Phase I trial to evaluate safety, pharmacokinetics, &antiviral activity of T-124

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

This is a phase I, open-label, dose-escalation study to evaluate the preliminary safety, tolerance, pharmacokinetics, and antiviral activity of T-1249 in HIV infected patients. Currently, several antiretroviral agents are licensed for use in the United States for the treatment of HIV infection. Broadly defined, these agents are characterized as belonging to one of two mechanistic classes, reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). However, heavily pretreated patients often possess multiple mutations of the reverse transcriptase and protease genes, resulting in multi-drug resistance. A pharmacologic agent effective at an alternative point in the virus replication cycle would make a valuable addition to the anti-HIV armamentarium. The investigational agent, T-1249, which belongs to a new pharmacologic class of compounds referred to as fusion inhibitors, is a 39-amino acid synthetic peptide composed of naturally occurring L-amino acid residues. Non-clinical safety studies indicate that neither the topical, subcutaneous, or intravenous administration of T-1249 is associated with an identifiable potential risk of particular severity or seriousness for subjects enrolling in the planned phase I study. In vitro studies indicate that T-1249 is non-mutagenic. This study will enroll 60 HIV-1 positive individuals, and will be a multi-center, dose escalation trial of T-1249 given to HIV-1 infected adults by subcutaneous injection (SQI). Twelve patients per arm will receive T-1249 subcutaneously at 6.25 mg/day (6.25 mg QD), 12.5 mg/day (6.25 mg BID or 12.5 mg QD), and 25 mg/day (12.5 mg BID and 25.0 mg QD). The study will consist of a 3- to 4-week screening/baseline period, a 2-week treatment period, and a 2-week follow-up period, for a total per-subject study duration of six to seven weeks. Eligible subjects who qualify for participation will enter a two-week baseline period, during which PT, APTT, D-dimers, fibrinogen, and HIV RNA assessments will be performed on a weekly basis. Subjects who complete the baseline phase will be assigned to one of five treatment cohorts and will enter a 14-day outpatient treatment period. During the treatment period subjects will return to the clinical research unit at defined intervals for safety, pharmacokinetic, and efficacy assessments. Within 14 days of completing the treatment period or prematurely discontinuing the study, subjects will return to the clinic for a final follow-up visit. A pharmacokinetic substudy will be performed. In addition to the assessments listed above, the first four subjects assigned to each dose cohort will undergo intensive (24-hour) pharmacokinetic sampling at three regularly scheduled study visits. On Study Day -7, subjects will receive a single intravenous dose of T-1249, followed by a 24-hour pharmacokinetic sampling period. On Study Days 0 and 7, the same subjects will again undergo a 24-hour pharmacokinetic sampling period following their regularly scheduled subcutaneous dose of T-1249.