FDA Grants RPDD to Paxalisib for Rare Pediatric Brain Cancer

The FDA has granted rare pediatric disease designation (RPDD) to paxalisib (GDC-0084) for the treatment of patients with atypical rhabdoid or teratoid tumors (AT/RT) in rare and highly-aggressive childhood brain cancer, according to Kazia Therapeutics Limited.¹

The basis of the RPDD comes from the promising preclinical data for paxalisib in AT/RT presented by Jeffrey Rubens, PhD, and colleagues at the 2022 American Association of Cancer Research (AACR) Annual Meeting.²

Previously, paxalisib was granted orphan drug designation (ODD) for AT/RT by FDA on June 16, 2022.

"This is the second time that paxalisib has been granted RPDD, and it demonstrates the importance of childhood brain cancer in the overall paxalisib development program. Brain cancer is the most common cause of cancer death in children, and outcomes in many forms of childhood brain cancer have not improved in decades. We very much hope that paxalisib can make a difference to families affected by both DIPG and AT/RT, and we will be working closely with clinicians, researchers, and FDA to determine the optimal way to move the drug forward," stated James Garner, MD, chief executive officer of Kazia Therapeutics Limited, in the press release.

Paxalisib was also granted an ODD for the malignant glioma indication, which includes glioblastoma in adults and diffuse intrinsic pontine glioma (DIPG) for pediatric patients. Currently, the Pacific Pediatric Neuro Oncology Consortium is leading a phase 2 study for the DIPG indication. The ongoing, phase 2 clinical trial of multiple drug therapies (NCT05009992) includes paxalisib.³

An estimated 216 patients will be enrolled in the study and randomized to receive 1 of 3 treatment regimens involving combinations of radiation therapy, the drug ONC201, and paxalisib.

The primary end point of the study is progression-free survival (PFS) at 6 months and overall survival (OS) at 7 months. Other exploratory end points of the trial include confirming the blood brain barrier penetration of ONC201 in DMG, assessing changes in immune cell infiltration in DMG tumor tissue, and toxicity.

Initial data from this study is expected at some point within 2023.

Additionally, a phase 1 study (NCT03696355) of paxalisib in DIPG is nearing completion. The study is led by St Jude’s Children’s Research Hospital in Memphis.⁴ The first phase of the study is the dose-escalation phase, which will consist of patients who will receive paxalisib in doses of 21 mg/m2, 27 mg/m2, 35 mg/m2, or 45 mg/m2 after they have completed radiation therapy.

The primary end point of the study is to estimate the maximum tolerated dose and recommended phase 2 dose paxalisib after standard radiation therapy. Secondary end points include overall response, duration of best overall response, PFS, and OS.

Data are expected to be published at the end of 2022.

References:

1. US FDA awards rare pediatric disease designation (RPDD) to paxalisib for AT/RT, a rare form of childhood brain cancer. News release. Kazia Therapeutics Limited. July 6, 2022. Accessed July 6, 2022.

Malebranche K, Findlay T, Eberhart C, Raabe E, Rubens J. The PI3K inhibitor paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid tumors. Presented at the 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Accessed June 20, 2022. https://bit.ly/3OuVExl

Combination therapy for the treatment of diffuse midline gliomas. ClinicalTrials.gov. Updated June 9, 2022. Accessed June 20, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05009992?term=NCT05009992&draw=2&rank=1

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/record/NCT03696355?term=NCT03696355&draw=2&rank=1