Paxalisib/Radiation Receives FDA FTD for PI3K+ Solid Tumor Brain Metastases

In August 2020, the FDA granted fast track designation to paxalisib for patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status following completion of initial radiation therapy.

The FDA has granted fast track designation to paxalisib plus radiotherapy as a treatment for solid tumor brain metastases with PI3K pathway mutations, according to a press release from Kazia Therapeutics.¹

The regulatory decision was based on interim analysis findings from a phase 1 study (NCT04192981) assessing the combination that were presented at the 2022 Annual Conference on Central Nervous System Clinical Trials and Brain Metastases. Among 9 evaluable patients, all had responded to treatment with paxalisib and radiotherapy. Historically, response rates with radiotherapy alone range from 20% to 40%, according to the press release.

“Brain metastases are rapidly emerging as a key pillar of paxalisib's clinical development,” John Friend, MD, chief executive officer at Kazia, said in the press 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 also.”

The goal of the phase 1 trial is to determine the safety of the combination regimen in patients with brain metastases or leptomeningeal disease from solid tumors with PIK3CA mutations. The trial has an estimated enrollment of 36 patients.

Paxalisib is being assessed using a 3+3 dose escalation design, with dose levels including 45 mg, 60 mg, and 75 mg every day. De-escalation to 30 mg is possible to aid in identifying the agent’s maximum tolerated dose (MTD). Whole brain radiotherapy will be administered at 30 Gy in 10 fractions. Investigators intend to assess 12 additional patients once the MTD of paxalisib combined with radiotherapy is determined.

The study’s primary end point is MTD, and the secondary end point is local recurrence rate.

To enroll on the study, patients are required to have a Karnofsky performance status of 70 or more and be 18 years of age or older. Notably, there is no limit to previous therapies, and those who received stereotactic radiosurgery are able to enroll if they do not have any new, non-irradiated brain lesions or leptomeningeal metastases. The study also includes those with a history of seizures related to brain metastases, as well as adequate organ, bone marrow, liver, and renal function.

Patients who previously received radiotherapy to the intended treatment site or whose metastases are eligible for single fraction stereotactic radiotherapy are not eligible for enrollment. Additional exclusion criteria include serious medical co-morbidities, diabetes requiring insulin treatment, a QT interval of 450 msec or more on EKG, cardiac dysfunction, or a known intolerance or hypersensitivity to paxalisib or other PI3K, Akt, or mTOR pathway inhibitors. A previous history of interstitial lung disease or radiation pneumonitis necessitating steroids was also grounds for exclusion.

In August 2020, the FDA granted fast track designation to paxalisib for patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status following completion of initial radiation therapy.²

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. July 6, 2023. Accessed July 7, 2023. https://bit.ly/3JIXb2T
2. US FDA awards fast track designation (FTD) to paxalisib for glioblastoma. News release. Kazia Therapeutics. August 20, 2020. Accessed July 7, 2023. https://bit.ly/3pD8eUI