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    DRUG:

    paxalisib (GDC-0084)

    i
    Other names: GDC-0084 , RG7666, GDC 0084, G02441729, SIM0395, SIM-395, G 02441729, G-02441729, GDC0084, RG-7666, RG 7666, SIM-0395, SIM 0395, SIM395, SIM 395, SVG103
    Company:
    Kazia, QIMR Berghofer Medical Research Institute, Roche, Simcere, SoVarGen
    Drug class:
    mTOR inhibitor, PI3K inhibitor, AKT inhibitor
    Related drugs:
    4d
    GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases (clinicaltrials.gov)
    P2, N=47, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Nov 2025 --> May 2026
    Trial completion date
    |
    HER-2 (Human epidermal growth factor receptor 2) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
    |
    HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 positive + HER-2 overexpression
    |
    Herceptin (trastuzumab) • paxalisib (GDC-0084)
    1m
    Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov)
    P2, N=33, Suspended, 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 suspension • Trial primary completion date
    |
    MGMT (6-O-methylguanine-DNA methyltransferase)
    |
    MGMT promoter methylation
    |
    metformin • paxalisib (GDC-0084)
    1m
    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, SoVarGen Co., Ltd.
    New P1/2 trial
    |
    paxalisib (GDC-0084)
    2ms
    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
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • RB1 (RB Transcriptional Corepressor 1) • CCND1 (Cyclin D1) • RARA (Retinoic Acid Receptor Alpha) • HSPA8 (Heat Shock Protein Family A (Hsp70) Member 8)
    |
    IDH wild-type
    |
    temozolomide • metformin • paxalisib (GDC-0084)
    3ms
    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
    |
    HRAS (Harvey rat sarcoma viral oncogene homolog)
    |
    paxalisib (GDC-0084)
    4ms
    Genetic Testing in Guiding Treatment for Patients With Brain Metastases (clinicaltrials.gov)
    P2, N=186, Suspended, Alliance for Clinical Trials in Oncology | Recruiting --> Suspended
    Trial suspension
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • PGR (Progesterone receptor) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    HER-2 positive • EGFR mutation • HER-2 negative • BRAF positive
    |
    Rozlytrek (entrectinib) • Verzenio (abemaciclib) • Krazati (adagrasib) • paxalisib (GDC-0084)
    6ms
    GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov)
    P2/3, N=1280, Recruiting, 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
    |
    IDH wild-type
    |
    temozolomide • Stivarga (regorafenib) • lomustine • VT1021 • AZD1390 • Hepacid (pegargiminase) • paxalisib (GDC-0084) • dianhydrogalactitol (VAL-083) • Vyglxia (troriluzole)
    6ms
    PNOC022: Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov)
    P2, N=360, Recruiting, University of California, San Francisco | Trial primary completion date: Dec 2025 --> Dec 2027
    Trial primary completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    sirolimus • Modeyso (dordaviprone) • paxalisib (GDC-0084)
    6ms
    Paxalisib Plus Olaparib or Pembrolizumab/Chemotherapy in Advanced Breast Cancer (ACTRN12624001340527)
    P1, N=24, Recruiting, Kazia Therapeutics | Not yet recruiting --> Recruiting
    Enrollment open • Trial initiation date
    |
    HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
    |
    HER-2 negative
    |
    Keytruda (pembrolizumab) • Lynparza (olaparib) • carboplatin • albumin-bound paclitaxel • paxalisib (GDC-0084)
    7ms
    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.
    Journal • IO biomarker
    |
    ALDH1A1 (Aldehyde Dehydrogenase 1 Family Member A1) • NNMT (Nicotinamide N-Methyltransferase)
    |
    paxalisib (GDC-0084)
    9ms
    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, 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
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) • INPP4B (Inositol polyphosphate-4-phosphatase type II B) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • INPP5D (Inositol Polyphosphate-5-Phosphatase D) • PIK3C3 (Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3) • PIK3R2 (Phosphoinositide-3-Kinase Regulatory Subunit 2 ) • PIK3R3 (Phosphoinositide-3-Kinase Regulatory Subunit 3)
    |
    paxalisib (GDC-0084)
    12ms
    Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov)
    P2, N=33, Recruiting, Weill Medical College of Cornell University | Trial primary completion date: Dec 2024 --> Dec 2025
    Trial primary completion date
    |
    MGMT (6-O-methylguanine-DNA methyltransferase)
    |
    MGMT promoter methylation
    |
    metformin • paxalisib (GDC-0084)