The FDA has granted fast track designation to the combination of paxalisib (GDC-0084) and radiation for the treatment of patients with brain metastases originating from a primary tumor.
A Phase I study (NCT04192981) is currently investigating the concurrent use of paxalisib with whole brain radiotherapy (WBRT) in approximately 36 patients with brain metastases from a solid tumor or leptomeningeal metastases with PI3K pathway mutations. Preliminary data from 12 patients in the study have been reported.
As of January 2022, the median follow-up in part A of the study was 4.5 months (ranging from 0.9 to 14.9 months). All 12 patients received paxalisib in combination with 30GY of WBRT administered in 10 fractions. Out of those treated, 10 had brain metastases from a primary tumor, while 2 had leptomeningeal metastases. The majority of patients (33%) had breast cancer as their primary malignancy, and 58% of the study population had PIK3CA mutations.
Robust responses were observed in all evaluable patients within 3 months of starting the study treatment, with all patients experiencing either a complete or partial response. No dose-limiting toxicities (DLTs) were observed in patients receiving the 45-mg dose of paxalisib. However, two DLTs occurred at the 60-mg dose, including grade III nausea and vomiting in one patient and grade 4 enterocolitis in another. As a result, the recommended phase II dose of paxalisib was set at 45 mg.
Based on the dose-escalation findings, the study has moved on to the dose-expansion phase, which aims to confirm the safety of the combination and explore preliminary efficacy. During the dose-expansion phase, investigators will evaluate patients for the primary endpoint of the maximum-tolerated dose of paxalisib and the secondary endpoint of local recurrence rate.
“Brain metastases are rapidly emerging as a key pillar of paxalisib’s clinical development. 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 CY2023, we will be working with investigators and advisors to drive forward our research in brain metastases also.”
– Dr. John Friend, Chief Executive Officer of Kazia
To be eligible for inclusion in the dose-expansion phase, patients must have histologically confirmed solid tumors harboring PI3KCA mutations and brain metastases and/or leptomeningeal metastases as confirmed by MR imaging. Patients are required to have a Karnofsky performance status of at least 70, be 18 years of age or older, be capable of swallowing medication, and have adequate organ, bone marrow, liver, and renal function.
Patients who have previously received radiation treatment or are currently receiving other agents classified as moderate and/or potent enzyme inducers or inhibitors are ineligible for enrollment in the study. The study also excludes patients with serious comorbidities, insulin-treated diabetes, cardiac dysfunction, a history of interstitial lung disease, and hypersensitivity or intolerance to paxalisib or another PI3K inhibitor.
