This study is for patients with newly diagnosed glioblastoma, as well as patients who have recurring glioblastoma. Subjects will be given daily paxalisib and metformin while also maintaining a ketogenic diet.
The purpose of this study is to assess the safety of Paxalisib while maintaining a ketogenic diet (a high fat, low carbohydrate diet) and Metformin (a drug approved by the Food and Drug Administration to treat type 2 diabetes), and to see what effects it has on glioblastoma.

Start Date14 Feb 2022

Sponsor / Collaborator

Weill Medical College of Cornell University

[+1]

NCT05009992 / RecruitingPhase 2IIT

A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. ONC201, panobinostat, and paxalisib are all enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.

Start Date20 Oct 2021

Sponsor / Collaborator

The University of California, San Francisco

[+1]

100 Clinical Results associated with Paxalisib

100 Translational Medicine associated with Paxalisib

100 Patents (Medical) associated with Paxalisib

Literatures (Medical) associated with Paxalisib

03 May 2024·Neuro-oncology

Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from PNOC

Article

Author: Molinaro, Annette M ; Kline, Cassie ; Franson, Andrea ; Waszak, Sebastian M ; Plasschaert, Sabine L A ; Prados, Michael ; Nazarian, Javad ; Koschmann, Carl ; Mueller, Sabine ; van der Lugt, Jasper

Abstract:

Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells.Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively.Results ONC201 and paxalisib combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992).Conclusions Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.

15 Mar 2024·The Journal of clinical investigation

Just a spoonful of metformin helps the medicine go down

Article

Author: Tzaridis, Theophilos ; Wechsler-Reya, Robert J

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.

15 Mar 2024·The Journal of clinical investigation

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Article

Author: Hulleman, Esther ; Manning, Elizabeth E ; de Bock, Charles E ; Vilain, Ricardo E ; Germon, Zacary P ; Dayas, Christopher V ; Findlay, Izac J ; Firestein, Ron ; Hua, Susan ; Jackson, Evangeline R ; Beitaki, Tyrone ; Aksu, Michael ; Colino-Sanguino, Yolanda ; Cairns, Murray J ; Parackal, Sarah G ; Kilburn, Lindsay B ; Jamaluddin, M Fairuz B ; Whittle, James R ; Ashley, David M ; Sun, Claire Xin ; Hocke, Emily A ; Murray, Heather C ; McEwen, Holly P ; Laternser, Sandra ; Kiltschewskij, Dylan ; Nixon, Brett ; Dun, Matthew D ; Daniel, Paul ; Koschmann, Carl ; Valvi, Santosh ; Duchatel, Ryan J ; Eisenstat, David D ; Jain, Vaibhav ; Mueller, Sabine ; Wheeler, Helen ; Nazarian, Javad ; Mannan, Abdul ; Gregory, Simon G ; Tsoli, Maria ; Raabe, Eric H ; Thomas, Bryce C ; Persson, Mika L ; Tinkle, Christopher L ; Phoenix, Timothy N ; Valdes-Mora, Fatima ; Douglas, Alicia M ; Skerrett-Byrne, David A ; Ziegler, David S ; Hansford, Jordan R ; Staudt, Dilana E ; Vitanza, Nicholas A ; Kearney, Padraic S ; Alvaro, Frank ; Cain, Jason E ; Verrills, Nicole M

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. 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-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.

News (Medical) associated with Paxalisib

23 Sep 2024

·www.prnewswire.com

Kazia Therapeutics Announces Presentation of EVT801 Clinical Data at 15th Biennial Ovarian Cancer Research Symposium

SYDNEY, Sept. 23, 2024 /PRNewswire/ -- Kazia Therapeutics Limited (NASDAQ: KZIA), an oncology-focused drug development company, is pleased to announce the presentation of data highlighting promising clinical activity of EVT801 in high grade serous (HGS) Ovarian Cancer at the 15th Biennial Ovarian Cancer Research Symposium, co-presented by American Association of Cancer Research (AACR) and the Rivkin Center for Ovarian Cancer Research on Saturday, September 21, 2024 in Seattle Washington. Dr. John Friend, CEO Kazia Therapeutics presented preliminary data from a Phase 1 first-in-human clinical trial evaluating the safety and tolerability of EVT801, a highly selective small molecule VEGFR3 inhibitor targeting tumour angiogenesis. The Phase 1 study met its primary objectives, with the maximal tolerated dose identified at 500mg twice a day (BID). The Phase 1 study also identified the recommended Phase 2 dose starting at 400mg BID. It was observed that EVT801 was tolerated across all doses, with the majority of toxicities being mild to moderate and transient in nature. Key points of the presentation included: A total of 26 patients were treated across 6 dosing cohorts ranging from 50mg once daily (QD) to 500mg twice daily (BID) Patients with eleven different cancer types (ex. colon, renal cell, pancreatic) were enrolled in the study, with heavily pretreated advanced ovarian cancer being the most prevalent indication (11 patients) Biomarkers have shown strong VEGFR3 expression in multiple indications, including ovarian cancer Encouraging clinical activity in High Grade Serous ovarian cancer patients with forty-six percent (46%) having stable disease or for at least three cycles, including two patients who received 9 cycles One patient had a partial response (-39% decrease) after 2 cycles of EVT801 therapy Dr John Friend, CEO of Kazia Therapeutics, commented: "I was honored to participate at the Ovarian Cancer Research Symposium and present our findings to fellow clinicians and ovarian cancer researchers from around the globe. Ovarian cancer is often diagnosed at late stages with poor patient prognosis, so the data from the Phase 1 study is extremely encouraging and gives us confidence that we could potentially have a first-in-class VEGFR-3 inhibitor with EVT801." Abstract: Phase I study of EVT801, a VEGFR-3 inhibitor, shows promising clinical activity in HGS ovarian cancer September 21, 2024 – 11:30am-1:30pm About Kazia Therapeutics Limited Kazia Therapeutics Limited (NASDAQ: KZIA) is an oncology-focused drug development company, based in Sydney, Australia. Our lead program is paxalisib, an investigational brain-penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat multiple forms of brain cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of ten clinical trials in this disease. A completed Phase 2 study in glioblastoma reported early signals of clinical activity in 2021, and a pivotal study in glioblastoma, GBM AGILE, has been completed with presentation of paxalisib arm data expected later in 2024 at a major medical conference. Other clinical trials involving paxalisib are ongoing in brain metastases, diffuse midline gliomas, and primary CNS lymphoma, with several of these trials having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the FDA in February 2018, and Fast Track Designation (FTD) for glioblastoma by the FDA in August 2020. Paxalisib was also granted FTD in July 2023 for the treatment of solid tumour brain metastases harboring PI3K pathway mutations in combination with radiation therapy. In addition, paxalisib was granted Rare Pediatric Disease Designation and Orphan Drug Designation by the FDA for diffuse intrinsic pontine glioma in August 2020, and for atypical teratoid / rhabdoid tumours in June 2022 and July 2022, respectively. Kazia is also developing EVT801, a small-molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to be active against a broad range of tumour types and has provided evidence of synergy with immuno-oncology agents. A Phase I study has been completed and preliminary data was presented at 15th Biennial Ovarian Cancer Research Symposium in September 2024. For more information, please visit or follow us on X @KaziaTx. Forward-Looking Statements This announcement may contain forward-looking statements, which can generally be identified as such by the use of words such as "may," "will," "estimate," "future," "forward," "anticipate," or other similar words. Any statement describing Kazia's future plans, strategies, intentions, expectations, objectives, goals or prospects, and other statements that are not historical facts, are also forward-looking statements, including, but not limited to, statements regarding: the timing for results and data related to Kazia's clinical and preclinical trials, Kazia's strategy and plans with respect to its programs, including paxalisib and EVT801, the potential benefits of EVT801 as a VEGFR3 inhibitor and the potential market opportunity for EVT801. Such statements are based on Kazia's current expectations and projections about future events and future trends affecting its business and are subject to certain risks and uncertainties that could cause actual results to differ materially from those anticipated in the forward-looking statements, including risks and uncertainties: associated with clinical and preclinical trials and product development, related to regulatory approvals, and related to the impact of global economic conditions. These and other risks and uncertainties are described more fully in Kazia's Annual Report, filed on form 20-F with the SEC, and in subsequent filings with the United States Securities and Exchange Commission. Kazia undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required under applicable law. You should not place undue reliance on these forward-looking statements, which apply only as of the date of this announcement. This announcement was authorized for release by Dr John Friend, CEO. SOURCE Kazia Therapeutics Limited WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 1Orphan DrugFast TrackClinical Result

11 Jul 2024

·www.biospace.com

Kazia Offers Secondary OS Data to Build FDA Case for Glioblastoma Drug

Pictured: 3D illustration of a tumor on a brain/iStock, wildpixel Kazia Therapeutics on Wednesday unveiled additional data from the Phase II/III GBM-AGILE study, picking out secondary efficacy signals as it eyes an FDA accelerated approval pathway for its investigational glioblastoma treatment paxalisib. GBM-AGILE is a large global study designed to test several investigational glioblastoma treatments versus current standard of care. In the case of paxalisib, the study used chemotherapy with temozolomide for newly diagnosed patients and with lomustine for those with recurrent disease. The primary outcome of interest was overall survival (OS). Paxalisib showed no signs of efficacy in the recurrent disease setting. Median OS in treated patients was 8.05 months, which was nearly two months shorter than the 9.69-month median OS in comparators treated with lomustine. The Australian biotech is currently conducting deeper analysis of these data “to elucidate potential signs for further consideration.” Kazia is focused on the subset of patients who were newly diagnosed with glioblastoma. In this population, paxalisib led to a median OS of 14.77 months, slightly longer than that in temozolomide counterparts, who survived for a median of 13.84 months. The biotech further zoomed in on a smaller slice of control patients who were enrolled into GBM-AGILE concurrently with paxalisib’s inclusion into the study. In this concurrent population, median OS for paxalisib grew to 15.54 months while that for comparators dipped to 11.89 months. Kazia CEO John Friend pointed to this survival difference, saying that the biotech is “excited to have shown a 3.8-month improvement in overall survival, an approximate 33% improvement, for newly diagnosed unmethylated patients with GBM compared to the concurrent standard-of-care arm.” “Having comparable [OS] data across two independent studies in a compelling outcome in this difficult to treat population,” Friend noted, adding that the biotech will bring these findings to the FDA to discuss “possible approaches” to an accelerated approval for paxalisib. The market reacted favorably to Kazia’s readout, with its stocks surging 142% on Wednesday, according to SeekingAlpha. Initially invented by Genentech, paxalisib works by inhibiting the action of PI3K, a key player in cell growth and division which are highly dysregulated in several cancers. Unlike most other PI3K blockers, paxalisib can cross the blood-brain barrier making it a promising candidate for malignancies of the central nervous system. In August 2022, Kazia reported that paxalisib failed to reach the pre-defined criteria for moving to the second phase of GBM-AGILE. However, at the time, the biotech was still blinded to the study’s results and could not fully understand the failure. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Accelerated ApprovalClinical ResultDrug Approval

10 Jul 2024

·www.fiercebiotech.com

Kazia prunes failed brain cancer trial data set to manufacture path to FDA

Kazia Therapeutics saw the survival signal after pruning the control cohort. Kazia Therapeutics has found a way to try to salvage a win from a failed late-phase brain cancer trial. By removing part of the control arm, the biotech has emerged with survival data it will share with the FDA to see whether a path to accelerated approval has opened up. The data come from a platform study sponsored by the Global Coalition for Adaptive Research. The trial has enrolled patients with newly diagnosed and recurrent glioblastoma, a hard-to-treat brain cancer, to receive molecules developed by companies including Bayer and Biohaven. The design allows researchers to compare a revolving cast of candidates to a standard-of-care control arm in a single study. In August 2022, Kazia said its contribution to the study, a PI3K/mTOR inhibitor discovered by Genentech, failed to meet the threshold for advancing to the next stage of the trial. Now, Kazia has shared the data behind the failure—and made the case that there is a positive story to tell. Investigators enrolled two subgroups of patients to receive Kazia’s candidate paxalisib. The molecule was numerically worse than the control treatment, lomustine, in patients with recurrent disease, achieving a median overall survival (OS) of 8.05 months compared to 9.69 months for the standard of care. That part of the study featured 213 patients, split roughly evenly between paxalisib and the control. Kazia focused its discussion of the data on the other subgroup, which enrolled newly diagnosed patients with a form of the disease that is less likely to respond to the chemotherapy drug temozolomide. In that subgroup, Kazia reported a median OS of 14.77 months in 54 recipients of paxalisib. The result was barely better than the 13.84 months seen in the temozolomide control cohort. However, Kazia found a subset of the control arm that painted a better picture of paxalisib. Because paxalisib was added to the platform trial around 18 months after the study began, roughly one-third of the 75 patients in the newly diagnosed control arm were enrolled before dosing of Kazia’s drug candidate started. Limiting the control arm to the 46 patients who were enrolled concurrently to Kazia’s prospect resulted in a median OS of 11.89 months. Kazia CEO John Friend, M.D., hailed the result as a “3.8 month improvement in overall survival, an approximate 33% improvement,” in a statement. The biotech now plans to discuss the data with the FDA to “determine if a potential path to accelerated approval is appropriate for paxalisib.” Kazia’s share price rose around 70% in premarket trading, but that jump only brought it up to 33 cents.

Clinical ResultAccelerated Approval

100 Deals associated with Paxalisib

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D11869	-	-	DB15186

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Phase 3	US	Biohaven Pharmaceuticals, Inc.	30 Jul 2019
Glioblastoma Multiforme	Phase 3	US	Polaris Group	30 Jul 2019
Glioblastoma Multiforme	Phase 3	US	Kintara Therapeutics, Inc.	30 Jul 2019
Glioblastoma Multiforme	Phase 3	US	Vigeo Therapeutics, Inc.	30 Jul 2019
Glioblastoma Multiforme	Phase 3	US	Kazia Therapeutics Ltd.	30 Jul 2019
Glioblastoma Multiforme	Phase 3	US	Bayer AG	30 Jul 2019
Glioblastoma Multiforme	Phase 3	AU	Bayer AG	30 Jul 2019
Glioblastoma Multiforme	Phase 3	AU	Polaris Group	30 Jul 2019
Glioblastoma Multiforme	Phase 3	AU	Kazia Therapeutics Ltd.	30 Jul 2019
Glioblastoma Multiforme	Phase 3	AU	Vigeo Therapeutics, Inc.	30 Jul 2019

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03522298 (GBM AGILE, PRNewswire) Manual	Phase 2/3	Glioblastoma Adjuvant	313	Paxalisib (newly diagnosed unmethylated (NDU) patients)	glisxkxktv(tjtlkcwekw) = diqktvgjks ceoviicilm (qkdpisornr ) View more	Positive	10 Jul 2024
NCT03522298 (GBM AGILE, PRNewswire) Manual	Phase 2/3	Glioblastoma Adjuvant	313	Standard of Care (SOC) (newly diagnosed unmethylated (NDU) patients)	glisxkxktv(tjtlkcwekw) = pzrkrqixqx ceoviicilm (qkdpisornr ) View more	Positive	10 Jul 2024
NCT05009992 (SNO2023) Manual	Phase 2	Diffuse Midline Glioma	68	ONC201+paxalisib	mrjggbcofm(xlliemscbm) = bdcjpjpnyf uqhahvbodh (espgblwaqv, lower 11.6) View more	Positive	10 Nov 2023
NCT04906096 (PRNewswire) Manual	Phase 2	Primary Central Nervous System Lymphoma	14	Paxalisib	uwlrhsvlfc(lwwgisrdke) = preliminarily observed in enrolled patients, including partial responses and stable disease syvcanjery (newsasmejg ) View more	Positive	01 Nov 2023
NCT03522298 (ESMO2022)	Phase 2	Glioblastoma	30	Paxalisib	lpdlugxsmk(zvuqdtrreu) = wsxblbufji vsoljpsrjw (cztrhysxsn ) View more	-	09 Sep 2022
NCT04192981 (Corporate Publications) Manual	Phase 1	Brain metastases PIK3CA Mutation	12	radiotherapy+paxalisib	jywzmksmiy(rfskpdffvm) = Paxalisib 45mg daily in combination with radiotherapy aflbgfazyo (yiksrqekhd )	Positive	08 Aug 2022
NCT03522298 (ASCO2022)	Phase 2	Glioblastoma	30	Paxalisib	wenvyiiwyp(ckgqsgoyio) = redtrjdlss bieeotebxn (yvskxalgfm ) View more	-	02 Jun 2022
NCT03522298 (AACR2021)	Phase 2	Glioblastoma Multiforme	30	Paxalisib 60mg (fasted)	aisgnkvbfk(iwvqbozkan) = pnkekadsae lemerlpvri (mgorexjvna ) View more	-	01 Jul 2021
NCT03522298 (AACR2021)	Phase 2	Glioblastoma Multiforme	30	Paxalisib 60mg (fed)	aisgnkvbfk(iwvqbozkan) = pnxmlfauvg lemerlpvri (mgorexjvna ) View more	-	01 Jul 2021
NCT03522298 (AACR2020)	Phase 2	Glioblastoma Multiforme	29	Paxalisib	nbdqgbuerp(siqrncojul) = DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents. acdhgwpckw (oyepomkfcl )	Positive	15 Aug 2020
NCT01547546 (Pubmed \| Clin Cancer Res) Manual	Phase 1	Malignant glioma of brain	47	GDC-0084	dfkivvqsfv(emwmzasjsj) = cexoxzfjds ldbosvmywl (vusyizrmrc ) View more	Positive	15 Apr 2020

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