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

Personalized pharmacokinetic-pharmacodynamic guided therapy via an induced pluripotent stem cell-derived multi-organoid platform in NF1-mutant breast cancer. (PubMed, Signal Transduct Target Ther) - "PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts."

Journal • PK/PD data • Breast Cancer • Oncology • Solid Tumor • NF1

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

New P2 trial • Oncology • Rhabdoid Tumor • Sarcoma • SMARCB1 • SMARCD3

Α-SYNUCLEIN ACTIVATES RAS–PI3K/AKT/MTOR SIGNALING TO DRIVE PATHOLOGY IN PARKINSON'S DISEASE (ADPD 2026) - "Treatment of α-SynA53T mice with GDC0084 (paxalisib), a brain-penetrant PI3K inhibitor, reduced AKT activation and lipid droplet accumulation, while enhancing lysosomal clustering and autophagy. Our findings identify α-Syn as a driver of Ras–PI3K/AKT/mTOR signaling and lipid dysregulation, and support PI3K inhibition as a potential therapeutic strategy to manage α-Syn pathology in PD."

CNS Disorders • Movement Disorders • Parkinson's Disease • PPARG

Kazia Therapeutics Reports Encouraging Preliminary Clinical Responses in Ongoing Phase 1b Study of Paxalisib in Late-Stage Metastatic Triple-Negative Breast Cancer (PRNewswire) - "Clinical Highlights: 2 of 2 evaluable patients enrolled in the Phase 1b trial achieved partial responses; One advanced metastatic TNBC patient achieved a confirmed complete metabolic response following re-treatment with pembrolizumab/chemotherapy plus paxalisib (under an expanded access protocol); Responses observed in patients with visceral disease and multi-organ metastases; Median time on treatment to date is approximately 6.1 months, with all patients continuing on therapy at the time of this update....The Company expects to activate two additional clinical sites by April 2026, with two further sites planned for mid-2026. Kazia continues to anticipate the targeted enrollment of twelve TNBC pts target by the end of 2026 and topline data readout in early 2027."

P1 data • Trial status • Triple Negative Breast Cancer

GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases (clinicaltrials.gov) - P2 | N=17 | Terminated | Sponsor: Dana-Farber Cancer Institute | N=47 ➔ 17 | Active, not recruiting ➔ Terminated; participants are no longer being examined or receiving intervention

Enrollment change • Trial termination • Brain Cancer • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • EIF4EBP1 • HER-2

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

GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Nov 2025 ➔ May 2026

Trial completion date • Brain Cancer • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • EIF4EBP1 • HER-2

Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov) - P2 | N=33 | Suspended | Sponsor: Weill Medical College of Cornell University | Trial completion date: Dec 2025 ➔ Jun 2026 | Recruiting ➔ Suspended | Trial primary completion date: Dec 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Trial suspension • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MGMT

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=15 | Not yet recruiting | Sponsor: SoVarGen Co., Ltd.

New P1/2 trial • CNS Disorders

Liquid Biopsy Tracking of PI3K-mTOR Residual Disease Signatures in Metastatic Breast Cancer (SABCS 2025) - "Ex vivo drug screening with PI3K-mTOR inhibitors, including the brain-penetrant paxalisib, was performed to evaluate their effects on mesenchymal phenotypes, disruption of circulating tumor cell (CTC) clusters, and immune reinvigoration.Results We identified a novel epigenetic switch that drives the transition to a more aggressive, drug-resistant mesenchymal phenotype in HER2-positive breast cancer, associated with activation of the nuclear chromatinised PI3K signaling pathway...This dual mechanism may enhance anti-tumor efficacy by converting immunologically 'cold' tumors into 'hot', more immunogenic tumors. By reshaping the tumor microenvironment, this approach has the potential to improve the clinical utility of immunotherapy and expand treatment options for patients with HER2-positive metastatic breast cancer."

Biopsy • IO biomarker • Liquid biopsy • Metastases • Residual disease • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ALDH1A1 • NNMT • TMB

A phase 1b, multi-centre, open-label, randomized study to evaluate the safety, tolerability, and clinical activity of combining paxalisib with olaparib or pembrolizumab/chemotherapy in patients with advanced breast cancer (SABCS 2025) - P1 | "Patients will receive daily paxalisib (15 mg or 30 mg) in 21-day cycles, pembrolizumab (200 mg IV every 3 weeks), and standard-of-care chemotherapy (investigator's choice: nab-paclitaxel or gemcitabine-carboplatin). Clinical: Upcoming data will include updated liquid biopsy biomarker analyses, encompassing CTC enumeration and phenotyping, as well as profiling of immune cell exhaustion and reinvigoration signatures.ConclusionsOur preclinical studies demonstrated that combining paxalisib with either immunotherapy or PARP inhibition significantly reduced CTC burden and reshaped the immune landscape, leading to a decrease in metastasis. These promising findings have advanced into a Phase 1b clinical trial in patients with advanced breast cancer, with updated analysis to be presented at this meeting."

Clinical • IO biomarker • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CTCs • HER-2 • PD-L1 • PTPRC

Adaptive Biotechnologies Showcases Leadership in Hematology-Oncology MRD with New clonoSEQ Data Driving Treatment Interventions at 2025 ASH Annual Meeting (GlobeNewswire) - "Notably, 17 abstracts utilizing Adaptive’s clonoSEQ test exemplify how next-generation sequencing-based measurable residual disease (MRD) status is guiding clinical actions to improve blood cancer patient care."

Clinical data • Diagnostic • B Acute Lymphoblastic Leukemia • Chronic Lymphocytic Leukemia • Multiple Myeloma • Non-Hodgkin’s Lymphoma

Kazia Therapeutics…announced that it has entered into a securities purchase agreement with certain established institutional and accredited investors for a private placement of equity securities (PIPE) (PRNewswire) - "Pursuant to the securities purchase agreement, the Company agreed to offer and sell to the investors an aggregate of approximately $50.0 million of ordinary shares and prefunded warrants, at a purchase price per share that is the equivalent of $5.00 per ADS, each ADS representing 500 ordinary shares....The Company currently intends to use the net proceeds from the offering...to support the continued clinical development of its lead program paxalisib..., advancing the PD-L1 degrader program, and for general corporate purposes."

Financing • Breast Cancer • CNS Tumor

Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS (LUMOS2) study (WFNOS 2025) - P2 | "LUMOS2 currently has four active arms each with n=19 participants: paxalisib (PIK3CA-MTOR inhibitor) for participants with PIK3CA pathway alterations, or randomization to one of three target-agnostic options: AK104 (PD-1/CTLA-4 bispecific antibody), selinexor (selective inhibitor of nuclear export), or niraparib plus AK104 (PARP inhibitor plus AK104). Feasibility of molecular guided therapy in recurrent grade 2-3 glioma based on comprehensive genomic profiling is established with trial recruitment to date."

IO biomarker • Brain Cancer • Oncology • Solid Tumor • CTLA4 • MTAP • PD-1 • PIK3CA

Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS (LUMOS2) study (SNO 2025) - P2 | "LUMOS2 currently has four active arms each with n=19 participants: paxalisib (PIK3CA-MTOR inhibitor) for participants with PIK3CA pathway alterations, or randomization to one of three target-agnostic options: AK104 (PD-1/CTLA-4 bispecific antibody), selinexor (selective inhibitor of nuclear export), or niraparib plus AK104 (PARP inhibitor plus AK104). Feasibility of molecular guided therapy in recurrent grade 2-3 glioma based on comprehensive genomic profiling is established with trial recruitment to date."

IO biomarker • Brain Cancer • Glioma • Solid Tumor • CTLA4 • MTAP • PD-1 • PIK3CA

Exploiting Cell-of-Origin Vulnerabilities to Guide Multimodal Strategies in Diffuse Midline Glioma (WFNOS 2025) - "To mitigate this, we developed multimodal strategies that combined clinically relevant PI3K/mTOR inhibitors (paxalisib, GCT-007, everolimus) with the antihyperglycemic agent metformin, which restored glucose homeostasis, suppressed insulin receptor activity, and extended survival in DMG xenograft models. Phosphoproteomic profiling identified therapy-induced activation of calcium-dependent PKC signaling, prompting combination with the brain-penetrant PKC inhibitor enzastaurin, further extending survival...Together, our findings define a multimodal, precision treatment strategy that targets core DMG genetic dependencies, rewires tumor cell identity, circumvents systemic resistance, and primes an immunologically “cold” tumor for immune engagement and clinical translation. We are currently designing an early-phase clinical trial that incorporates sequential small-molecule therapies and ICIs delivered via focused ultrasound, aiming to provide patients with a meaningful and..."

IO biomarker • Brain Cancer • CNS Disorders • Diabetes • Diffuse Midline Glioma • Glioma • Multiple Sclerosis • Solid Tumor • CD8 • H3-3A • HLA-DRA • IR • PD-L1 • PIK3CA

Exploiting Cell-of-Origin Vulnerabilities to Guide Multimodal Strategies in Diffuse Midline Glioma (SNO 2025) - "To mitigate this, we developed multimodal strategies that combined clinically relevant PI3K/mTOR inhibitors (paxalisib, GCT-007, everolimus) with the antihyperglycemic agent metformin, which restored glucose homeostasis, suppressed insulin receptor activity, and extended survival in DMG xenograft models. Phosphoproteomic profiling identified therapy-induced activation of calcium-dependent PKC signaling, prompting combination with the brain-penetrant PKC inhibitor enzastaurin, further extending survival...Together, our findings define a multimodal, precision treatment strategy that targets core DMG genetic dependencies, rewires tumor cell identity, circumvents systemic resistance, and primes an immunologically "cold" tumor for immune engagement and clinical translation. We are currently designing an early-phase clinical trial that incorporates sequential small-molecule therapies and ICIs delivered via focused ultrasound, aiming to provide patients with a..."

IO biomarker • Brain Cancer • CNS Disorders • Diabetes • Diffuse Midline Glioma • Glioma • Multiple Sclerosis • Solid Tumor • CD8 • H3-3A • HLA-DRA • IR • PD-L1 • PIK3CA

Q4 BUSINESS UPDATE (PRNewswire) - "Kazia is proud to announce acceptance of two scientific presentations at the 2025 San Antonio Breast Cancer Symposium (SABCS) to be held December 10–14, 2025."

Clinical data • Breast Cancer • Triple Negative Breast Cancer

Kazia Therapeutics Achieves Initial iCR (Immune-Complete Response) in Metastatic TNBC… (PRNewswire) - "This outcome suggests a profound radiologic response in a highly aggressive metastatic cancer subtype. This development builds upon Kazia's October 2, 2025 announcement reporting an 86% reduction in tumor burden after only three weeks of treatment in the same patient. A PET/CT scan performed after approximately three months of therapy demonstrated complete metabolic resolution of all previously identified lesions, consistent with an initial iCR. The patient remains on therapy and under active clinical monitoring."

Clinical data • Triple Negative Breast Cancer

α-synuclein activates the pi3k/akt pathway: implications for parkinson's disease therapy (Neuroscience 2025) - "In-vivo treatment of young, asymptomatic α-SynA53T transgenic mice with GDC-0084 (paxalisib), a blood-brain barrier-permeable PI3K inhibitor, restored healthy AKT activity levels, reduced levels of PSer129 and α-Syn oligomers, decreased neuronal lipid droplet accumulation, and promoted lysosomal clustering. These findings establish a role for α-Syn in p110α activation during early, asymptomatic stages of the disease and highlight the therapeutic potential of PI3K inhibition as a disease-modifying strategy"

CNS Disorders • Movement Disorders • Parkinson's Disease • PIK3CA • PPARG

Paxalisib: Repurposing of PI3K pathway modulators for the treatment of PTEN hamartoma tumour syndrome. (Neuroscience 2025) - "Currently there are no approved treatments for PHTS although a randomised placebo controlled trial of the mTOR inhibitor everolimus demonstrated a statistically significant improvement in the social domain. Pharmacokinetic and pharmacodynamic studies suggest that paxalisib, at tested doses, crosses the blood brain barrier and inhibits PI3K pathway activity at exposures correlated with in vitro inhibition of aberrant PTEN loss neuronal change. Paxalisib is a promising candidate for assessment in a preclinical PHTS disease model and may be a potential candidate for clinical evaluation."

CNS Disorders • Psychiatry • PTEN

Activation of chaperone-mediated autophagy suppresses glioblastoma by promoting wild-type IDH1/isocitrate dehydrogenase 1 degradation. (PubMed, Autophagy) - "This phenotype was further exacerbated by chronic temozolomide treatment in both in vitro and in vivo glioblastoma models. Notably, CMA-activating compounds, including the RARA (retinoic acid receptor alpha) antagonist CA77.1, the class I phosphoinositide 3-kinase (PI3K) inhibitor paxalisib, and metformin, effectively reduced IDH1 and CCND1 levels while suppressing glioblastoma cell growth. Together, our findings suggest that dysfunction of the CMA-IDH1-CCND1 regulatory cascade drives progression of IDH1-wild-type glioblastoma and provide a mechanistic basis for repurposing CMA activators as potential therapeutic agents for these tumors."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • Targeted Protein Degradation • CCND1 • HSPA8 • IDH1 • RARA • RB1

Exploiting Cell-of-Origin Vulnerabilities to Guide Multimodal Strategies in Diffuse Midline Glioma (WFNOS 2025) - "To mitigate this, we developed multimodal strategies that combined clinically relevant PI3K/mTOR inhibitors (paxalisib, GCT-007, everolimus) with the antihyperglycemic agent metformin, which restored glucose homeostasis, suppressed insulin receptor activity, and extended survival in DMG xenograft models. Phosphoproteomic profiling identified therapy-induced activation of calcium-dependent PKC signaling, prompting combination with the brain-penetrant PKC inhibitor enzastaurin, further extending survival...Together, our findings define a multimodal, precision treatment strategy that targets core DMG genetic dependencies, rewires tumor cell identity, circumvents systemic resistance, and primes an immunologically "cold" tumor for immune engagement and clinical translation. We are currently designing an early-phase clinical trial that incorporates sequential small-molecule therapies and ICIs delivered via focused ultrasound, aiming to provide patients with a..."

IO biomarker • Brain Cancer • CNS Disorders • Diabetes • Diffuse Midline Glioma • Glioma • Multiple Sclerosis • Solid Tumor • CD8 • H3-3A • HLA-DRA • IR • PD-L1 • PIK3CA

Synthesis and evaluation of pyrimidine derivatives for Glioblastoma Multiforme inhibition. (PubMed, Biochem Biophys Res Commun) - "In an orthotopic transplantation GBM model, compared with GDC-0084, KJ-25 significantly suppressed tumor growth. These results suggest that KJ-25 is a promising candidate drug for the treatment of GBM, providing a strategy for improving the prognosis of this refractory malignant tumor."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • Transplantation • HRAS

Kazia Therapeutics Limited…announced its intention to request and hold a follow-up Type C meeting with the U.S. Food & Drug Administration (FDA) to discuss overall survival (OS) findings in newly diagnosed glioblastoma (GBM) patients treated with paxalisib and to seek agency feedback on a potential regulatory pathway… (The Manila Times) - "Consistent with this framework, Kazia will propose initiation of the post-approval, randomized Phase 3 confirmatory study prior to submission of the NDA..."

FDA event • New P3 trial • Glioblastoma