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)

13d

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 | Recruiting --> Active, not recruiting

13 days ago

Enrollment closed • Combination therapy

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

Optimal Precision TherapIes to CustoMISE Care in Childhood and Adolescent Cancer (clinicaltrials.gov)

P1/2, N=82, Recruiting, Australian & New Zealand Children's Haematology/Oncology Group | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Jul 2024

4 months ago

Enrollment open • Trial initiation date

temozolomide • irinotecan • pimasertib (AS703026) • paxalisib (GDC-0084)

5ms

Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov)

P2, N=360, Recruiting, University of California, San Francisco | Phase classification: P1/2 --> P2

5 months ago

Phase classification • Combination therapy

BRAF (B-raf proto-oncogene)

dordaviprone (ONC201) • paxalisib (GDC-0084)

5ms

Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov)

P1/2, N=360, Recruiting, University of California, San Francisco | Phase classification: P2 --> P1/2 | Trial completion date: Jun 2027 --> Jun 2029

5 months ago

Phase classification • Trial completion date • Combination therapy

BRAF (B-raf proto-oncogene)

dordaviprone (ONC201) • paxalisib (GDC-0084)

6ms

Paxalisib (GDC-0084) In Recurrent Or Refractory PCNSL (clinicaltrials.gov)

P2, N=25, Recruiting, Lakshmi Nayak, MD | Trial completion date: May 2025 --> Dec 2026 | Trial primary completion date: May 2024 --> Dec 2025

6 months ago

Trial completion date • Trial primary completion date

paxalisib (GDC-0084)

6ms

Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov)

P2, N=324, Recruiting, University of California, San Francisco | Active, not recruiting --> Recruiting | N=143 --> 324

6 months ago

Enrollment open • Enrollment change • Combination therapy

dordaviprone (ONC201) • paxalisib (GDC-0084)

8ms

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 | Recruiting --> Active, not recruiting | N=36 --> 21

8 months ago

Enrollment closed • Enrollment change

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)

8ms

Safety, Pharmacokinetics and Efficacy of Paxalisib (GDC-0084) in Newly-diagnosed Glioblastoma (clinicaltrials.gov)

P2, N=30, Completed, Kazia Therapeutics Limited | Active, not recruiting --> Completed

8 months ago

Trial completion

temozolomide • paxalisib (GDC-0084)

8ms

Mass Balance Recovery, Metabolite Profile, and Metabolite Identification of [14C]-Paxalisib in Healthy Male Subjects (clinicaltrials.gov)

P1, N=6, Completed, Kazia Therapeutics Limited | Active, not recruiting --> Completed | Trial completion date: Mar 2023 --> Jan 2024

8 months ago

Trial completion • Trial completion date

paxalisib (GDC-0084)

10ms

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma. (PubMed, J Clin Invest)

The brain penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-sequencing, identifying changes in myelination and tumor immune microenvironment crosstalk. Together, we have identified a clinically relevant DIPG therapeutic combinatorial approach.

10 months ago

Journal

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)

metformin • Kinenza (enzastaurin) • paxalisib (GDC-0084)

10ms

Optimal Precision TherapIes to CustoMISE Care in Childhood and Adolescent Cancer (clinicaltrials.gov)

P1/2, N=82, Not yet recruiting, Australian & New Zealand Children's Haematology/Oncology Group

10 months ago

New P1/2 trial

temozolomide • irinotecan • pimasertib (AS703026) • paxalisib (GDC-0084)

12ms

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov)

P2/3, N=1030, Recruiting, Global Coalition for Adaptive Research

12 months ago

Trial completion date • Trial primary completion date

IDH wild-type

temozolomide • Stivarga (regorafenib) • lomustine • VT1021 • Hepacid (pegargiminase) • paxalisib (GDC-0084) • dianhydrogalactitol (VAL-083) • troriluzole (BHV-4157)

12ms

Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov)

P2, N=143, Active, not recruiting, University of California, San Francisco | Recruiting --> Active, not recruiting | N=324 --> 143

12 months ago

Enrollment closed • Enrollment change • Combination therapy

dordaviprone (ONC201) • paxalisib (GDC-0084)

1year

PNOC022: A Combination Therapy Trial using an Adaptive Platform Design for patients with Diffuse Midline Gliomas (DMGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression (SNO 2023)

Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2). The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.

1 year ago

Clinical • Combination therapy

TP53 (Tumor protein P53) • DRD2 (Dopamine Receptor D2)

TP53 mutation

dordaviprone (ONC201) • paxalisib (GDC-0084)

1year

Phase I study of paxalisib and radiotherapy for CNS disease harboring PI3K pathway mutations: pilot analysis of circulating tumor DNA for patient eligibility confirmation and post-treatment response (SNO 2023)

For patients on genomically-driven targeted therapy and RT combination trials, alterations detected using plasma ctDNA, especially PIK3CA, may be used to rapidly assess eligibility. Serial ctDNA collection may serve as a potential response biomarker with further validation.

1 year ago

P1 data • Clinical • Circulating tumor DNA

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • INPP4B (Inositol polyphosphate-4-phosphatase type II B)

PIK3CA mutation • PIK3CA E545K • PIK3CA E545

MSK-IMPACT • MSK-ACCESS

paxalisib (GDC-0084)

1year

Combining ONC201 and paxalisib for the treatment of diffuse midline glioma (DMG); the preclinical results underpinning the international Phase II clinical trial (NCT05009992). (SNO 2023)

The patient continuing to receive the combination at progression and following reirradiation also experienced a marked decrease in tumor size (MR axial diagnosis scan = 1248 mm2, current tumour area = 315 mm2, ~75% reduction), 10 months following radiological detection of progression. These data inform the phase II clinical trial (NCT05009992).

1 year ago

P2 data • Preclinical

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)

TP53 mutation • PIK3CA mutation

dordaviprone (ONC201) • paxalisib (GDC-0084)

1year

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 completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

1 year ago

Trial completion date • Trial primary completion date

MGMT (6-O-methylguanine-DNA methyltransferase)

MGMT promoter methylation

metformin • paxalisib (GDC-0084)

over1year

Paxalisib (GDC-0084) In Recurrent Or Refractory PCNSL (clinicaltrials.gov)

P2, N=25, Recruiting, Lakshmi Nayak, MD | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2023 --> May 2024

over 1 year ago

Trial completion date • Trial primary completion date

paxalisib (GDC-0084)

over1year

GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases (clinicaltrials.gov)

P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

over 1 year ago

Trial completion date • Trial primary completion date

paxalisib (GDC-0084)

over1year

Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth. (PubMed, Cell Death Discov)

We show that T2A rapidly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited following chronic treatment. We then translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures and in spheroid expansion, with combinatory treatment significantly enhancing this effect. Thus, we propose a new approach for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.

over 1 year ago

Journal

AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)

sirolimus • paxalisib (GDC-0084)

over1year

ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. (PubMed, Cancer Res)

Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

over 1 year ago

Journal • Combination therapy

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • DRD2 (Dopamine Receptor D2)

TP53 mutation • PIK3CA mutation

dordaviprone (ONC201) • paxalisib (GDC-0084)

over1year

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma. (PubMed, Cancer Res)

Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

over 1 year ago

Journal • Combination therapy

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • DRD2 (Dopamine Receptor D2)

TP53 mutation • PIK3CA mutation

dordaviprone (ONC201) • paxalisib (GDC-0084)

over1year

Combination of the PI3k inhibitor Paxalisib with the nucleoside analog Gemcitabine over-activates the integrated stress response and induces atypical teratoid/rhabdoid tumor cell death (AACR 2023)

Ongoing treatment of mice bearing CHLA06 orthotopic tumors demonstrate that combination therapy further extends median survival. Our studies suggest that pharmacologically activating the ISR may be an effective strategy to target AT/RT and combination of Paxalisib and Gemcitabine may be an effective treatment to help extend survival in this deadly disease.

over 1 year ago

Tumor cell

PPP1R15A (Protein Phosphatase 1 Regulatory Subunit 15A) • ATF4 (Activating Transcription Factor 4) • ANXA5 (Annexin A5)

gemcitabine • paxalisib (GDC-0084)

almost2years

GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases (clinicaltrials.gov)

P2, N=47, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Nov 2022 --> Nov 2024

almost 2 years ago

Trial primary completion date • Combination therapy

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

Herceptin (trastuzumab) • paxalisib (GDC-0084)

2years

Combination of ribociclib with BET-bromodomain and PI3K/mTOR inhibitors for medulloblastoma treatment in vitro and in vivo. (PubMed, Mol Cancer Ther)

A reverse combination screen using the BET inhibitor JQ1 as anchor, revealed CDK4/6i as the most potentiating drugs...Despite in vitro synergy, combination of ribociclib with the PI3K/mTOR inhibitor paxalisib did not significantly improve the survival of G3 and SHH MB bearing mice compared to ribociclib alone...Importantly, in one untreated Group3 medulloblastoma model HD-MB03, the PI3K/AKT/MTORC1 gene set was enriched in vitro compared to in vivo suggesting that the pathway displayed increased activity in vitro. Our data illustrate the difficulty in translating in vitro findings in vivo.

2 years ago

Preclinical • Journal

MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)

Kisqali (ribociclib) • JQ-1 • paxalisib (GDC-0084)

2years

Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov)

P2, N=33, Recruiting, Weill Medical College of Cornell University | Not yet recruiting --> Recruiting

2 years ago

Enrollment open

MGMT (6-O-methylguanine-DNA methyltransferase)

MGMT promoter methylation

metformin • paxalisib (GDC-0084)

2years

Antagonism of DRD2 using ONC201 increased expression of antigen presentation pathway proteins in diffuse midline glioma, recruiting tumor infiltrating lymphocytes in vivo (SNO 2022)

In vivo, ONC201 promoted the expression of EMILIN-3, a TGF-β antagonist that is known to inhibit HLA-A/B2M expression, possibly explaining the increased MHC-I activity. This study uncovers a novel link between treatment of DMG with ONC201 and paxalisib and the role dopaminergic peripheral nerves signaling may play on the sequestration of T cells within lymphoid organs and lymphopenia.

2 years ago

Preclinical • Tumor-Infiltrating Lymphocyte • IO biomarker

HLA-A (Major Histocompatibility Complex, Class I, A) • B2M (Beta-2-microglobulin) • TGFB1 (Transforming Growth Factor Beta 1) • DRD2 (Dopamine Receptor D2) • S1PR1 (Sphingosine-1-Phosphate Receptor 1)

dordaviprone (ONC201) • paxalisib (GDC-0084)

over2years

GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases (clinicaltrials.gov)

P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

over 2 years ago

Trial completion date • Trial primary completion date

paxalisib (GDC-0084)

over2years

Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death (AACR 2022)

Evaluation of combination treatment for apoptotic effects in vitro and in vivo are ongoing. These findings identify RG2833 and Paxalisib as a promising combination therapy for DIPG.

over 2 years ago

IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3) • XIAP (X-Linked Inhibitor Of Apoptosis) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)

BCL2 expression

paxalisib (GDC-0084) • RG2833

over2years

GDC-0084 in Combination With Trastuzumab for Patients With HER2-Positive Breast Cancer Brain Metastases (clinicaltrials.gov)

P2, N=47, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Nov 2021 --> Nov 2022

over 2 years ago

Trial primary completion date • Combination therapy

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

Herceptin (trastuzumab) • paxalisib (GDC-0084)

almost3years

Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov)

P2, N=33, Not yet recruiting, Weill Medical College of Cornell University

almost 3 years ago

New P2 trial

MGMT (6-O-methylguanine-DNA methyltransferase)

MGMT promoter methylation

metformin • paxalisib (GDC-0084)

3years

Neurocytological Advances in the Treatment of Glioblastoma Multiforme. (PubMed, Cureus)

Regorafenib, paxalisib, and dianhydrogalactitol (VAL-083) are showing initial promise to decrease disease progression...Selinexor, recombinant nonpathogenic polio-rhinovirus, and GBM-vaccine of autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector have all also shown initial clinical benefit in terms of prolonging survival. Most trials observe modest improvement in outcomes with a positive safety profile. Nevertheless, the need for further studies is warranted, along with the trending of post-therapeutic biomarkers in order to better access future patient outcomes.

3 years ago

Review • Journal

IL4 (Interleukin 4)

Stivarga (regorafenib) • Xpovio (selinexor) • paxalisib (GDC-0084) • dianhydrogalactitol (VAL-083)

over3years

Genetic Testing in Guiding Treatment for Patients With Brain Metastases (clinicaltrials.gov)

P2, N=150, Recruiting, Alliance for Clinical Trials in Oncology | Trial primary completion date: Jul 2021 --> Oct 2024

over 3 years ago

Clinical • Trial primary completion date

EGFR (Epidermal growth factor receptor) • 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 • ROS1 mutation

Rozlytrek (entrectinib) • Verzenio (abemaciclib) • paxalisib (GDC-0084)

over4years

[VIRTUAL] Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status (AACR-II 2020)

The current phase II study (NCT03522298) aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Part 1 is complete. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents.

over 4 years ago

Clinical • P2 data • PK/PD data

mTOR (Mechanistic target of rapamycin kinase)

temozolomide • paxalisib (GDC-0084)

over4years

Multi-parametric MR-PET imaging predicts pharmacokinetics and clinical response to GDC-0084 in patients with recurrent high-grade glioma. (PubMed, Clin Cancer Res)

Results from the current study suggest composite biomarkers created from multi-parametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.

over 4 years ago

Clinical • PK/PD data • Journal

mTOR (Mechanistic target of rapamycin kinase)

paxalisib (GDC-0084)