24 DIRECTORS’ REPORT Phase II Study in DIPG with the Pacific Pediatric Neuro-Oncology Consortium In November 2021, an international phase II study sponsored by the Pacific Pediatric Neuro-Oncology Consortium (PNOC) commenced recruitment. The study is designed to examine the combination of paxalisib with ONC201 (Chimerix, Inc), and potentially other therapies in the future, for the treatment of DIPG and diffuse midline gliomas (DMGs). Recruitment remains ongoing, with initial data anticipated in CY2023. Preclinical Data in DIPG The PNOC DIPG study is supported by preclinical data from an international consortium of scientists led by Associate Professor Matt Dun at the Hunter Medical Research Institute at the University of Newcastle, Australia. Dr Dun’s work has identified PI3K pathway activation as a primary resistance mechanism to ONC201 and has demonstrated synergistic efficacy when the two drugs are combined in preclinical models of DIPG. This work was the subject of a poster presentation at the annual International Symposium on Pediatric Neuro-Oncology (ISPNO) conference in Hamburg, Germany, in June 2022. Dr Dun also reported case studies of two patients who had received the combination through compassionate access and who had demonstrated marked clinical improvement while on therapy. Preclinical Data in AT/RT At the American Association of Cancer Research (AACR) Annual Meeting in New Orleans, LA, in April 2022, Professor Jeffrey Rubens and colleagues presented preclinical data describing the combination of paxalisib with two other investigational cancer therapies for the treatment of atypical teratoid / rhabdoid tumours (AT/RT), a rate form of childhood brain cancer. Dr Ruben’s team noted both single agent activity for paxalisib and synergy in combination with an HDAC inhibitor and a MEK inhibitor. Paxalisib Development in Brain Metastases Phase II Study in HER2+ Breast Cancer Brain Metastases at Dana Farber Cancer Institute A phase II investigator-initiated clinical study is ongoing at Dana-Farber Cancer Institute in Boston, MA, exploring paxalisib in combination with Herceptin (trastuzumab) for HER2+ breast cancer brain metastases, a population for which there are no approved pharmacological treatments (NCT03765983). The Dana-Farber study is primarily funded by the hospital, with support via a financial grant from Kazia. Initial interim efficacy data is expected in 2H CY2022. Phase II Genomically Guided Study in Brain Metastases Paxalisib is one of the three pharmacological agents being investigated in a multi-drug, genomically-guided clinical study in brain metastases (NCT03994796), sponsored by the Alliance for Clinical Trials in Oncology and substantially funded by the US National Cancer Institute. The study assigns patients to either paxalisib, abemaciclib (Eli Lilly & Co), or entrectinib (Genentech, Inc) on the basis of their tumour’s genetic characteristics. Each drug is investigated in parallel in three patient cohorts: breast cancer, lung cancer, and other tumours. In June 2022, Kazia was informed that paxalisib had graduated to an expansion stage of the study in breast cancer, with work ongoing in the other two cohorts. Phase I Study in Brain Metastases in Combination with Whole Brain Radiotherapy Paxalisib is the subject of a phase I study in combination with whole brain radiotherapy for the treatment of brain and leptomeningeal metastases, sponsored by Memorial Sloan Kettering Cancer Center in New York, NY (NCT04192981). Whole brain radiotherapy (WBRT) is a ubiquitous therapeutic modality in this patient population, with an estimated 200,000 patients receiving treatment each year in the United States alone. The first stage of the study comprises approximately 12 patients and is designed to determine the maximum tolerated dose of paxalisib when combined with WBRT. On the basis of promising results, the study has the potential to open a second stage which will recruit a further 12 patients. Post period, on August 5 2022, the company announced an upcoming oral presentation of promising new data from an ongoing phase 1 clinical trial of paxalisib in combination with radiotherapy for the treatment of brain metastases, sponsored by Memorial Sloan Kettering Cancer Center in New York, NY . Interim data from the first stage of the study reports that all 9 evaluable patients experienced complete or partial response, representing an overall response rate (ORR) of 100%, according to RANO-BM criteria. The patients comprised a range of primary tumours, with breast cancer the most common, representing one third of patients. The trial is designed in two stages: an initial exploratory stage and a confirmatory expansion stage. Recruitment to the expansion stage has already commenced, with the objective of recruiting an additional 12 patients. Paxalisib Development in Primary CNS Lymphoma (PCNSL) Phase II Study in PCNSL at Dana-Farber Cancer Institute A phase II study is ongoing at Dana Farber Cancer Institute in Boston, MA, to investigate paxalisib as monotherapy in patients with PCNSL (NCT04906096). Four of the five PI3K inhibitors that have received FDA approval have been indicated for lymphoma outside the CNS, and so this may be considered a high potential indication for paxalisib. The study commenced recruitment in 2021 and remains ongoing as at 30 June 2022.
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