FDA Awards Fast Track Designation to Paxalisib With Radiation for Brain Metastases


An investigation of treatment with concurrent paxalisib and whole brain radiotherapy is underway in a phase 1 clinical trial.

  • With a FDA fast track designation, the development of paxalisib and radiotherapy for brain metastases will be expedited.1

  • This new designation follows a prior fast track designation for paxalisib monotherapy in glioblastoma.

  • Developer of paxalisib, Kazia Therapeutics, will continue to have conversations with the FDA regarding further development of the drug in patients with brain metastases.

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.1

"Radiation therapy is an essential treatment for central nervous system metastases, a challenging complication in patients with metastatic cancer. Effective therapies of central nervous system metastases can prevent neurologic symptoms and prolong survival in patients. From our previous work, we learned that brain metastases with activating PI3K pathway mutations are more resistant to radiation therapy and thus have worse disease control. Paxalisib is therefore a logical choice of drug and, combined with radiotherapy, it may help overcome this resistance," Jonathan Yang, MD, PhD, director of metastatic disease and developmental therapeutics, Department of Radiation Oncology, University of Washington, told Targeted OncologyTM. "I think the FDA, by expediting the development of this combination, recognizes not only the need for more effective drug and radiation therapy combination treatments, but also the importance of precision radiation oncology strategies based on tumor molecular profiling."

Concurrent paxalisib with whole brain radiotherapy (WBRT) is a being investigated in a phase 1 study (NCT04192981) of approximately 36 patients brain metastases from a solid tumor or those with leptomeningeal metastases harboring PI3K pathway mutations.1,2 Data from 12 patients in the study have been reported.3

Median follow-up in part A was 4.5 months (0.9-14.9 months) as of January 2022. All 12 patients received paxalisib with 30GY of WBRT in 10 fractions. Of those treated, 10 had brain metastases from a primary tumor and 2 had leptomeningeal metastases. The majority of patients (33%) treated had breast cancer as their primary malignancy, and 58% of the population had PIK3CA mutations.2

About the Phase 1 Study

Trial Name: A Phase I Study With Expansion Cohort of Concurrent GDC-0084 With Radiation Therapy for Patients With Solid Tumor Brain Metastases or Leptomeningeal Metastases Harboring PI3K Pathway Mutations

ClinicalTrials.gov Identifier: NCT04192981

Sponsor: Memorial Sloan Kettering Cancer Center
with Kazia Therapeutics, Inc.

Recruitment Contact:
Brandon Imber, MD, PhD6312126346, imberb@mskcc.org

Completion Date: December 2025

Robust responses were observed in all evaluable patients within 3 months of starting study treatment. All patients experienced either a complete or partial response. No dose-limiting toxicities (DLTs) occurred in patients treated with the 45-mg dose of paxalisib, however 2 DLTs occurred at the 60-mg dose. The DLTs shown at the 60-mg dose were grade 3 nausea and vomiting in 1 patient and grade 4 enterocolitis in the other. Therefore, 45 mg was set as the recommended phase 2 dose of paxalisib.

The dose-escalation findings lead the initiation of the dose-expansion phase of the study, which was designed to confirm the safety of the combination and investigate preliminary efficacy. In the dose expansion phase of the study, investigators will evaluate patients for the primary end point of maximum-tolerated dose of paxalisib and the secondary end point of local recurrence rate.

To be eligible for inclusion in the dose-expansion phase of the study, patients must have histologically confirmed solid tumors harboring PI3KCA mutations and brain metastases and/or leptomeningeal metastases per MR imaging. All patients are also required to have a Karnofsky performance status of at least 70, be 18 years of age or older, be able to swallow medication, and have adequate organ, bone marrow, liver, and renal function.

Patients are ineligible to enroll in the study if they were previously treated with radiation, or are actively receiving other agents classified as moderate and/or potent enzyme inducers or inhibitors. The study also excludes patients with serious comorbidities, insulin-treated diabetes, cardiac dysfunction, history of interstitial lung disease, and hypersensitivity or intolerance to paxalisib or another PI3K inhibitor.

"Brain metastases are rapidly emerging as a key pillar of paxalisib's clinical development," said John Friend, MD, chief executive officer of Kazia, in a press release.1 "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."


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. July 7, 2023. Accessed July 7, 2023. https://tinyurl.com/4vry53zd

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 7, 2023. https:// clinicaltrials.gov/ct2/show/NCT04192981

3. Yang J, Mann J, Pike L, et al. MMAP-05 phase I study of concurrent paxalisib and radiation therapy in patients with solid tumor brain metastases or leptomeningeal metastases harboring pi3k pathway mutations: results from the dose-escalation cohort. Neurooncol Adv. 2022;4(suppl1):i15-i16. doi: 10.1093/noajnl/vdac078.061

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