TJ. Lysis-centrifugation blood cultures in the detection of tissue-proven invasive candidiasis. Disseminated versus single-organ infection. Diagn Microbiol Infect Dis. 1993 Aug-Sep;17(2):103-9. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med. 1982 Jan;72(1):101-11.
Starting date: October 1998
Last updated: March 3, 2008
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