PNOC015: An Open Label Single Arm Study of MTX110 Delivered by Convection-enhanced Delivery (CED) in Patients with Diffuse Intrinsic Pontine Glioma (DIPG) Previously Treated with External Beam Radiation Therapy

Sabine Mueller, Cassie Kline, Javier Villanueva-Meyer, Carly Hoffman, Shannon Raber, Erin Bonner, Javad Nazarian, Shannon Lundy, Annette Molinaro, Michael Prados, Mariella Filbin, Nalin Gupta

Disclosures

Research support from:
Novartis
Bristol Meyers Squibb
Pfizer
Midatech
Regeneron
Oncoceutics
Del Mar

Rationale for Trial Design

  • Children with diffuse intrinsic pontine glioma (DIPG) conintue have a dismal prognosis with median survival rates of about 9 months
  • No standard therapy besides radiation therapy has been established
  • Potentially effective therapeutic agents may fail due to poor blood-brain barrier penetration
  • Direct intraparenchymal drug delivery such as CED can overcome these barriers and ensure adequate drug exposure to tumor cells
  • Panobinostat has been shown to be an effective cytotoxic agent across different DIPG model systems
  • MTX110, a soluble form of panobinostat, has favorable convection properties in prior large animal (pig) studies

PNOC 015 Trial Design

Newly diagnosed patient with DIPG after completion of standard of care radiation

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Enrollment on PNOC015

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Assignment to appropriate dose level with potential to dose escalated based on tolerability

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Repeat CED with co-infusion of Prohance every 4 to 6 weeks pending tolerability and feasibility of ongoing disease control

Demographics

7 eligible participants were enrolled between May 2018 – March 2020

  • Median age: 8 years (range 5-20)
  • Median number of CED cycles: 4 (range 2-8)
  • Median follow-up time from study enrollment: 418 days (range 137-614)
Sex Age at diagnosisPathology at diagnosisTotal treatment cycles (CED)Progression free survival (months)Overall survival (months)
F5Diffuse midline glioma H3K27M-mutant2414
M9Diffuse midline glioma H3K27M-mutant4717
M7Diffuse midline glioma H3K27M-mutant81426
M11NA – no biopsy done4821
M20Diffuse midline glioma H3K27M-mutant2921
M5Diffuse midline glioma H3K27M-mutant2311
M8Diffuse midline glioma H3K27M-mutant4511

PNOC 015 Adverse Events

  • Predominantly grade 1 toxicities
  • Five (5) grade 3 events
  • No grade 4 events
figure 2

CED of MTX110 leads to effective convection in DIPGs

PNOC015: Overall survival outcome

figure 4

PNOC015 Summary

  • CED with MTX-110 in patients with DIPG is feasible, tolerable, and may lead to prolonged survival
  • Co-infusion with Prohance can be used to determine ratio of Volume(infusion): Volume(distribution) – ranges between 1:3 to 1:3.5
  • OS is promising but remains to be reviewed in the context of available molecular data for each patient and also in the setting that some patients may have undergone re-irradiation
  • Several patients progressed outside the treatment field, suggesting that either larger infusion volumes or combination with systemic therapy should be considered in future trials
  • Ongoing assessment of imaging parameters as well as QOL assessments

Acknowledgement

  • Nalin Gupta
  • Cassie Kline
  • Carly Hoffmann
  • Javier Villanueva-Meyer
  • Annette Molinaro
  • Shannon Raber
  • Erin Bonner
  • Javad Nazarian
  • Mariella Filbin
  • Michael Prados
  • Families and patients
  • Funding sources:
    • The Pediatric Brain Tumor Foundation, DIPG Collaborative; Midatech Inc.
    • Midatech as a sponsor had no involvement in study analysis