Clinical Trial: Investigating Voriconazole to Prevent Systemic Fungal Infection

Official Title: Open-Label, Intravenous to Oral Switch, Multi Dose, Multi-Center Study to Investigate the Pharmacokinetics, Safety & Tolerability of Voriconazole in Hospitalized Children Aged 2 to Less Than 12 Yrs who Req Tx for the Prev of Systemic Fungal Infection


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Sponsored by:	National Cancer Institute (NCI)
Information provided by:	Warren G Magnuson Clinical Center (CC)

Condition	Treatment or Intervention	Phase
Neutropenia Leukemia Lymphoma Aplastic Anemia	Drug: Voriconazole	Phase II

The objective of this study is to evaluate the safety, tolerability and pharmacokinetics of intravenous and oral voriconazole at two dosage levels in an immunocompromised pediatric patient population. The plasma concentrations of the major metabolite of voriconazole (N-Oxide) in these patients will be performed. The study is designed as a multi-center, open-label, multiple dose study of intravenous and oral voriconazole. Intravenous voriconazole will be administered prophylactically twice daily to immunocompromised children at high risk for invasive mycoses. The patient population consists of children aged 2 to less than 12 years; two age groups will be studied (2 to less than 6, 6 to less than 12). The planned sample size is 36 children with 18 children in each cohort. For those children who do not complete 4 days of oral dosing, a replacement patient will be added. Immunocompromised children at high risk for invasive mycoses will receive voriconazole prophylactically. Therapy will be initiated within 48 hours after completion of chemotherapy. Voriconazole therapy will continue until recovery from neutropenia. Children in the first cohort will initially receive a loading dose of 6 mg/kg IV q12h X 2 doses followed by 4 mg/kg q 12h through Day 4 of therapy. On day 5, patients will receive 6 mg/kg q 12h through Day 8. On Day 9, patients will be switched to an oral solution of voriconazole at a dosage of 4 mg/kg q 12h. If the patient is unable to take oral medication on day 9, IV treatment may continue up to day 20. Pharmacokinetics will be obtained on the fourth day of oral therapy. An interim analysis will be performed and if the median AUC (tau) of voriconazole in the first 12 patients following 6 mg/kg q 12h dosing is less than 40,000ng.hr/mL and there are no safety concerns, the remaining 18 patients will receive voriconazole after Day 4 at a dosage of 8 mg/kg. If the median AUC (tau) of voriconazole in the first 12 patients following 6 mg/kg q 12h dosing is more than 40,000.hr/mL and there are no safety concerns, the remaining 18 patients will be dosed at 5mg/kg q 12h. Twelve-hour pharmacokinetics will be collected on Days 4, 8 and 12 of therapy in both dosage cohorts.

INCLUSION CRITERIA:
a. Children aged from 2 to less than 12 years who require treatment for the prevention of systemic fungal infection, and who can tolerate being switched to oral therapy between Days 9 and 20 in Cohort I and II A, or Days 5 to 20 in Cohort IIB.
b. Children who are expected to develop neutropenia (ANC less than 500 cells/mm(3)) lasting for more than 10 days following chemotherapy for of the following conditions:
i. Leukemia
ii. Lymphoma
iii. Aplastic Anemia
iv. As the preparative regimen for bone marrow or stem cell transplantation.
c. Patients who are anticipated to live more than 3 months.
d. Females of childbearing potential (post-menarchal) must have a negative pregnancy test at entry.
e. Informed consent of the parent or legally authorized representative must be obtained prior to entry.
f. Assent will be obtained from minors capable of understanding.
EXCLUSION CRITERIA:
a. Patients who are receiving and cannot discontinue the following drugs at least 24 hours prior to study start or if they need to commence any of the following during the study: terfenadine, pimozide, quinidine, astemizole, and cisapride (due to the possibility of QTc prolongation with these drugs) and omeprazole (an inhibitor of CYP2C19, CYP2C9, and in lesser extent CYP3A4 isoenzymes) which is known to increase plasma voriconazole levels and ergot alkaloids.
b. Patients who have received the following drugs within 14 days prior to study entry: rifampicin, rifampin, rifabutin, carbamazepine, phenytoin, nevirapine and long acting barbiturates as these are inducers of hepatic enzymes and may result in undetectable levels of voriconazole.
c. Patients who have received sirolimus, as voriconazole is known to increase significantly sirolimus blood levels.
d. Severe hypokalemia (less than 3.2 mmol/L). Potassium may be corrected to a level greater than 3.2 mmol/L to enroll patient onto study.
e. Patients who are taking or are likely to receive any investigational drugs except those used for treatment of a child's cancer, antiretroviral agents and drugs used for treatments of any AIDS defining opportunistic infections, all of which are allowed.
f. Patients who are enrolled in investigational anticancer drug trials that exclude the use of other investigational agents should not be enrolled in this study.
g. Patients with a history or hypersensitivity to or severe intolerance of azole antifungal agents.
h. Patients who have already been entered onto this voriconazole protocol once.
i. Patients with a medical history or current evidence of cardiac arrhythmia.
j. Patients with an AST, ALT or total bilirubin greater than 5 X ULN.
k. Patients with moderate and severe renal impairment (i.e., calculated creatinine clearance less than 30mL/min). Creatinine clearance will be calculated using the following equation: 0.55 X height (cm)/serum creatinine (mg/dL).
l. Any other condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment.