DIPG-10. A Phase I trial of panobinostat following radiation therapy in children with diffuse intrinsic pontine glioma (DIPG) or H3K27M-mutated thalamic diffuse midline glioma (DMG): Report from the Pediatric Brain Tumor Consortium (PBTC-047)

Abstract

INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children with progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving children with non-progressive DIPG/DMG using an alternative schedule. Primary objectives were to describe the toxicity profile and define the MTD; secondary objectives were to describe progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with non-progressive DIPG or H3K27M-mutated thalamic DMG were eligible >14 days following standard radiation therapy only. Panobinostat was given every other day, 3x/week, on alternate weeks. Patients who received at least one dose of panobinostat were evaluable for toxicity. Four dose levels (DL) were evaluated: DL1 (16mg/m2/dose), DL2 (22 mg/m2/dose), DL3 (28 mg/m2/dose) and DL4 (36 mg/m2/dose). Dose escalation was determined by a continuous reassessment method. Correlative studies included pharmacokinetics obtained on course 1, day 1, and day 3 prior to subsequent dosing. RESULTS: Thirty-four eligible patients (median age, 7.6 [3-16] years) were enrolled with 29 evaluable for dose finding; DL1, n=3; DL2, n=10; DL3, n=11; DL4, n=5. The primary toxicities were myelosuppression and gastrointestinal. Eight DLTs occurred: DL2, Grade 3 thrombocytopenia (n=1); DL3, Grade 4 neutropenia (n=3), Grade 4 neutropenia and Grade 4 thrombocytopenia, (n=1); DL4, Grade 2 nausea (n=1), Grade 3 increased ALT (n=1), Grade 4 thrombocytopenia (n=1). Median PFS from drug initiation was 4.4 (1-11.2) months; median OS from diagnosis was 11.7 (4.5-25) months. These did not significantly differ from the PBTC historical cohort (PFS, p-value 0.4967; OS, p-value 0.6457). CONCLUSION: The MTD of panobinostat administered on this schedule to children with non-progressive DIPG/DMG is 22 mg/m2/dose. The primary DLT was myelosuppression. There was no significant improvement in PFS or OS in this cohort.

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors

“…By applying the estimated pharmacokinetic parameters from clinical plasma data and K p,uu obtained in our mouse model to predict the brain concentration-time profile in patients, we were able to demonstrate that, following multiple 20 mg oral doses, there was inadequate exposure of active panobinostat in the brain to treat brain tumors like medulloblastoma and DMG. The low exposure of free panobinostat in the brain shown in our simulation can help explain the lack of in vitro-in vivo correlation for oral panobinostat in clinical studies for CNS tumors (Lee et al, 2015;Wood et al, 2018;Monje et al, 2022). This delivery issue can be supported by the undetectable level of panobinostat in patients' CSF following systemic dosing.…”

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

“…It was reported that panobinostat had limited tolerability and variable pharmacokinetics in the paediatric patients with DIPG/DMG and showed no clinical benefit between treatment groups. It was suggested that further treatment regimens, enhanced drug delivery methods and combination therapies should be considered in future clinical studies using panobinostat 129 . Other clinical studies that use panobinostat include a phase 1 trial using Marizomib, a proteasome inhibitor in combination with panobinostat in pHGGs (NCT04341311) and phase 1/2 trials that are looking at the safety profile and drug tolerability of MTX110, a water soluble nanoformulation of panobinostat, in children newly diagnosed with DIPG (NCT03566199 and NCT04264143).…”

Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit

“…While vorinostat was well tolerated it did not have any effect on survival with 1-year EFS of 5.85% ( Su et al, 2022 ) This negative result was likely multifactorial, with some contribution being limited CNS penetration ( Hanson et al, 2013 ; Guntner et al, 2020 ). Panobinostat has been studied in a phase 1 trial through the Pediatric Brain Tumor Consortium (PBTC) for DIPG, with results having recently being published ( Cooney et al, 2018 ; Monje et al, 2022 ). In the first stratum of patients, the maximal tolerated dose on a schedule of 3 weeks on/1 week off M/W/F was lower than expected at 10 mg/m2/dose with dose-limiting toxicities (DLT) being primarily hematologic.…”