paxalisib (GDC-0084) / Roche, Kazia, Simcere, SoVarGen, QIMR Berghofer Medical Research Institute - LARVOL DELTA

Targeting Kinase Signaling in Glioblastoma: Structural Optimization, Blood-Brain Barrier Dynamics and Combinatorial Translational Strategies. (PubMed, Int J Mol Sci) - "Reviewing recent clinical failures, such as paxalisib and osimertinib, underscores that single-node monotherapies fail due to compensatory pathway hyperactivation and clonal heterogeneity, whereas multi-targeted agents or rational dual-node combinations prevent rapid tumor adaptation. Finally, bridging the translational gap requires complementing conventional serum-cultured cell lines with patient-derived glioma stem cells and orthotopic xenografts to better recapitulate the cellular architecture of the disease. Ultimately, overcoming the therapeutic challenges in glioblastoma demands a fundamental pivot toward rigorous neuro-pharmacological design and multi-lineage network oncology."

Journal • Review • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Kazia Therapeutics Limited…announced that the first patient has been dosed in Arm A of PNOC035, a Phase 2 platform study evaluating paxalisib in combination with gemcitabine for patients ages 1 to 39 with recurrent or progressive atypical teratoid/rhabdoid tumor (AT/RT) (PRNewswire) - "PNOC035 is conducted by the Pediatric Neuro-Oncology Consortium (PNOC), an open-label, multi-center platform study. In Arm A, patients receive oral, once-daily paxalisib in combination with intravenous gemcitabine on Days 1, 8 and 15 of each 28-day treatment cycle."

Trial status • Rhabdoid Tumor

Pharmacokinetics and pharmacodynamics of paxalisib in newly diagnosed glioblastoma patients with unmethylated MGMT promoter status: Final phase II study results (ESMO 2022) - P2, P2/3 | "At the MTD FDG-PET data provide evidence that paxalisib has the ability to exert biological effect in tumour tissue, irrespective of fed or fasted status. Further evaluation is ongoing in GBM AGILE (NCT03970447)."

Clinical • P2 data • PK/PD data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Kazia Therapeutics Limited Announces Oversubscribed Closing of Up to $120 Million Public Offering (PRNewswire) - "If all milestone-linked warrants are exercised in full, the Offering would provide Kazia with approximately $80 million in additional gross proceeds, for total potential gross proceeds of approximately $120 million....Kazia intends to use the net proceeds from the Offering primarily to fund clinical development of paxalisib, including ongoing and planned studies in triple-negative breast cancer, HR+/HER2- breast cancer, and pMMR colorectal cancer, as well as for working capital and general corporate purposes."

Financing • pMMR • Colorectal Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer

Kazia has filed a patent that is supported by the Company's preclinical findings and has identified a high-risk subset of metastatic HR+/HER2- breast cancer defined by a novel PI3K/mTOR biomarker, with tissue- and blood-based tests associated with poor survival (PRNewswire)

Patent • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Kazia Therapeutics Limited…announced new data showing its lead asset, paxalisib, achieved a 100% clinical benefit rate in six evaluable patients with Stage IV triple-negative breast cancer (TNBC) (PRNewswire) - "Five of the six patients achieved an objective response - a measurable 30% or greater reduction in tumor burden after treatment - including one complete response and four partial responses, resulting in an objective response rate of 83 percent. The remaining patient achieved stable disease. Importantly, these results were achieved with the convenience of oral dosing and a favorable safety and tolerability profile, with no paxalisib-related serious adverse events and no grade 3 or higher hyperglycemia, stomatitis or mucositis, toxicities commonly associated with PI3K/mTOR pathway inhibition....Translational analyses demonstrated reductions in terminally exhausted CD8+ T cells across all six patients, with a median reduction of 51 percent within approximately three weeks of treatment."

P1 data • Triple Negative Breast Cancer

Enrollment in the Company's ongoing Phase 1b study evaluating paxalisib in combination with pembrolizumab (Keytruda) and chemotherapy in advanced metastatic TNBC is expected to be completed by July 2027, with interim clinical updates anticipated throughout 2026 and 2027 (PRNewswire)

Enrollment status • P1 data • Triple Negative Breast Cancer

Kazia Therapeutics Limited…announced new preclinical data demonstrating the safety and anti-tumor activity of paxalisib in HR+/HER2- breast cancer, including evidence that paxalisib resensitized CDK4/6 inhibitor-resistant tumors to standard-of-care therapy (PRNewswire) - "Preclinical data show paxalisib combined with standard-of-care therapy is well tolerated and produces statistically significant antitumor activity....Alongside its IP filing, Kazia is amending the protocol of its ongoing TNBC clinical trial to add a three-arm expansion evaluating paxalisib in patients with pre-treated HR+/HER2- metastatic breast cancer....The Company expects sites for this expansion to be activated and the first patient enrolled before the end of 2026, with full enrollment anticipated by the end of 2027. Clinical updates are anticipated throughout 2027, with a full readout anticipated in 2028."

P1 data • Preclinical • Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer

Safety, Tolerability, and Pharmacokinetics of SVG103 (Paxalisib) in Focal Cortical Dysplasia Type II (FCD-II), Tuberous Sclerosis Complex (TSC) or Hemimegalencephaly (HME) (clinicaltrials.gov) - P1/2 | N=12 | Recruiting | Sponsor: Sovargen | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2027 ➔ Mar 2027 | Initiation date: Mar 2026 ➔ Jul 2026

Enrollment open • Trial completion date • Trial initiation date • CNS Disorders

Kazia Therapeutics Limited…announced the filing of a provisional patent application supporting a novel therapeutic strategy designed to prevent metastatic recurrence in patients with high-risk early-stage triple-negative breast cancer (TNBC) (GlobeNewswire) - "The patent filing is supported by new preclinical findings from a model designed to replicate high-risk early-stage TNBC. In the model, standard treatment -neoadjuvant chemotherapy, anti-PD-1 immunotherapy and surgical resection - followed by adjuvant paxalisib reduced residual disease and local recurrence by 95% (p<0.0001) and lung metastatic burden by 40% (p<0.027)....In these studies, paxalisib completely disrupted (100%) the circulating tumor cell (CTC) clusters that were detected. Together with emerging clinical observations from the Company's ongoing metastatic TNBC study, these findings strengthen the translational rationale for advancing paxalisib across multiple stages of disease."

Patent • Preclinical • Triple Negative Breast Cancer

Sensitisation pathways revealed by CRISPR-based combinatorial dependency analysis in paediatric high-grade glioma (ISPNO 2026) - "Each cell line was transduced with a genome-wide knockout library and subsequently exposed to 11 different compounds, including FDA-approved agents (Trametinib, ONC201, Temozolomide, Ribociclib, Infigratinib, Avapritinib, Erlotinib, and Alpelisib) and additional pathway inhibitors (TP0184, ACT001 and Paxalisib). Finally, KEGG analysis of pan-therapy dependency genes identified significant enrichment of the ubiquitin system, spliceosome, kinetochore dephosphorylation, and mitotic checkpoint complex pathways, suggesting the presence of conserved, lineage-independent vulnerabilities across pHGGs. Together, these finding highlight the presence of a robust pan-dependency signature across drugs and points to conserved vulnerabilities that may offer complementary therapeutic opportunities."

Brain Cancer • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • Targeted Protein Degradation • PI3K

Melatonin Effects on PI3K/Akt Pathway and Cognitive Function in Hypoxic Rat Hippocampal Neurons. (PubMed, Clin Lab) - "Melatonin may alleviate oxidative stress induced by intermittent hypoxia by regulating the PI3K/ AKT signaling pathway and related antioxidant protein expression, thereby improving cognitive function in rats. PI3K inhibitors effectively blocked the upregulation of these proteins, whose expression levels showed no significant difference overall compared to the untreated group."

Journal • Preclinical • Cognitive Disorders

Precision Targeting of PI3K/mTOR in Diffuse Midline Glioma: GCT007 as a Novel Brain-Penetrant PIK3CA Inhibitor (ISPNO 2026) - P1 | "However, in Phase I studies (NCT01547546), the systemic pan-PI3K inhibitor, paxalisib, induces adverse events in patients (e.g., hyperglycemia), undermining treatment efficacy...Phosphoproteomic profiling following PI3K/AKT/mTOR inhibition showed activated calcium-dependent PKC signaling, therefore, we tested GCT-007 in combination with the brain-penetrant PKC inhibitors: enzastaurin, and JLD14 (novel therapy in development in our laboratory) and with immune checkpoint inhibitor anti-PD1 therapies...Together these findings define a precision treatment strategy which targets DMG genetic dependencies, circumvents therapeutic resistance and primes the tumor for immune engagement. Ongoing spatial profiling of the tumor immune microenvironment and organ-toxicity is underway to support translation."

IO biomarker • Brain Cancer • Diabetes • Diffuse Midline Glioma • Gastroenterology • Gastrointestinal Disorder • Glioma • Immunology • Mucositis • Solid Tumor • PIK3CA • PIK3CD • PIK3CG

Innovative precision-guided MAPK inhibition: expanding therapeutic benefits in pediatric glioma (ISPNO 2026) - "Mitogen-activated protein kinase kinase (MEK; trametinib/pimasertib) or extracellular signal-regulated kinase (ERK; ulixertinib) inhibition was combined with rapidly accelerated fibrosarcoma (RAF; tovorafenib) or phosphatidylinositol 3-kinase (PI3K; paxalisib) inhibition to compare vertical MAPK versus horizontal MAPK/PI3K pathway blockade. This study demonstrates that dual MEK and RAF inhibition with clinically relevant, brain-penetrant agents is highly effective against HGG and DMG tumors, independent of MAPK status. Studies ascertaining relevant biomarkers within this setting are currently underway to guide enrollment of children into the OPTIMISE clinical trial."

Clinical • Brain Cancer • Diffuse Midline Glioma • Fibrosarcoma • Glioma • High Grade Glioma • Pediatrics • Sarcoma • Solid Tumor

Evaluation of the antitumor effect of paxalisib in combination with oncolytic virotherapy for Diffuse Midline Glioma (ISPNO 2026) - "The mechanistic basis involves both direct PI3K/mTOR inhibition and enhanced anti-tumor immunity. These findings support clinical translation of this combination approach for DMG and other pediatric CNS malignancies with PI3K/mTOR pathway activation."

Combination therapy • Oncolytic virus • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

Genetic Testing in Guiding Treatment for Patients with Brain Metastases (clinicaltrials.gov) - P2 | N=186 | Recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Trial completion date: Jun 2026 ➔ Jun 2028 | Trial primary completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • KRAS • NTRK • PGR • ROS1

Deciphering cellular sates associated with response to dordaviprone (ONC201) in diffuse midline glioma patients from the PNOC022 clinical trial (ISPNO 2026) - "Preliminary results from the PNOC DMG-ACT (DMG-Adaptive Combination Trial) PNOC022 suggest improved overall survival in patients treated with the combination of dordaviprone and paxalisib, compared with outcomes reported across prior DMG studies conducted by the Pediatric Neuro-Oncology Consortium. Further interrogation identified state-specific biomarkers, including GPR17 (OC-like) and GFAP/CD44 (AC-/MES-like), highlighting candidate biomarkers that may predict therapy response and enable patient stratification. We are currently expanding our analysis with validation cohorts to strengthen these findings and to define a clinically actionable, predictive hierarchy of DMG cellular states that informs patient outcomes and treatment response following combination therapy."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Solid Tumor • GFAP

Genetic Testing in Guiding Treatment for Patients With Brain Metastases (clinicaltrials.gov) - P2 | N=186 | Recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Oct 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • KRAS • NTRK • PGR • ROS1

Study of Novel Therapies for Young People With Recurrent/Progressive Atypical Teratoid Rhabdoid Tumor (ATRT) (clinicaltrials.gov) - P2 | N=29 | Recruiting | Sponsor: Sabine Mueller, MD, PhD | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Rhabdoid Tumor • Sarcoma • SMARCB1 • SMARCD3

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma. (PubMed, Neuro Oncol) - "This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design."

Heterogeneity • IO biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2

WITHDRAWN: Influence of paxalisib-mediated PI3K/mTOR inhibition on tumor immunity and immunotherapy resistance in colorectal cancer. (ASCO 2026) - "These data identify the p85β/EZH2 epigenetic axis as a key driver of metastatic progression and immune suppression in colorectal cancer. Pharmacologic targeting of this pathway with the dual PI3K–mTOR inhibitor, Paxalisib, remodels tumor-intrinsic and immune regulatory programs, leading to reduced metastatic progression and immune reinvigoration. This work provides a strong preclinical rationale for further clinical investigation of dual PI3K/mTOR-based strategies to overcome immunotherapy resistance in CRC."

IO biomarker • Breast Cancer • Colorectal Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer

Kazia Therapeutics Limited…announced plans to expand its ongoing Phase 1b clinical trial evaluating lead asset paxalisib in combination with standard-of-care therapies in patients with advanced triple negative breast cancer ("TNBC"). (PRNewswire) - "Based on continued encouraging safety, tolerability and clinical activity data observed to date, planned enrollment has increased from 12 to 36 patients. The expansion is intended to further evaluate the safety, tolerability, dose optimization and preliminary efficacy of the paxalisib-based combination regimen with pembrolizumab and chemotherapy. The expanded dataset is expected to provide a more meaningful assessment of objective response rate ('ORR'), progression-free survival ('PFS') and translational biomarkers. Additional clinical trial updates are anticipated throughout 2026 and into 2027."

Trial status • Triple Negative Breast Cancer

Genetic Testing in Guiding Treatment for Patients With Brain Metastases (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: Alliance for Clinical Trials in Oncology | Suspended ➔ Active, not recruiting | N=186 ➔ 50

Enrollment change • Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRAF • ER • KRAS • NTRK • PGR • ROS1

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=2250 | Recruiting | Sponsor: Global Coalition for Adaptive Research | N=1280 ➔ 2250

Enrollment change • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

Improving survival of atypical teratoid/rhabdoid tumor orthotopic xenografts through the combination of PI3K inhibitor paxalisib and nucleoside analog gemcitabine (AACR 2024) - "In CHLA-06 orthotopic tumors combination therapy extended median survival from 22 days for control to 82.5 days (p<0.0001). Based on these findings, the Pacific Pediatric Neuro-Oncology Consortium (PNOC) is planning to include paxalisib/gemcitabine combination therapy in the next international clinical trial for patients with relapsed/recurrent AT/RT."

Brain Cancer • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • ANXA5 • ATF4 • PPP1R15A