P11.84.A PHASE 1 TRIAL OF MARIZOMIB ALONE AND IN COMBINATION WITH PANOBINOSTAT IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Warren K E , Greenspan L , Strachan M , Plant A , Chi S N , Vogelzang J , Ligon K , Alexandrescu S , Baxter P A , Vitanza N , Chen N , Coraccio K , Yuan Y , London W B , Monje M 
Published: September 2023

Abstract

BACKGROUND
DIPG is an aggressive brainstem tumor with no effective therapy beyond the temporizing effects of radiation (RT). Preclinical studies demonstrated synergistic activity of marizomib (MRZ), an irreversible CNS-penetrant, pan-proteosome inhibitor, when administered with the HDAC inhibitor, panobinostat. In a study of adults with glioblastoma, MRZ was associated with significant CNS adverse events of interest (ataxia, balance disorder, dizziness, dysarthria, fall, gait disturbance, hallucination) in the majority of patients. We performed a novel Bayesian design, dual phase 1 trial of MRZ administered as a single agent and in combination with panobinostat to children with DIPG. Primary objectives were to determine the toxicity profile, dose limiting toxicities (DLT), and maximum tolerated dose (MTD) of MRZ at doses up to 0.8 mg/m2 alone and when administered in combination with panobinostat, and to characterize the plasma pharmacokinetics of MRZ as a single agent in children with DIPG.

MATERIAL AND METHODS
Eligible patients were &lt;22 years with DIPG who received prior standard RT. When available, tumor tissue was centrally reviewed for molecular diagnosis. Patients initially received MRZ alone (Course A1). If tolerated, they received the combination of MRZ and panobinostat on subsequent courses (Course B1, B2, etc.). MRZ starting dose was 0.6 mg/m2IV on Days 1 and 15 of a 28-day cycle. If no DLT was observed during Course A1, patients received MRZ in combination with panobinostat 22 mg/m2/dose p.o. every other day, 3 times/week, on a one week on, one week off schedule. Dose escalation/ de-escalation for single agent and combination was guided using the Bayesian optimal interval design.

RESULTS
Four patients enrolled; one withdrew prior to initiating therapy due to disease progression (PD). Median age at study entry was 7.7 (range, 4.8-8.7)yrs. Three were evaluable for MRZ toxicities, two were evaluable for the combination MRZ + panobinostat. All patients were treated at dose level 1. No DLTs or CNS AEs attributed to MRZ were observed. Adverse events were related to disease/tumor progression or considered mild (grade 1 headache, emesis, diarrhea, fatigue, lymphopenia, thrombocytopenia) with the exception of sinus tachycardia and dyspnea (grade 2) (n=1). All patients died of PD; median time from on study to death for 3 treated patients was 95 days (range, 50-112). Pre- and post-study tissues were obtained where possible for qualitative exploratory pharmacokinetic, pharmacodynamic, molecular and patient model analyses. The study was terminated early due to withdrawal of support from BMS.

CONCLUSION
Children with DIPG tolerated single agent MRZ at a dose of 0.6 mg/m2/dose on Days 1 and 15 and in combination with panobinostat without any DLT or CNS toxicity. Target dose levels were not evaluated as clinical development program for marizomib ended and the study was discontinued early.