Paxalisib/Gemcitabine Combination Dosed in First Patient With CNS Tumor

The first patient has been dosed in arm A of the phase 2 PNOC035 (NCT07447076) platform study evaluating paxalisib in combination with gemcitabine for patients aged 1 to 39 years old with recurrent or progressive atypical teratoid/rhabdoid tumor (AT/RT), according to a news release from Kazia Therapeutics Limited.¹ The multicenter trial is conducted by the Pediatric Neuro-Oncology Consortium (PNOC) and targets a population for which no FDA-approved therapies currently exist. AT/RT is considered one of the most aggressive forms of pediatric brain cancer.

What is the design of the PNOC035 trial?

PNOC035 is an open-label, multicenter platform study that allows multiple treatment arms to be evaluated within a shared trial infrastructure, with patients enrolling in an arm based on availability and arm-specific eligibility criteria. In Arm A, patients will receive oral, once-daily paxalisib in combination with intravenous gemcitabine administered on days 1, 8, and 15 of each 28-day treatment cycle. Enrollment spans a wide age range, from children as young as 1 year to young adults up to age 39.

Across all arms, patients are required to have recurrent or progressive AT/RT; have confirmation of methylation report, co-enrollment on the PNOC-030 trial, or sufficient tumor tissue available for methylation-based subgrouping; and full recovery from acute effects of prior anti-cancer therapy.²

In arm A, patients are required to be evaluable per RAPNO criteria for medulloblastoma and other leptomeningeal seeding tumors, to be able to swallow intact capsules, and have adequate metabolic and cardiac function. Excusion criteria to arm A include prior exposure to gemcitabine or paxalisib, concomitant use of an antihyperglycemic agent, and chronic diarrhea greater than grade 2.

The primary outcomes in arm A for phase 1 were the recommended phase 2 dose and proportion of patients who experienced a dose-limiting toxicity; in phase 2, it was the rate of clinical benefit.

What preclinical data supported the combination in AT/RT?

The rationale for testing paxalisib with gemcitabine came from an orthotopic AT/RT preclinical model, in which the combination increased median survival almost 4-fold compared with untreated controls, from 22 to 82.5 days (P <.0001). The 2 agents also showed complementary anti-tumor activity across multiple AT/RT cell lines. The study extends paxalisib's pediatric neuro-oncology development beyond diffuse midline glioma, where the agent has also been studied, into AT/RT.

What is paxalisib’s regulatory history in AT/RT?

The FDA has granted paxalisib both orphan drug designation and rare pediatric disease designation for AT/RT. The drug’s developer has noted that these designations do not themselves constitute FDA approval or an endorsement of any therapeutic claim. If paxalisib were to eventually receive marketing approval for AT/RT, which would require successful completion of clinical development and FDA regulatory review, Kazia could become eligible for a pediatric priority review voucher from the agency. Paxalisib, an investigational brain-penetrant inhibitor of the PI3K/Akt/mTOR pathway, has also been granted orphan drug and fast track designations in glioblastoma and fast track designation for solid tumor brain metastases harboring PI3K pathway mutations.

Why is a new treatment option needed for recurrent AT/RT?

AT/RT typically affects infants and very young children, and no therapies are currently approved for the recurrent or progressive setting, leaving families with limited options once the disease returns.

“AT/RT typically affects infants and very young children, and families facing this devastating diagnosis have limited treatment options,” stated John Friend II, MD, chief executive officer of Kazia Therapeutics, in the press release.¹ “Despite decades of research, there are still no approved therapies for recurrent or progressive AT/RT, underscoring the urgent need for new treatment options. We've remained committed to pediatric brain cancer because this is an area where the need is especially great and the options are often fewest. Reaching this milestone with the PNOC035 team is a meaningful step forward, and we look forward to working closely with PNOC as enrollment progresses."

References

1. Kazia Therapeutics announces first patient dosed in PNOC035 clinical study evaluating paxalisib for recurrent pediatric AT/RT brain cancer. News release. Kazia Therapeutics Limited. September 9, 2026. Accessed September 9, 2026. https://tinyurl.com/2su2anp6
2. Study of novel therapies for young people with recurrent/​progressive atypical teratoid rhabdoid tumor (ATRT). ClinicalTrials.gov. Updated June 23, 2026. Accessed September 9, 2026. https://tinyurl.com/358429nr