Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

Summary

Participation Requirements

Description

Description This is a multicenter, phase 1 trial of Panobinostat (LBH589) for children with diffuse intrinsic pontine glioma tumors. Panobinostat is a pan-HDAC inhibitor of Class I, II and IV histone deacetylases (HDACs) involved in the deacetylation of histone and non-histone cellular proteins. Pan...

Description This is a multicenter, phase 1 trial of Panobinostat (LBH589) for children with diffuse intrinsic pontine glioma tumors. Panobinostat is a pan-HDAC inhibitor of Class I, II and IV histone deacetylases (HDACs) involved in the deacetylation of histone and non-histone cellular proteins. Panobinostat inhibits purified total cellular histone deacetylase activity (IC50 = 0.03 uM) and activities of most HDAC isoforms (IC50 <10nM). In addition, panobinostat induces expression of the cell-cycle control genes including CDKN1A (p21), and selectively inhibits the proliferation of a variety of tumor cells compared to normal cells. It has been extensively profiled for its in vitro and in vivo pharmacological activity on a variety of tumor cell lines and tumor xenograft mice models. Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell cultures and orthotopic xenograft model systems, and the potentially important role of histone deacetylases and histone 3 K27M mutations in relation to pontine malignancies, the investigators are conducting a Phase 1 study of panobinostat in children with recurrent/progressive DIPG. The primary objectives of the study are to (1) describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG taken every other week; (2) estimate the maximum tolerated dose and/or the recommended Phase 2 dose of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG taken every other week; and (3) evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG taken every other week. Schema STRATUM 1: Only patients with recurrent or progressive DIPG will be enrolled initially. Panobinostat will be administered every other day, 3 times/week, p.o. preferably on a Monday/Wednesday/Friday schedule for three weeks, followed by a rest period. Three weeks of therapy plus the one week rest period (total 4 weeks) will constitute one course. Treatment will continue for up to two years (26 courses) unless the patient experiences progressive disease, unacceptable toxicity or any of the off-study criteria. The starting dose (dose level 1) is 10 mg/m2/day. Below are the proposed dose levels to be studied: Dose level # Panobinostat oral dose (mg) Minimum BSA Restriction 0*: 5 mg/m2/day MWF, three weeks on, one week off (1 course = 28 days). Patients must have a BSA ? 0.80 m2. 1 (starting dose level): 10 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ? 0.65 m2. 2: 16 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ? 0.65 m2. 3: 22 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ? 0.65 m2. 4: 28 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ? 0.50 m2. 5: 36 mg/m2/day MWF, three weeks on, one week off, (1 course = 28 days). Patients must have a BSA ? 0.50 m2. Panobinostat will be administered as a single agent * Dose level 0 represents a potential treatment dose for patients requiring a dose reduction from dose level 1 and may be used as a contingency dose level if the starting dose level of panobinostat is not tolerated in the initial cohort. STRATUM 2: Patients with DIPG who have received adequate radiation therapy but have not yet progressed will be enrolled in the currently open Stratum 2. Panobinostat will be administered every other day, 3 times/week, every other week p.o. preferably on a Monday/Wednesday/Friday schedule. Total 4 weeks will constitute one course. Treatment will continue for up to two years (26 courses) unless the patient experiences progressive disease, unacceptable toxicity or any of the off-treatment criteria. The starting dose (dose level 1) is 16 mg/m2/day. Below are the proposed dose levels to be studied: Dose level # Panobinostat oral dose (mg) Minimum BSA Restriction Negative 1*: 5 mg/m2/day MWF, every other week (1 course = 28 days). Patients must have a BSA ? 0.80 m2. 0*: 10 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ? 0.65 m2. 1 (expected starting dose level): 16 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ? 0.65 m2. 2: 22 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ? 0.65 m2. 3: 28 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ? 0.50 m2. 4: 36 mg/m2/day MWF, every other week, (1 course = 28 days). Patients must have a BSA ? 0.50 m2. Panobinostat will be administered as a single agent * Dose levels 0 and -1 represent potential treatment doses for patients requiring a dose reduction from dose level 1 and may be used as a contingency dose level if the starting dose level of panobinostat is not tolerated in the initial cohort.

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