Paxalisib Plus Radiation Earns FDA Fast Track Status for PI3K+ Solid Tumor Brain Metastases

The FDA has granted a fast track designation to paxalisib (formerly GDC-0084) in combination with radiation therapy for the treatment of patients with solid tumor brain metastases harboring PI3K pathway mutations.¹

The designation is based on data from an interim analysis of a phase 1 trial (NCT04192981), which showed that all 9 evaluable patients responded to the combination.

“Brain metastases are rapidly emerging as a key pillar of paxalisib’s clinical development,” John Friend, MD, chief executive officer of Kazia Therpeutics Limited, stated in a news release. “We have seen a high level of interest from clinicians in the emerging data from this patient population, and it is exciting to now have that interest complemented by FDA's award of fast track designation. With important data read-outs expected in adult and childhood brain cancer during [2023], we will be working with investigators and advisors to drive forward our research in brain metastases.”

The ongoing phase 1 study is enrolling patients at least 18 years of age with histologically confirmed solid tumor malignancies harboring PIK3CA mutations with brain metastases and/or leptomeningeal metastases involving the brain.² Patients are required to have a Karnofsky performance status of at least 70, as well as adequate organ, bone marrow, liver, and renal function. Notably, patients who underwent prior stereotactic radiosurgery or who have a seizure history related to brain/leptomeningeal metastases are allowed to enroll.

Key exclusion criteria include prior radiotherapy to the intended treatment site that precludes developing a treatment plan that respects tissue tolerances, brain metastases eligible for single-fraction stereotactic radiation therapy, or serious medical comorbidities precluding radiotherapy.

The dose-escalation portion of the trial utilizes a 3+3 design with 3 cohorts, where patients are receiving 45 mg, 60 mg, or 75 mg of paxalisib per day, in combination with 30 Gy of whole brain radiation therapy in 10 fractions. Once the maximum tolerated dose (MTD) of paxalisib is established, 12 additional patients will be enrolled at that dose.

Determining the MTD is the study’s primary end point. Local recurrence rate serves as a key secondary end point.

Additional data from the phase 1 study are expected in the first quarter of 2024, and discussions regarding the potential design of a registrational study are ongoing.¹

Previously, paxalisib received orphan drug designation from the FDA for the treatment of glioblastoma in February 2018, and a fast track designation for glioblastoma in August 2020. Furthermore, it was awarded rare pediatric disease designation and orphan drug designation from the regulatory agency for diffuse intrinsic pontine glioma in August 2020, and for atypical teratoid/rhabdoid tumors in June 2022 and July 2022, respectively.

References

1. Kazia's paxalisib receives fast track designation from FDA for treatment of solid tumor brain metastases harboring PI3K pathway mutations in combination with radiation therapy. News release. Kazia Therapeutics Limited. July 6, 2023. Accessed July 6, 2023. https://www.biospace.com/article/releases/kazia-s-paxalisib-receives-fast-track-designation
2. GDC-0084 with radiation therapy for people with PIK3CA-mutated solid tumor brain metastases or leptomeningeal metastases. ClinicalTrials.gov. Updated July 3, 2023. Accessed July 6, 2023. https://clinicaltrials.gov/ct2/show/NCT04192981