9 Kazia Theraputics Limited Annual Report 2023 Paxalisib in Paediatric Brain Cancer Brain cancer is the most common malignancy of childhood cancer and represents about one-third of all childhood cancer deaths. The PI3K/AKT/mTOR pathway is frequently upregulated in paediatric cancers and therefore therapeutics that target those pathways could lead to long-awaited regulatory approvals. Diffuse intrinsic pontine glioma (DIPG) is the most common of a group of childhood brain cancers known as diffuse midline gliomas (DMGs). The disease currently has no FDA approved drug treatments and average survival from diagnosis is approximately 10 months. Kazia recognizes the critical importance and immense unmet need and is exploring paxalisib in two common forms of childhood cancer -DMG and advanced childhood cancer with PI3K/mTOR mutations. PNOC022 phase II study The PNOC022 phase II study is sponsored by the Pacific Pediatric Neuro-Oncology Consortium (PNOC), an international consortium focused on the development of novel combination therapies. It is an adaptive platform study that is examining paxalisib in combination with ONC201. The study enrolment has been progressing well since opening in late 2021 and the study teams at PNOC and University of California, San Francisco (UCSF) are analysing interim data for the study, which is expected to be reported in 2H CY2023. OPTIMISE phase II study Kazia entered into a collaboration with the Australian and New Zealand Children’s Haematology / Oncology Group (ANZCHOG) in March 2023 for a phase II clinical study examining paxalisib as a targeted therapeutic in children with advanced solid tumours, including brain tumours. The OPTIMISE phase II study is the first Australian-led clinical trial of paxalisib and will combine paxalisib with chemotherapy for children with PI3K pathway mutations. Enrolment for this study is expected to commence in 4Q CY2023. St Jude Children’s Research Hospital phase I study The objective of this phase I investigator study in children with Diffuse Intrinsic Pontine Glioma (DIPG) to establish a maximum tolerated dose (MTD) was presented in November 2020 at the SNO Annual Meeting. The paediatric MTD of 27 mg/m2 was established and the safety profile and pharmacokinetics were highly consistent with the adult data. The long term survival follow-up was completed this year and will be incorporated into the clinical study report. Paxalisib in Brain Metastases Brain metastases occur when cancer cells spread from their original site to the brain, and treatment options are very limited. Brain metastases are a common complication of many tumours, but are particularly common in breast cancer, lung cancer, and melanoma. Brain metastases are typically highly resistant to treatment and survival rates are generally low. Radiotherapy is a common treatment modality for brain metastases. Despite some reported efficacy of radiotherapy, patients typically become resistant over time, and repeat courses of radiotherapy can be associated with significant neurological toxicity. Additionally, PI3K pathway mutations are common in brain metastasis and are frequently associated with a poor prognosis. Paxalisib in combination with radiotherapy Paxalisib is being studied in combination with radiotherapy in an ongoing phase I clinical study for the treatment of patients with brain metastases who harbour PI3K pathway mutations, sponsored by Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY. Encouraging safety and clinical activity from this study was presented by the principal investigator, Dr. Jonathan Yang, in August 2022 at the 2022 Annual Conference on CNS Clinical Trials and Brain Metastases, jointly organized by the Society for Neuro-Oncology and the American Society for Clinical Oncology held in Toronto, Canada. The expansion cohort is currently being enrolled and two world- renowned cancer centres have joined MSKCC in this study: Miami Cancer Institute and Fred Hutchinson Cancer Center in Seattle, WA. Preliminary data from the expansion cohort is anticipated by 1Q CY2024. Chairman and CEO’s Letter Key Milestones Introduction to Kazia’s CEO Pipeline Review Environment, Society and Governance Financial Reports
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