FDA Grants Orphan Drug Designation to Paxalisib for Atypical Rhabdoid, Teratoid Tumors

The FDA has granted an orphan drug designation to paxalisib for use as a potential therapeutic option for patients with atypical rhabdoid and teratoid tumors, a rare and highly aggressive pediatric brain cancer, according to an announcement from Kazia Therapeutics Limited, the developer of the drug.¹

“Childhood brain cancer has emerged as an important area of focus for the paxalisib program. We have been working for some years with several world-leading researchers in diffuse intrinsic pontine glioma [DIPG], one of the most aggressive childhood cancers,” James Garner, MBBS, chief executive officer at Kazia Therapeutics Limited, stated in a news release. “Recent data presented at the AACR conference by Jeffrey Rubens, MD, and colleagues from Johns Hopkins Medical School has shown the potential of the drug to also add benefit in AT/RT, another form of childhood brain cancer that is very poorly served by existing treatments. This represents an important new opportunity for paxalisib, and one that we continue to explore enthusiastically with our collaborators and advisors.”

Paxalisib is a brain-penetrant inhibitor of the PI3K/AKT/mTOR pathway that is being developed to treat patients with glioblastoma, the most common and most aggressive form of primary brain cancer in adults.

The agent previously received an orphan drug designation in glioblastoma in February 2018, and for malignant glioma in August 2020. In August 2020, the FDA also granted fast track designation to the agent for glioblastoma.

The agent is currently being investigated in a phase 2 trial (NCT05009992) sponsored by the Pacific Pediatric Neuro-Oncology Consortium. The study is combining several investigational drugs for the treatment of patients with diffuse midline gliomas, a category that includes DIPG.

The study has an estimated enrollment of 216 patients who will be randomized to receive 1 of 3 treatment regimens combining paxalisib, radiation therapy, and ONC201.³

The primary end point of the study is 6-month progression-free survival (PFS) and 7-month overall survival (OS). Initial data from the study are expected in 2023.

A phase 1 study (NCT03696355) of paxalisib in DIPG, led by St Jude Children’s Research Hospital in Memphis, Tennessee, is also underway. The trial consists of a dose-escalation and -expansion phase where patients will receive paxalisib in doses of 21 mg/m², 27 mg/m², 35 mg/m², or 45 mg/m² after completion of standard radiation therapy.⁴

The primary end points of this study include establishing the maximum tolerated dose and the recommended phase 2 dose of paxalisib following standard radiation therapy, the incidence of adverse effects, and the pharmacokinetics of the agent. Secondary end points include best overall response, duration of best overall response, PFS, and OS.

Final data are anticipated to be filed for publication by the end of 2022.

The agent is also under study in the international, randomized, phase 2/3 GBM AGILE trial (NCT03970447), which is expected to enroll 1030 patients with newly diagnosed and recurrent glioblastoma.⁵

For patients with newly diagnosed disease, the agent will be administered orally at a dose of 45 mg daily for 28 days for the first cycle and if tolerated will be increased to 60 mg daily for all 28-day cycles thereafter.

In the recurrent setting, paxalisib will be administered orally at a dose of 45 mg daily for 21 days for the first cycle and if tolerated will be increased to 60 mg daily for all 21-day cycles thereafter.

The primary end point is OS, with secondary end points of PFS, tumor response, and duration of response.

References

1. US FDA awards orphan drug designation (ODD) to paxalisib for AT/RT, a rare form of childhood brain cancer. News release. Kazia Therapeutics Limited. June 17, 2022. Accessed June 20, 2022. https://prn.to/3HLiHCc
2. US FDA awards fast track designation (FTD) to paxalisib for glioblastoma. News release. Kazia Therapeutics Limited. August 20, 2020. Accessed June 20, 2022. https://prn.to/3y0QrHl
3. Combination therapy for the treatment of diffuse midline gliomas. ClinicalTrials.gov. Updated June 9, 2022. Accessed June 20, 2022. https://clinicaltrials.gov/ct2/show/NCT05009992
4. Study of GDC-0084 in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma or diffuse midline gliomas. ClinicalTrials.gov. Updated March 24, 2022. Accessed June 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03696355
5. A trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma (GBM AGILE). ClinicalTrials.gov. Updated June 14, 2022. Accessed June 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03970447