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

Paxalisib Plus Olaparib or Pembrolizumab/Chemotherapy in Advanced Breast Cancer (ANZCTR) - P1 | N=24 | Recruiting | Sponsor: Kazia Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Trial initiation date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • HER-2 • PD-L1

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=1280 | Recruiting | Sponsor: Global Coalition for Adaptive Research | Trial completion date: Jun 2028 ➔ Jun 2030 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

PNOC022: Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov) - P2 | N=360 | Recruiting | Sponsor: University of California, San Francisco | Trial primary completion date: Dec 2025 ➔ Dec 2027

Trial primary completion date • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • BRAF

Kazia Therapeutics Reports Early Efficacy Data from First Triple-Negative Breast Cancer Patient Receiving Paxalisib Combination Regimen achieving >50% Reduction in Circulating Tumor Cells in Phase 1b Trial (PRNewswire) - P1b | N=24 | PaxPlus-ABC (ACTRN12624001340527) | Sponsor: Kazia Therapeutics | "Kazia...is pleased to announce preliminary results from the first patient in its Phase 1b trial evaluating a combination regimen of Paxalisib, pembrolizumab (Keytruda), and standard chemotherapy after completing Cycle 1 (21 days) of dosing...Results at Day 21 (End-of-Cycle 1): >50% reduction in total CTC count; Comparable reduction in CTC clusters—these aggregates are associated with heightened metastatic potential; Reduction in the mesenchymal phenotype of the remaining CTCs; this phenotype is one of the hallmarks of aggressive metastatic seeding cancer cells; First-in-human data support potential for potent CTC mobilization suppression by this combination...Enrollment continues in the Phase Ib study, expanding cohort size to assess safety, tolerability, and pharmacodynamics; Planned comprehensive analysis of immune microenvironment and CTC kinetics across all patients through serial monitoring."

P1 data • Trial status • Triple Negative Breast Cancer

Paxalisib (GDC-0084) In Recurrent Or Refractory PCNSL (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Lakshmi Nayak, MD | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma. (PubMed, Cell) - "Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM."

Journal • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Psychiatry • Solid Tumor

Depleting the action of EZH2 through PI3K-mTOR inhibition to overcome metastasis and immunotherapy resistance in triple-negative breast cancer. (PubMed, Mol Cancer Ther) - "Dual PI3K-mTOR inhibition with paxalisib not only promotes a favorable mesenchymal to epithelial phenotype but also inhibits signatures associated with MICs, including the highly aggressive CSC phenotype, persister cancer cell phenotype (p65, FOXQ1, NRF2, NNMT), and a cancer drug resistance signature (ABCB5, SNAIL, ALDH1)...PI3K-mTOR blockade acts upstream of EZH2, impacting both the classical repressive catalytic p85β-EZH2-H27ME3 and active EZH2-NFκB pathways. Our data suggest that dual targeting of the PI3K-mTOR pathway disrupts both the catalytic and non-catalytic axes of EZH2 to inhibit metastasis and enhance cancer immune visibility, potentially increasing the utility of immunotherapy in resistant individuals."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ALDH1A1 • CTCs • NNMT

Kazia Therapeutics Announces Transformative Preclinical Data Demonstrating Paxalisib's Potential to Overcome Immunotherapy Resistance in Triple-Negative Breast Cancer (TNBC) (PRNewswire) - "Kazia Therapeutics Limited...announced the publication of transformative preclinical research in the journal Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research that underscores the powerful potential of its lead asset, paxalisib, in reshaping the treatment landscape for triple-negative breast cancer (TNBC)....Dual targeting of PI3K and mTOR but not PI3K alone inhibits cancer cell proliferation and migration in vitro. Paxalisib remodels the TNBC tumor microenvironment, increasing CD4+ and CD8+ T cell infiltration and activation. The combination of paxalisib with KEYTRUDA (pembrolizumab) demonstrated synergistic antitumor activity in advanced breast cancer, resulting in robust tumor regression and prolonged survival in preclinical models."

Preclinical • Triple Negative Breast Cancer

Kazia Therapeutics Announces First Patient Dosed in Phase 1b Trial of Paxalisib in Advanced Breast Cancer (PRNewswire) - "Kazia Therapeutics Limited...announced that the first patient has been dosed in a Phase 1b clinical trial sponsored by Kazia. The study evaluates paxalisib, the Company's dual PI3K/mTOR inhibitor, in combination with olaparib or pembrolizumab for patients with advanced breast cancer. This multi-center, open-label, randomized trial is designed to assess the safety, tolerability, and preliminary efficacy of multiple paxalisib-based treatment combinations. The study also includes deep biomarker profiling to support future development and early signals of clinical activity."

Trial status • Breast Cancer

The gut microbiome in pediatric diffuse midline gliomas: Correlative study results from the PNOC022 trial. (ASCO 2025) - "This report focuses on the combination therapy arm involving dordaviprone and paxalisib, administered to patients (aged 2–39 years) who had completed standard-of-care radiation therapy (Cohort 2). Baseline high alpha-diversity in the gut microbiome is significantly associated with improved PFS and trended towards improved OS in pediatric patients with DMG in cohort 2 of PNOC022. Age-adjusted survival models reinforced its prognostic value for PFS and OS. These findings highlight the potential impact the gut microbiome has on outcomes and will be explored further and warrant our ongoing investigation in PNOC022."

Clinical • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor

GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases (clinicaltrials.gov) - P1 | N=21 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Brain Cancer • Oncology • Solid Tumor • AKT1 • AKT2 • INPP4B • INPP5D • PIK3C3 • PIK3CA • PIK3CB • PIK3CD • PIK3CG • PIK3R1 • PIK3R2 • PIK3R3 • PTEN

Kazia Therapeutics and the Hebrew University of Jerusalem Receives a Grant from The Michael J. Fox Foundation to Evaluate the Therapeutic Potential of Paxalisib as a Treatment for Parkinson's Disease (PRNewswire) - "Kazia Therapeutics Limited...today announced a research grant awarded from The Michael J. Fox Foundation for Parkinson's Research (MJFF) to fund research between The Hebrew University of Jerusalem (Hebrew University) and Kazia to explore the therapeutic potential of paxalisib as a treatment for Parkinson's disease (PD)...The grant will fund collaborative preclinical studies at Professor Ronit Sharonʼs lab (Hebrew University) aimed at establishing an operational link between a specific pathway in the pathophysiology of PD and paxalisib. The research will assess the impact of paxalisib on mouse survival, motor and non-motor performances, as well as specific biochemical, pathological and molecular disease biomarkers that will be determined in brains of treated mice."

Financing • CNS Disorders • Parkinson's Disease

Low & Anaplastic Grade Glioma Umbrella Study of MOlecular Guided TherapieS (LUMOS-2): study protocol for a phase 2, prospective, multicentre, open-label, multiarm, biomarker-directed, signal-seeking, umbrella, clinical trial for recurrent IDH mutant, grade 2/3 glioma. (PubMed, BMJ Open) - P2 | "LUMOS-2 will begin with three therapeutic treatment arms: paxalisib, cadonilimab and selinexor...A report describing the results of the study will be submitted to international meetings and peer-reviewed journals. ACTRN12623000096651."

Biomarker • Clinical protocol • Journal • P2 data • Brain Cancer • CNS Tumor • Glioma • Head and Neck Cancer • Oncology • Solid Tumor

Kazia Therapeutics announces the launch of a groundbreaking trial with paxalisib in combination with immunotherapy in women with advanced breast cancer (PRNewswire) - "Kazia Therapeutics Limited...is pleased to announce the regulatory approval and launch of a clinical trial evaluating the combination of paxalisib and immunotherapy in patients with advanced breast cancer...The ABC-Pax (Advanced Breast Cancer – Paxalisib) study is the first known trial conducted to assess the safety and efficacy of paxalisib in combination with KEYTRUDA (pembrolizumab) or LYNPARZA (olaparib) in women with triple negative breast cancer. ABC-Pax is a multi-centre, open-label phase 1b study that will enroll 24 patients from top cancer centres in Queensland, Australia and patients will receive the combination therapy for up to 12 months....The ABC-Pax trial will also evaluate a non-invasive liquid biopsy digital pathology platform developed by Professor Rao and her team, which can monitor the behaviour of cancer cells and immune cells in real time from a blood sample."

New P1 trial • Triple Negative Breast Cancer

Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: Weill Medical College of Cornell University | Trial primary completion date: Dec 2024 ➔ Dec 2025

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

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

Kazia Therapeutics Shares Fall After FDA Declines Accelerated Drug Approval (Market Watch) - "Kazia Therapeutics stock retreated Tuesday after the FDA said it could consider standard, but not accelerated, approval for the company's brain cancer drug...Shares of the oncology-focused drug company fell 26% to $2.28 in morning trading. The stock is down about 48% this year...The FDA said it would generally not approve accelerated approval for paxalisib, Kazia said Tuesday. It could consider support for a standard approval."

Stock price • Glioblastoma

Kazia Therapeutics Provides Update on Paxalisib Regulatory Pathway Following Type C Meeting with FDA (PRNewswire) - "Kazia Therapeutics...provided a regulatory update on paxalisib for the treatment of glioblastoma (GBM) following its Type C clinical meeting with the United States Food and Drug Administration...Following discussions with the FDA and feedback from Kazia's recent Type C meeting, the FDA's current position is that data on OS would generally not be appropriate for accelerated approval, but could be considered to support a traditional/standard approval. The Agency further commented that the secondary endpoint OS data from the GBM-AGILE study are supportive and informative for designing and executing a pivotal registrational study in pursuit of a standard approval...Importantly, the Company aligned with the FDA on key aspects of the design of a proposed registrational/pivotal phase 3 study, including patient population, primary endpoint, and the comparator arm to be used....'we expect to provide an outline for our path forward to maximize shareholder value by the end of January 2025.'"

Clinical protocol • FDA event • New P3 trial • Glioblastoma

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

Paxalisib Plus Olaparib or Pembrolizumab/Chemotherapy in Advanced Breast Cancer (ANZCTR) - P1 | N=24 | Not yet recruiting | Sponsor: Kazia Therapeutics

Metastases • New P1 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • HER-2 • PD-L1

Immunotherapy and PI3K/mTOR inhibition combination to mediate metastasis and immunotherapy resistance in triple-negative breast cancer (SABCS 2024) - "Once tumours reached ~50-100 mm3, the PI3K-mTOR inhibitor, Paxalisib, was administered daily by oral gavage in combination with either anti-PD-1 (pembrolizumab) treatment or PARP inhibitor (olaparib). Paxalisib in combination with the PARP inhibitor olaparib, but not monotherapy alone, also reduced primary tumor burden and metastases. Moving forward, work is ongoing to elucidate the PI3K-mTOR mechanism of overcoming metastasis and drug resistance as well as the translation of the data into a clinical development program for patients with TNBC and advanced breast cancer."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ALDH1A1 • IL6 • NNMT

Final results of a phase II trial evaluating paxalisib with trastuzumab for patients (pts) with HER2 positive metastatic breast cancer with active brain metastases. (PRNewswire) - P2 | N=47 | NCT03765983 | "In a second abstract, clinical investigators presented efficacy and safety data in heavily pretreated patients (median prior 8 lines of therapy) with HER2 positive breast cancer with active brain metastases. Although the primary endpoint of overall response rate (ORR) was not met, patients receiving a combination of paxalisib and trastuzumab (ENHERTU) had a median overall survival of 16.5 months, which compares favorably versus historical control studies....In this heavily pre-treated population of pts with HER2+ active BCBM, the combination of paxalisib 30 mg daily with trastuzumab was feasible, with a toxicity profile consistent with a class effect of PI3K/mTOR inhibitors. However, it was associated with minimal clinical activity."

P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer

Kazia Therapeutics to Present Data Highlighting Synergistic Activity Between Paxalisib and Immunotherapy in Immunotherapy-Resistant Triple Negative Breast Cancer Model at the San Antonio Breast Cancer Symposium (PRNewswire) - "The addition of paxalisib to immunotherapy in the 4T1 TNBC mouse model reduced primary tumor burden, lung metastases, and liver inflammation whilst overcoming toxicity complications and resistance associated with standard-of-care immunochemotherapy. Paxalisib in combination with the PARP inhibitor olaparib, but not monotherapy alone, also reduced primary tumor burden and metastases."

Preclinical • Triple Negative Breast Cancer

Final results of a phase II trial evaluating paxalisib with trastuzumab for patients (pts) with HER2 positive metastatic breast cancer with active brain metastases. (SABCS 2024) - P2 | "In this heavily pre-treated population of pts with HER2+ active BCBM, the combination of paxalisib 30 mg daily with trastuzumab was feasible, with a toxicity profile consistent with a class effect of PI3K/mTOR inhibitors. However, it was associated with minimal clinical activity."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA • PTEN

MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma (SNO 2024) - "Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor, in vivo doubles median survival in a highly aggressive murine orthotopic GBM model. Furthermore, combining MT-125 with sunitinib produces tumor free remissions of >100 days--2.5-fold greater than median survival of either drug alone—in approximately 40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM."

Brain Cancer • CNS Disorders • CNS Tumor • Glioblastoma • Hematological Disorders • Oncology • Psychiatry • Solid Tumor