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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:
    5d
    GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov)
    P2/3, N=2250, Recruiting, Global Coalition for Adaptive Research | N=1280 --> 2250
    Enrollment change
    |
    IDH wild-type
    |
    temozolomide • Stivarga (regorafenib) • lomustine • VT1021 • AZD1390 • Hepacid (pegargiminase) • paxalisib (GDC-0084) • dianhydrogalactitol (VAL-083) • Vyglxia (troriluzole) • tinostamustine (EDO-S101)
    1m
    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.
    PK/PD data • Journal
    |
    NF1 (Neurofibromin 1)
    |
    paxalisib (GDC-0084)
    1m
    Study of Novel Therapies for Young People With Recurrent/Progressive Atypical Teratoid Rhabdoid Tumor (ATRT) (clinicaltrials.gov)
    P2, N=29, Not yet recruiting, Sabine Mueller, MD, PhD
    New P2 trial
    |
    SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • SMARCD3 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily D, Member 3)
    |
    gemcitabine • paxalisib (GDC-0084)
    3ms
    GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases (clinicaltrials.gov)
    P2, N=17, Terminated, Dana-Farber Cancer Institute | N=47 --> 17 | Active, not recruiting --> Terminated; participants are no longer being examined or receiving intervention
    Enrollment change • Trial termination
    |
    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)
    3ms
    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)
    4ms
    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)
    4ms
    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)
    5ms
    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)
    5ms
    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)
    7ms
    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)
    8ms
    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)
    9ms
    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)