Study of Panobinostat (LBH589) in Patients With Sickle Cell Disease

Summary

Participation Requirements

Description

This is a one-arm, open-label, Phase I, dose-escalation study of Panobinostat administered via different dosing schedules. In each schedule, this study is designed to determine the MTD (maximum tolerated dose) and DLT (dose limiting toxicities) of panobinostat as a single agent, and to characterize ...

This is a one-arm, open-label, Phase I, dose-escalation study of Panobinostat administered via different dosing schedules. In each schedule, this study is designed to determine the MTD (maximum tolerated dose) and DLT (dose limiting toxicities) of panobinostat as a single agent, and to characterize the safety and tolerability of panobinostat in adult patients with sickle cell disease who have failed to respond to hydroxyurea therapy (clinically or hematologically) or are intolerant of or refuse hydroxyurea therapy. The study consists of a Screening Phase, Treatment Phase, and Post-Treatment Follow-up. Screening Phase: Subjects will be screened for eligibility within 28 days of baseline visit (Day 1). Screening assessments will include informed consent, physical exam, vital signs (height, weight, blood pressure, heart rate, height, weight, and respirations), review of medical history, review of concomitant medications, 12-lead electrocardiogram (ECG), echocardiogram, and laboratory assessments. Screening laboratory assessments will include the following: CBC with differential, reticulocytes, complete chemistry panel, LDH, serum ferritin, thyroid function testing, Hb F percentage, F-cells, viral serology, urine albumin/creatinine ratio, and serum pregnancy in all females of childbearing potential. Approximately 15 ml (1 tablespoon) of blood will be collected at the screening visit. Treatment Phase: The Treatment Phase is twelve weeks in duration. Each subject will be assigned to a specified dose level and dosing schedule and will remain with the assigned regimen, if tolerated, throughout the twelve-week period. Patients at a given dosing regimen must complete at least 4 weeks of treatment before treatment decisions are made for subsequent participants. Regardless of specific dosing assignment, all subjects will take study drug thrice weekly (Monday, Wednesday, and Friday) throughout the duration of the 12-week treatment period. The first three patients to enroll in the study will be assigned to a dose level of 15 mg panobinostat, with continuous thrice weekly treatment for the entire 12-week treatment period. Based on how well this regimen is tolerated, the next group of three subjects will either be assigned the same regimen or a reduced, intermittent schedule of three weeks on treatment followed by one week off. Treatment decisions will continue accordingly, after each group of three subjects is treated with a given regimen. Six patients must be treated safely at a given dosing regimen before enrollment can advance to the next, higher level. Once the Maximum Tolerated Dose is determined, all subsequent patients will be enrolled to that regimen, with a total of up to 18 subjects enrolled. The four dosing regimens to be explored are: 15 mg MWF 3 weeks on, 1 week off (only needed if starting regimen requires dose de-escalation) 15 mg MWF every week (starting dose) 20 mg MWF 3 weeks on, 1 week off 20 mg MWF every week During the Treatment Phase, safety and efficacy assessments will be performed at specified times, and will include: physical examination, vital signs (weight, blood pressure, heart rate, height, weight, and respirations), adverse events assessment, ECG, quality of life questionnaire (ASCQMe), and laboratory assessments. Treatment Phase lab assessments are to be performed at specified visits and include CBC with differential, reticulocytes, complete chemistry panel, LDH, serum ferritin, Hb F percentage, F-cells, thyroid function testing, urine albumin/creatinine ratio, and urine pregnancy test for women of childbearing potential. Approximately 15 ml (3 teaspoons) of blood will be collected at each treatment visit. Every four weeks, an additional 5 ml of blood will be collected for inflammatory markers and protein biomarkers, for a total of 20 ml. On Day 1 (pre-treatment) and Day 85 (post-treatment), when additional samples are collected for genetic/ mechanistic studies, total volume collected is 25 ml. Study drug will initially be dispensed at the baseline visit and every four weeks thereafter. Study drug accountability should be assessed at every visit. All baseline assessments will be completed prior to the first dose of study drug. Follow-Up Phase: A follow-up visit will be performed 4 weeks after end of treatment. Follow-up assessments will include: physical examination, vital signs, adverse events assessment, ECG, and laboratory assessments (CBC with differential, reticulocytes, complete chemistry panel, LDH, Hb F percentage, F-cells, and inflammatory markers). Approximately 15 ml (3 teaspoons) of blood will be collected at the follow-up visit.

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