Paxalisib Shows Early Efficacy in Newly Diagnosed Glioblastoma

Paxalisib (GDC-0084) had a strong signal of clinical efficacy in patients with newly diagnosed glioblastoma, according to the interim analysis of a phase II clinical trial (NCT03522298). Survival was compared to previous data on the FDA-approved standard of care, temozolomide, from another study. Although the comparison of different studies is not precise, the magnitude of numerical difference in survival provides evidence that this agent may extend life in patients with glioblastoma, Kazia Therapeutics announced in a press release.

“This is an excellent result, and we are delighted with the emerging data,” said James Garner, chief executive officer, Kazia, in a press release. “The 'gold standard' for any new cancer treatment is the ability to extend life - an especially challenging goal in a disease such as glioblastoma - and this data provides our first evidence that paxalisib may achieve this objective in a very challenging patient population."

The interim analysis reviewed survival of patients in Part A (n = 9) and Part B (n = 21). The median overall survival (OS) was 17.7 months in Part A with a strong signal of clinical efficacy.¹The median OS with the standard of care temozolomide, approved by the FDA, is 12.7 months in this patient population, according to a study published in the New England Journal of Medicine.²

Progression-free survival (PFS) was reported for the entire study population, including Parts A and B and was 8.5 months, which is slightly better than previous reports from these data in November 2019 (8.4 months). The longest-treated patient was progression-free 19 months after diagnosis.¹Temozolomide has been associated with a PFS of 5.3 months.²

Paxalisib demonstrated a consistent safety profile compared with prior experiences with the drug. The most common treatment-related adverse events (AEs) included hyperglycemia, oral mucositis, and low-grade rash.¹

The primary end point of the trial is dose-limiting toxicities. Secondary end points include incidence of treatment-emergent AEs, serious AEs, treatment-emergent grade 3/4 clinical laboratory abnormalities, change in electrocardiogram parameter, change in left ventricular ejection fraction, PFS, and OS.

Paxalisib is a small molecule inhibitor of the PI3K/AKT/mTOR pathway. The agent is under development for the treatment of glioblastoma multiforme, which is the most common and aggressive form of primary brain cancer in adult patients. The phase II study was launched in 2018. The agent received an Orphan Drug designation in February 2018 from the FDA.

"There have not been any new drug treatments for newly-diagnosed glioblastoma patients for over 20 years, and we aspire to change that situation,” Garner said. “We believe that paxalisib is rapidly becoming 1 of the most promising drug candidates in the global pipeline for this very challenging disease and we will be working strenuously to make it available to patients as quickly and efficiently as possible."

The trial remains ongoing with approximately half the total enrolled patients still receiving treatment at the time of analysis. An additional number of patients remain in follow-up.

To be enrolled in the trial, patients must have undergone maximal surgical resection of their tumor and received initial treatment with XRT/TMZ within 6 weeks of surgery, consisting or XRT by external beam to a partial brain field. They should also have measurable disease according to RANO criteria for inclusion to the expansion cohort, although patients with non-measurable disease can be included in the dose-escalation cohorts. Patients who received radiotherapy to the brain or cytotoxic drug therapy could not be included in the study.

An additional 4 studies of paxalisib are underway for various forms of brain cancer. Initial efficacy data for several of these trials are expected to be presented at some point in 2020.

The interim results of the phase II were accepted for presentation at the 2020 Annual Meeting of the American Association of Cancer Research, which was planned for April 24-29, 2020. Due to the cancellation of the meeting, Kazia plans to present further data in the second half of 2020, and final data of the phase II trial are expected to be presented in the first half of 2021.

References:

1. Kazia’s Paxalisib Shows Positive Overall Survival Signal in Phase II Glioblastoma Study [news release]. Sydney, Australia: Kazia Therapeutics Limited; April 7, 2020. https://yhoo.it/2JP8QOA. Accessed April 8, 2020.
2. Hegi ME, Diserens AC, Gorlia T, et al. MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma [Published Online March 10, 2005].N Engl J Med. DOI: 10.1056/NEJMoa043331.