High dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a non-human primate model

DDEL-09
David I. Sandberg1, Natasha Kharas1, , Bangning Yu1, Christopher F. Janssen1, Amanda Trimble1, Leomar Y. Ballester1, Rajan Patel1, Afroz S. Mohammad1, William F. Elmquist2, Rachael W. Sirianni12
1 McGovern Medical School, University of Texas Health Science Center at Houston, Houston TX
2 University of Minnesota, Minneapolis MN

Drug delivery in pediatric neuro-oncology

  • The blood-brain barrier (BBB) remains a significant obstacle to effective treatment of pediatric brain tumors, particularly in a recurrent or metastatic setting
  • Direct administration of chemotherapy to the CSF is one method that could bypass the BBB to improve tumor exposure to drug while minimizing systemic toxicity
  • Instillation of a 4th ventricle catheter enables locoregional delivery of chemotherapy
    • Preclinical (Sandberg, et al., J Neurosurg Pediatr 2008; Sandberg, et al., J Neurooncol. 2010; Sandberg, et al., Sandberg and Kerr, Childs Nerv Sys 2016; Sandberg, et al., J Neurosurg Pediatr 2020)
    • Clinical (NCT02458339, NCT02905110, NCT02940483)
figure 1

Panobinostat (LBH-589)

  • Histone deactylase inhibitors (HDACi)
    • Histone acetylation is frequently disregulated in cancer
    • HDACi promote acetylation of histones, which yields anticancer effects
  • MTX-110
    • Water soluble formulation of panobinostat achieved via a cyclodextrin inclusion complex (produced by MidaTech Pharma)
  • Panobinostat (LBH-589)
    • Pan-HDACi demonstrated to be efficacious against multiple pediatric brain tumors, including Group 3 Medulloblastoma (MB)
      • Pei, et al., Cancer Cell 2016
    • Very poorly water soluble and lipophilic (logP ~2.8)
figure 2

Approach

  • Instillation of 4th ventricle catheter
    • 4 rhesus macaque monkeys
    • Posterior fossa craniectomy
    • Insertion of 4th ventricle catheter and lumbar drain
  • Drug infusion and sampling
    • Infusions consist of 0.5mL of 300uM panobinostat (as MTX110)
    • Group I (n=2): 1 treatment cycle consisting of 5 daily, consecutive infusions
    • Group II (n=2): 4 treatment cycles performed over 8 weeks
    • Sampling of plasma, 4th ventricle CSF, and lumbar CSF conducted at regular intervals
  • Analyses
    • Detailed neurological evaluations
    • MRI scan to confirm catheter placement
    • Postmortem histological assessment of brain, spinal cord, and peripheral tissues
    • Plasma and CSF processed by mass spectrometry for pharmacokinetic measurements

Results: catheter placement

figure 3
  • Catheter placement was confirmed by MRI and visual inspection at necropsy
  • Ventricles were of normal size with no evidence for any gross abnormality

Results: toxicity

figure 4
  • Detailed neurological /behavioral assessments were normal throughout the study
  • Focal ependymal disruption in the pons was observed in 3 out of 4 primates, which was most likely a result of catheter placement. Mild, focal inflammatory infiltrates were observed regionally in the meninges, choroid plexus, and subependymal zone of the brainstem
  • All other assessments were normal

Results: drug levels

  • No panobinostat was detected in any plasma sample
  • Drug levels were highest in the 4th ventricle samples and declined over time
  • Lumbar samples yielded lower concentration of drug that became undetectable at later time points
  • Repeat dosing studies demonstrated highly reproducible peak/trough levels with no evidence for drug accumulation over multiple treatment cycles
figure 5

Conclusions

  • 4th ventricle catheters were successfully instilled in rhesus macaque monkeys to enable locoregional infusion of the chemotherapeutic agent MTX110 (water soluble panobinostat)
  • Treatments were well-tolerated, with no evidence of toxicity under this dosing regimen
  • Drug levels in the 4th ventricle and lumbar samples suggest rapid distribution of panobinostat and likely clearance to tissue and/or via turnover of CSF
  • Drug levels in the CNS reached a therapeutic range
  • These preclinical data support an expectation of safety for administration of MTX110 via the 4th ventricle
    • Clinical trial is ongoing (NCT04315064)

Acknowledgements

Funding sources:

  • The Ian’s Friends Foundation
  • The Dr. Marnie Rose Foundation
  • Dr. Dick Basset
  • The National Institutes of Health
    • R01NS111292 (NINDS)
    • R01HD099543 (NICHD)
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