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 diagnosis | Pathology at diagnosis | Total treatment cycles (CED) | Progression free survival (months) | Overall survival (months) |
| F | 5 | Diffuse midline glioma H3K27M-mutant | 2 | 4 | 14 |
| M | 9 | Diffuse midline glioma H3K27M-mutant | 4 | 7 | 17 |
| M | 7 | Diffuse midline glioma H3K27M-mutant | 8 | 14 | 26 |
| M | 11 | NA – no biopsy done | 4 | 8 | 21 |
| M | 20 | Diffuse midline glioma H3K27M-mutant | 2 | 9 | 21 |
| M | 5 | Diffuse midline glioma H3K27M-mutant | 2 | 3 | 11 |
| M | 8 | Diffuse midline glioma H3K27M-mutant | 4 | 5 | 11 |
PNOC 015 Adverse Events
- Predominantly grade 1 toxicities
- Five (5) grade 3 events
- No grade 4 events
CED of MTX110 leads to effective convection in DIPGs
PNOC015: Overall survival outcome
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