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.

开始日期2022-02-14

申办/合作机构

Weill Medical College of Cornell University

[+1]

NCT05009992 / Recruiting临床2期IIT

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.

开始日期2021-10-20

申办/合作机构

The University of California, San Francisco

[+1]

100 项与 Paxalisib 相关的临床结果

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100 项与 Paxalisib 相关的转化医学

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100 项与 Paxalisib 相关的专利（医药）

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项与 Paxalisib 相关的文献（医药）

2024-05-03·Neuro-Oncology

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

Article

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

AbstractBackground 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.

2024-03-15·Journal of Clinical Investigation

Just a spoonful of metformin helps the medicine go down

Article

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

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.

2024-03-15·Journal of Clinical Investigation

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

Article

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

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.

项与 Paxalisib 相关的新闻（医药）

2024-10-13

·药明康德

100%患者获临床缓解的CAR-T疗法；晚期癌症疾病控制率达92%的TCR-T疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. T细胞受体T细胞（TCR-T）疗法IMA203在一项1b期临床试验中令92%转移性黑色素瘤患者的疾病获得控制，且患者的中位缓解持续时间（DOR）超过一年。 2. B细胞成熟抗原（BCMA）靶向自体嵌合抗原受体（CAR）-T细胞疗法Ribrecabtagene autoleucel（DRL-1801）用于治疗复发/难治性多发性骨髓瘤患者的1期临床试验结果亮眼，首批8名接受治疗的患者均获得了临床缓解。 3. 用于治疗胶质母细胞瘤（GBM）的树突状细胞疫苗DOC1021相比于标准治疗（SOC）有望大幅延长患者的中位总生存期（OS）。药明康德内容团队整理 IMA203：公布1b期临床试验数据 Immatics公布了其在研TCR-T疗法IMA203用以治疗转移性黑色素瘤患者的最新1b期临床数据，这些患者先前接受过大量治疗。IMA203是由Immatics专有的ACTengine平台所开发的TCR-T细胞疗法，靶向由HLA-A*02呈递的黑素瘤抗原PRAME。PRAME是一种在各种实体瘤中经常表达的蛋白质，因此IMA203具潜力治疗广泛的癌症患者群体。此次公布的结果显示，92%患者的疾病获得控制且患者的中位DOR超过一年。根据此积极数据，Immatics预定在今年12月启动SUPRAME注册性3期试验，预计病患招募将于2026年完成，并在2026年初进行预定的中期分析。 Ribrecabtagene autoleucel（DRL-1801）：公布1期临床试验数据 Aurigene Oncology公司宣布其新型BCMA靶向自体CAR-T细胞疗法Ribrecabtagene autoleucel（DRL-1801）用于治疗复发/难治性多发性骨髓瘤的1期临床试验中首批8名患者的初步结果。所有患者都接受过大量的前期治疗，中位治疗线数为5.5线。大多数患者此前也曾接受过移植手术，并在移植后出现疾病进展。结果显示，100%的患者获得了临床缓解，其中有5名（62.5%）患者获得了严格的完全缓解（CR）。安全性方面，所有患者均未出现高级别的细胞因子释放综合征（CRS）或神经毒性。 DOC1021：公布1期临床试验的中期数据 Diakonos Oncology公司公布了其树突状细胞疫苗DOC1021用于治疗胶质母细胞瘤患者的1期开放标签试验的中期分析结果。该公司的树突状细胞疫苗由患者自身的免疫细胞与从肿瘤样本中提取的RNA和蛋白质结合制成。这种独特的方法可以靶向完整的癌症抗原谱，而无需进行任何基因修饰。通过利用天然的免疫信号通路，这种策略使免疫系统能将癌细胞视同受病毒感染的细胞一样进行识别和清除。此次公布的结果显示，15例患有挑战性肿瘤、MGMT未甲基化（通常预后不良）患者中有14例存活超过12个月。目前，中位随访时间为16个月，中位OS尚未达到。Kaplan-Meier（KM）分析将接受DOC1021治疗的患者与接受完整SOC的年龄匹配历史对照组患者进行比较，两组在统计学上具有差异（p=0.03）。KM预测接受DOC1021治疗的患者的OS为19.7个月，而接受SOC的未甲基化GBM患者的预期OS为12.7个月。安全性方面，没有剂量限制性毒性或令人担忧的严重不良事件（SAE）。 VIP943：公布1期临床试验数据 Vincerx Pharma公司公布了其抗体偶联药物（ADC）VIP943治疗复发/难治性急性髓系白血病（AML）、高危骨髓增生异常综合征（HR-MDS）和B细胞急性淋巴细胞白血病（B-ALL）的1期临床试验的结果。VIP943由抗CD123抗体、一种在细胞内切割的独特连接子和一种新型驱动蛋白纺锤体蛋白抑制剂（KSPi）有效载荷组成。Vincerx的CellTrapper技术可确保KSPi有效载荷积聚在靶细胞中，限制非靶细胞、非分裂细胞的吸收，从而减少非特异性释放。该1期剂量递增研究共招募了22名患者，他们很少对单一疗法产生应答。9名患者（6名AML患者和3名HR-MDS患者）至少接受了3次有效剂量的VIP943治疗。截至目前，1名复发性AML患者获得了完全缓解伴血液学不完全恢复（CRi），1名HR-MDS患者获得了完全缓解伴较少血液学恢复（CRL）。截至2024年8月的数据，VIP943显示出良好的安全性和耐受性，没有报告剂量限制性毒性，SAE与预期一致。 VK0214：公布1b期临床试验数据 Viking Therapeutics公司公布了其新型甲状腺激素受体β（TRβ）小分子激动剂VK0214在X-连锁肾上腺白质营养不良（X-ALD）患者中进行的1b期临床试验的积极数据。X-ALD是一种罕见的致命代谢性疾病，由ABCD1基因突变引起，这种突变会导致肾上腺脑白质营养不良蛋白（ALDP）功能障碍，从而引起脂肪酸的异常累积。临床前研究表明，甲状腺激素受体β型可以调节ABCD2相关基因的表达，ABCD2能够编码一种称为肾上腺脑白质营养不良相关蛋白（ADLRP）的代偿转运体，通过增加ABCD2表达可以使特定脂肪酸水平恢复正常。此次公布的研究结果表明，在为期28天的研究期间，VK0214每天用药一次的安全性和耐受性良好。此外，与安慰剂相比，接受VK0214治疗患者血浆中的超长链脂肪酸（VLCFAs）和其他血脂水平明显降低。 ▲VK0214治疗28天后患者的VLCFA与基线相比的变化（图片来源：参考资料[5]） ▲VK0214治疗28天后患者的其他血脂与基线相比的变化（图片来源：参考资料[5]） Paxalisib：公布1期临床试验的新数据 Kazia Therapeutics公司公布其口服PI3K/mTOR双抑制剂paxalisib联用放射疗法治疗PI3K通路突变实体瘤脑转移（BM）或软脑膜转移（LM）患者的1期临床试验的数据。此次公布的结果显示，paxalisib联用放疗总体耐受性良好。研究中最常报告的不良反应是恶心、呕吐和高血糖。接受45 mg paxalisib联用放疗患者中有67%获得了部分缓解（PR），接受最大耐受剂量治疗的患者中有超过三分之二的人获得了颅内缓解，这与单独使用全脑放疗的历史缓解率相比毫不逊色。 ELVN-001：公布1期临床试验的新数据 Enliven Therapeutics公司公布其小分子激酶抑制剂ELVN-001治疗复发/难治性或对现有酪氨酸激酶抑制剂（TKI）不耐受的慢性髓系白血病（CML）患者的1期临床试验的积极数据。ELVN-001是一种强效、高选择性、潜在“best-in-class”的小分子激酶抑制剂，专门针对CML患者的致癌驱动因子BCR-ABL融合蛋白。ELVN-001还具有针对耐药性最强的BCR-ABL1耐药突变体T315I和其他已知耐药突变体的活性。截至2024年6月25日的数据，ELVN-001的耐受性保持良好，没有患者减少剂量，未报告≥3级治疗相关的非血液学毒性反应。第24周时，患者的初始累积主要分子缓解（MMR）率为44%（8/18），与已获批的BCR-ABL1酪氨酸激酶抑制剂在1期临床试验中的数据相比具有优势。 Camonsertib：公布1期联合治疗试验数据 Repare Therapeutics公司公布了潜在”best-in-class”口服小分子ATR抑制剂camonsertib结合姑息性放疗，治疗携带ATM突变转移性肿瘤的1期临床试验数据。该试验纳入了17例携带ATM突变的转移性肿瘤患者，其中12人携带致病性ATM基因突变，5人携带ATM基因突变的意义不明变异（VUS）。这些患者的原发性癌症组织学来源包括胃肠道（n=5）、胰腺（n=5）、乳腺癌（n=2）、肺（n=2）、膀胱（n=2）和甲状腺（n=1）。此次公布的结果显示，2个月时，致病性ATM突变组有2例CR、5例PR和4例疾病稳定（SD）患者，而VUS组有1例PR和4例SD患者。6个月时，在9名可评估患者中，致病性ATM突变组有2例CR、4例PR和1例SD患者，而VUS组有1例SD和1例疾病进展患者。该早期临床数据表明camonsertib联合放疗治疗有可能对携带致病性ATM突变的肿瘤患者进行放射增敏，从而获得更高的临床益处。 Misetionamide：公布1期临床试验的中期数据 Panavance Therapeutics公司公布了其小分子疗法misetionamide（GP-2250）联用吉西他滨治疗晚期不可切除或转移性胰腺导管腺癌患者1期临床试验的中期数据。Misetionamide具有独特的作用机制，可抑制两种致癌转录因子c-MYC和NFκB。此次公布的结果显示，与单独使用吉西他滨的历史结果相比，接受misetionamide联用吉西他滨治疗患者的无进展生存期更长，约40%的患者达到PR或SD。此外，misetionamide联用吉西他滨的安全性良好。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Vincerx Reports Positive Initial Clinical Data from Ongoing VIP943 Phase 1 Dose-Escalation Study and Provides Pipeline and Corporate Updates. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/10/07/2959307/0/en/Vincerx-Reports-Positive-Initial-Clinical-Data-from-Ongoing-VIP943-Phase-1-Dose-Escalation-Study-and-Provides-Pipeline-and-Corporate-Updates.html [2] CNS 2024 Conference Presentation: Diakonos Oncology’s Autologous Dendritic Cell Vaccine (DOC1021) Yields 93% 12-Month Survival for Glioblastoma Patients. Retrieved October 11, 2024, from https://www.diakonosoncology.com/news/cns-2024-conference-presentation-diakonos-oncologys-autologous-dendritic-cell-vaccine-doc1021-yields-93-12-month-survival-for-glioblastoma-patients/ [3] Enliven Therapeutics Announces Positive Data Update from Phase 1 Clinical Trial of ELVN-001 in Chronic Myeloid Leukemia. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/09/28/2954762/0/en/Enliven-Therapeutics-Announces-Positive-Data-Update-from-Phase-1-Clinical-Trial-of-ELVN-001-in-Chronic-Myeloid-Leukemia.html [4] Kazia Therapeutics Announces Presentation of Promising Phase I Data Evaluating Concurrent Paxalisib and Radiation Therapy in Patients with Solid Tumor Brain Metastases or Leptomeningeal Metastases Harboring PI3K Pathway Mutations at the American Society for Radiation Oncology 66th Annual Meeting. Retrieved October 11, 2024, from https://www.prnewswire.com/news-releases/kazia-therapeutics-announces-presentation-of-promising-phase-i-data-evaluating-concurrent-paxalisib-and-radiation-therapy-in-patients-with-solid-tumor-brain-metastases-or-leptomeningeal-metastases-harboring-pi3k-pathway-mutations--302265538.html [5] Viking Therapeutics Announces Results from Phase 1b Clinical Trial of VK0214 in Patients with X-ALD. Retrieved October 11, 2024, from https://www.prnewswire.com/news-releases/viking-therapeutics-announces-results-from-phase-1b-clinical-trial-of-vk0214-in-patients-with-x-ald-302270769.html [6] Repare Therapeutics Announces Phase 1 Data Highlighting Camonsertib in Combination with Radiotherapy Treatment Presented at the ASTRO Annual Meeting. Retrieved October 11, 2024, from https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-phase-1-data-highlighting [7] Panavance Therapeutics Provides Update on Phase 1 Clinical Trial of Misetionamide in Pancreatic Cancer at 2024 Visceral Medicine Congress. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/10/09/2960394/0/en/Panavance-Therapeutics-Provides-Update-on-Phase-1-Clinical-Trial-of-Misetionamide-in-Pancreatic-Cancer-at-2024-Visceral-Medicine-Congress.html [8] Aurigene Oncology Limited Announces Promising Results of Phase 1 Study for India’s First Trial for Novel Autologous CAR-T Cell Therapy for Multiple Myeloma. Retrieved October 11, 2024, from https://www.businesswire.com/news/home/20241008755325/en/Aurigene-Oncology-Limited-Announces-Promising-Results-of-Phase-1-Study-for-India%E2%80%99s-First-Trial-for-Novel-Autologous-CAR-T-Cell-Therapy-for-Multiple-Myeloma/ [9] Immatics Announces Updated Phase 1b Clinical Data on ACTengine® IMA203 TCR-T Targeting PRAME in Melanoma Patients and Provides Update on Upcoming SUPRAME Phase 3 Trial. Retrieved October 10, 2024 from https://www.globenewswire.com/news-release/2024/10/10/2961129/0/en/Immatics-Announces-Updated-Phase-1b-Clinical-Data-on-ACTengine-IMA203-TCR-T-Targeting-PRAME-in-Melanoma-Patients-and-Provides-Update-on-Upcoming-SUPRAME-Phase-3-Trial.html [10] BlueRock Therapeutics’ investigational cell therapy bemdaneprocel for Parkinson’s disease shows positive data at 24-months. Retrieved October 11, 2024, from https://www.bayer.com/en/us/cell-therapy-bemdaneprocel [11] Estrella Immunopharma Achieves Complete Response in First Patient Treated with CD19- Redirected ARTEMIS® T-cells. Retrieved October 11, 2024, from https://www.estrellabio.com/news/estrella-immunopharma-achieves-complete-response-in-first-patient-treated-with-cd19--redirected-artemis%C2%AE-t-cells [12] INKmune Demonstrates Excellent Safety and Increased NK-Cell Activity in First Dosing Cohort. Retrieved October 11, 2024, from https://inmunebio.com/index.php/newsroom/2024-news/muneemonstratesxcellentafetyandncreasede20240926050502 [13] Theriva Biologics Announces Positive Outcome of Data and Safety Monitoring Committee (DSMC) Review in Phase 1b/2a Clinical Trial of SYN-004 (ribaxamase) in Allogeneic Hematopoietic Cell Transplant Recipients. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/10/03/2957647/0/en/Theriva-Biologics-Announces-Positive-Outcome-of-Data-and-Safety-Monitoring-Committee-DSMC-Review-in-Phase-1b-2a-Clinical-Trial-of-SYN-004-ribaxamase-in-Allogeneic-Hematopoietic-Cel.html [14] Alentis Therapeutics Receives FDA IND Clearance for ALE.P02, a Novel CLDN1-ADC for the Treatment of Squamous Cancers. Retrieved October 11, 2024, from https://pipelinereview.com/alentis-therapeutics-receives-fda-ind-clearance-for-ale-p02-a-novel-cldn1-adc-for-the-treatment-of-squamous-cancers/ [15] NeuroBo Pharmaceuticals Announces Positive Top-Line Data From the SAD Part 1 of Its Phase 1 Clinical Trial Evaluating DA-1726 for the Treatment of Obesity. Retrieved October 11, 2024, from https://www.prnewswire.com/news-releases/neurobo-pharmaceuticals-announces-positive-top-line-data-from-the-sad-part-1-of-its-phase-1-clinical-trial-evaluating-da-1726-for-the-treatment-of-obesity-302261698.html [16] Calidi Biotherapeutics Announces FDA Clearance of the Northwestern University IND Application for CLD-101 Clinical Trial in High-Grade Glioma. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/09/30/2955149/0/en/Calidi-Biotherapeutics-Announces-FDA-Clearance-of-the-Northwestern-University-IND-Application-for-CLD-101-Clinical-Trial-in-High-Grade-Glioma.html [17] Adcendo Announces US FDA Clearance of IND Application for Phase I/II First-in-Human ADCElerate-01 Trial of ADCE-D01 (uPARAP Receptor Targeting ADC) Trial in Patients With Metastatic and/or Unresectable Soft Tissue Sarcoma (STS). Retrieved October 11, 2024, from https://pipelinereview.com/adcendo-announces-us-fda-clearance-of-ind-application-for-phase-i-ii-first-in-human-adcelerate-01-trial-of-adce-d01-uparap-receptor-targeting-adc-trial-in-patients-with-metastatic-and-or-unresectabl/ [18] Safety and immunogenicity of CD40.HIVRI.Env, a dendritic cell-based HIV vaccine, in healthy HIV-uninfected adults: a first-in-human randomized, placebo-controlled, dose-escalation study (ANRS VRI06). Retrieved October 11, 2024, from https://www-thelancet-com.libproxy1.nus.edu.sg/journals/eclinm/article/PIIS2589-5370(24)00424-3/fulltext [19] Myrtelle Announces Significant Reduction in N-Acetylaspartate (NAA), a Key Biomarker, in Patients Treated in Its Phase 1/2 Clinical Trial of the Investigational Gene Therapy rAAV-Olig001-ASPA for Canavan Disease. Retrieved October 11, 2024, from https://www.prnewswire.com/news-releases/myrtelle-announces-significant-reduction-in-n-acetylaspartate-naa-a-key-biomarker-in-patients-treated-in-its-phase-12-clinical-trial-of-the-investigational-gene-therapy-raav-olig001-aspa-for-canavan-disease-302263264.html [20] Kiromic BioPharma Reports Favorable 10-Month Follow-Up Results for the First Patient Treated in its Deltacel-01 Clinical Trial. Retrieved October 11, 2024, from https://www.businesswire.com/news/home/20241001186898/en/Kiromic-BioPharma-Reports-Favorable-10-Month-Follow-Up-Results-for-the-First-Patient-Treated-in-its-Deltacel-01-Clinical-Trial [21] Recursion Announces FDA Clearance of Investigational New Drug Application for REC-1245, a Potential First-In-Class RBM39 Degrader for Biomarker-Enriched Solid Tumors and Lymphoma. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/10/02/2956875/0/en/Recursion-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-REC-1245-a-Potential-First-In-Class-RBM39-Degrader-for-Biomarker-Enriched-Solid-Tumors-and-Lymphoma.html [22] Kymera Therapeutics Announces FDA Clearance of Investigational New Drug Application for KT-621, a First-in-Class, Oral STAT6 Degrader. Retrieved October 11, 2024, from https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-announces-fda-clearance-investigational-0 [23] Vanqua Bio Announces Positive Interim Results from Phase 1 Clinical Trial of VQ-101, an Orally Administered, Brain-Penetrant, Allosteric Activator of GCase for the Treatment of GBA-Parkinson’s and Related Disorders. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/10/09/2960411/0/en/Vanqua-Bio-Announces-Positive-Interim-Results-from-Phase-1-Clinical-Trial-of-VQ-101-an-Orally-Administered-Brain-Penetrant-Allosteric-Activator-of-GCase-for-the-Treatment-of-GBA-Pa.html [24] Traws Pharma Announces Positive Topline Phase 1 Data for Flu Candidate, Tivoxavir Marboxil. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/10/08/2959584/0/en/Traws-Pharma-Announces-Positive-Topline-Phase-1-Data-for-Flu-Candidate-Tivoxavir-Marboxil.html [25] Gain Therapeutics Presents Phase 1 GT-02287 Data at International Congress of Parkinson’s Disease and Movement Disorders Demonstrating Increase in GCase Activity in Healthy Volunteers. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/09/30/2955049/0/en/Gain-Therapeutics-Presents-Phase-1-GT-02287-Data-at-International-Congress-of-Parkinson-s-Disease-and-Movement-Disorders-Demonstrating-Increase-in-GCase-Activity-in-Healthy-Volunte.html [26] Kura Oncology Announces Publication of Ziftomenib Phase 1 Results in The Lancet Oncology. Retrieved October 11, 2024, from https://www.globenewswire.com/news-release/2024/09/30/2955703/35186/en/Kura-Oncology-Announces-Publication-of-Ziftomenib-Phase-1-Results-in-The-Lancet-Oncology.html [27] Allakos Announces Phase 1 Trial Results of Subcutaneous AK006 in Healthy Volunteers. Retrieved October 11, 2024, from https://investor.allakos.com/news-releases/news-release-details/allakos-announces-phase-1-trial-results-subcutaneous-ak006 [28] Ultragenyx Provides Update on Stage 1 Cohorts in Pivotal Phase 1/2/3 Cyprus2+ Study Evaluating UX701 Gene Therapy for the Treatment of Wilson Disease. Retrieved October 4, 2024, from https://www.globenewswire.com/news-release/2024/10/03/2958032/0/en/Ultragenyx-Provides-Update-on-Stage-1-Cohorts-in-Pivotal-Phase-1-2-3-Cyprus2-Study-Evaluating-UX701-Gene-Therapy-for-the-Treatment-of-Wilson-Disease.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

细胞疗法临床结果免疫疗法疫苗临床1期

2024-09-23

·PRNewswire

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

临床1期孤儿药快速通道临床结果

2024-07-24

·CPHI制药在线

PI3K抑制剂剑指胶质母细胞瘤，Paxalisib Ⅱ/Ⅲ期临床试验结果积极

近日， Kazia Therapeutics宣布，旗下PI3K/mTOR抑制剂Paxalisib对比标准治疗（SOC）用于胶质母细胞瘤的II/III期GBM-AGILE研究取得了积极结果，达到了总生存期（OS）这一主要终点，非甲基化的新发胶质母细胞瘤（NDU）患者的总生存期有临床意义的改善，受此消息催化，Kazia股价两天暴涨超6倍。具体来看，在GBM-AGILE（NCT03522298）研究的目的是评估Paxalisib作为手术切除和使用TMZ进行初始化疗后的辅助治疗药物，在新诊断的MGMT启动子未甲基化的GBM患者中的安全性、耐受性、第二阶段推荐剂量（RP2D）、药代动力学（PK）和临床活性，本次试验共纳入了313名新诊断的MGMT未甲基化和复发性GBM患者。在有效性方面，对于新诊断的MGMT启动子未甲基化的GBM患者，Paxalisib组的中位总生存期（OS）为15.54个月，而标准治疗（SOC）组为11.89个月，Paxalisib组在总生存期上显著优于SOC组。并且敏感性分析的结果进一步证实了这一结果，Paxalisib组和SOC组的中位总生存期分别为15.54个月和11.70个月。而对于复发性胶质母细胞瘤患者，结果并不相同。Paxalisib组和SOC组的中位总生存期分别为8.05个月和9.69个月。因而对于复发性胶质母细胞瘤，Paxalisib还需进一步的探索和改进。在安全性方面，Paxalisib组未发现新的安全性信号，患者耐受性良好。总结来说，对于新诊断的MGMT启动子未甲基化的GBM患者，目前的标准疗法获益有限，但Paxalisib已经表现出了优于标准疗法的潜力，有望为这类患者带来新的替代治疗方案。 Paxalisib是一款具有高效血脑屏障穿透性的PI3K/mTOR通路抑制剂剂。该药在2018年2月被美国FDA授予胶质母细胞瘤的“孤儿药”称号，并在2020年8月被授予胶质母细胞瘤的快速通道指定。2022年7月，该药被授予罕见儿科疾病认定(RPDD)，用于治疗罕见高侵袭性儿童脑癌中的非典型横纹肌瘤或畸形肌瘤(AT/RT)患者。2016年Novogen（Kazia前身）从基因泰克方面获得该药物的授权，此外，2021年3月29日该公司与先声药业集团有限公司的附属公司签署独家许可协议，获得在大中华区的所有适应症的商业化开发权利。值得一提的是，2022年8月1日，Kazia宣布Paxalisib未能满足进入大型关键GBM临床试验第二阶段的“预先定义的标准”，受此消息影响，该消息一经披露后， Kazia的股价大跌近53%，并且陷入了持续震荡下跌的泥潭。此次胶质母细胞瘤的II/III期临床的成功让Kazia实现了逆风翻盘。 PI3K/AKT/mTOR是细胞内重要的信号通路之一，在调节细胞生长、运动、存活、代谢和血管生成过程中起着重要作用。然而PI3K/AKT/mTOR通路的过度激活不仅会导致肿瘤的发展，还会引起耐药性的产生。在乳腺癌、结直肠癌和血液癌症等几乎所有的人类癌症中，几乎都存在PI3K/AKT/mTOR通路失调的现象。 PI3K由三个亚基组成。根据其不同的结构和特定的底物，PI3K分为3类：I类、II类和III类。I类PI3K是与人类癌症最相关的类型，包括PI3Kα、PI3Kβ、PI3Kδ、PI3Kγ四个亚型。II类PI3K和III类PI3K主要控制膜运输，间接调节信号转导。其中，II类PI3K成员包括PI3KC2α、PI3KC2β和PI3KC2γ三个亚型，III类PI3K由催化亚基Vps34和调节亚基 Vps15组成。全球范围内，现共有五款PI3K抑制剂获批上市，分别为吉利德（Gilead）的idelalisib、拜耳医药（Bayer）的copanlisib、Verastem公司的duvelisib以及诺华（Novartis）的alpelisib（BYL719）。虽然已经批准了五种PI3K抑制剂，但仍有许多关于耐受性、患者选择、敏感性标记、耐药性发展和毒理学挑战的未决问题需要解决。相比其他PI3K抑制剂，Paxalisib能够穿过其他抑制剂几乎无法穿透的血脑屏障。最近的研究表明，高达70%的脑转移(BCBM)患者发生磷脂酰肌醇3-激酶(PI3K)通路的激活。磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α (PIK3CA)的致癌改变导致PI3K/蛋白激酶B (Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)通路的增强激活，这一通路已被证明促进各种癌症类型的发生、发展和治疗抵抗，包括her2阳性乳腺癌。抑制这一关键通路是治疗BCBM的一种有吸引力的策略。尽管近年来开发了许多靶向该通路的抑制剂，但美国FDA尚未批准PI3K抑制剂用于治疗脑转移瘤。 2023年7月6日，肿瘤药物研发公司Kazia Therapeutics Limited宣布称，其主导项目Paxalisib已被美国食品药品监督管理局（FDA）授予快速通道认定（FTD），用于治疗在放疗中表达PI3K信号通路突变的固体肿瘤脑转移。 FDA决定授予FTD的依据是来自一项正在进行的I期临床试验（NCT04192981）的中期分析的临床数据。在该临床试验中，原发肿瘤的脑转移患者接受Paxalisib与放疗联合治疗。该临床数据由临床试验的主要研究员Jonathan Yang博士在2022年由神经肿瘤学会（SNO）和美国临床肿瘤学会（ASCO）联合组织的CNS临床试验和脑转移年会上进行了报告。该试验中的所有9例可评估患者（100%）对Paxalisib与放疗的联合治疗都有反应。已发表的基准数据显示，仅放疗的典型反应率约为20%~40%。脑干胶质母细胞瘤（H3K27M DIPG）和弥漫性中线胶质母细胞瘤（DMG）是罕见但致命的神经系统肿瘤，通常发生于脑干。H3K27M 是一个与恶性肿瘤相关的基因突变，这种变异在儿童中常见，此突变发生在组蛋白H3的编码基因H3F3A（H3.3）或HIST1H3B（H3.1）中，导致第27位赖氨酸（K）被甲硫氨酸（M）替代。这些肿瘤由于位置困难以及其高度侵袭性而难以治疗，因此治疗选择有限，预后通常较差。据报道，口服小分抗癌疗法 ONC201 对确诊为复发性 H3K27M DMG 患者具有初步临床疗效。近日，由多国研究团队联合发表于Cancer Research题为ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma的文章，主要探讨了ONC201与Paxalisib联合治疗H3K27突变的弥漫性中线胶质瘤（DMG）的疗效。这篇研究文章揭示了ONC201对DIPG细胞的作用机制及其局限性，强调了PI3K/Akt信号通路在肿瘤耐药中的关键作用。通过体内外实验，证明了ONC201与Paxalisib联合治疗的协同效应，为进一步的临床试验提供了重要依据。这些发现为开发更有效的DIPG治疗方案提供了新的思路。参考来源 1.Jackson ER,et al. Cancer Res. 2023 May 17;OF1-OF17. doi: 10.1158/0008-5472.CAN-23-0186. 2.Fiani B, Covarrubias C, Onyedimma C, Jarrah R. Neurocytological Advances in the Treatment of Glioblastoma Multiforme. Cureus. 2021 Jul 10;13(7):e16301. doi: 10.7759/cureus.16301. PMID: 34405064; PMCID: PMC8352800. 3.Tawbi HA, Forsyth PA, Algazi A, et al.Combined nivolumab and ipilimumab in melanoma metastatic to the brain.N Engl J Med.2018;379(8):722–730. Kluger HM, Chiang V, Mahajan A, et al.Long-term survival of patients with melanoma with active brain metastases treated with pembrolizumab on a phase II trial.J Clin Oncol. 2019;37(1):52–60. 内容来源于网络，如有侵权，请联系删除。

孤儿药快速通道临床结果

100 项与 Paxalisib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11869	-	-	DB15186

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
多形性胶质母细胞瘤	临床3期	加拿大	Bayer AG	2019-07-30
多形性胶质母细胞瘤	临床3期	美国	Kazia Therapeutics Ltd.	2019-07-30
多形性胶质母细胞瘤	临床3期	德国	Biohaven Pharmaceuticals, Inc.	2019-07-30
多形性胶质母细胞瘤	临床3期	美国	Biohaven Pharmaceuticals, Inc.	2019-07-30
多形性胶质母细胞瘤	临床3期	瑞士	Kazia Therapeutics Ltd.	2019-07-30
多形性胶质母细胞瘤	临床3期	澳大利亚	Kintara Therapeutics, Inc.	2019-07-30
多形性胶质母细胞瘤	临床3期	澳大利亚	Vigeo Therapeutics, Inc.	2019-07-30
多形性胶质母细胞瘤	临床3期	澳大利亚	Biohaven Pharmaceuticals, Inc.	2019-07-30
多形性胶质母细胞瘤	临床3期	瑞士	Kintara Therapeutics, Inc.	2019-07-30
胶质母细胞瘤	临床3期	-	江苏先声药业有限公司	-

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05009992 (Biospace) 人工标引	临床2期	弥漫性中线胶质瘤一线	132	paxalisib in combination with ONC201 (Cohort 1)	(簾壓遞顧選鏇廠觸構簾) = 艱鹽壓鹽餘艱壓簾獵觸選繭鏇構鹽齋鬱願製夢 (範選網繭鏇築淵廠網憲 )	积极	2024-06-27
NCT05009992 (Biospace) 人工标引	临床2期	弥漫性中线胶质瘤一线	132	paxalisib in combination with ONC201 (Cohort 2)	(簾壓遞顧選鏇廠觸構簾) = 窪夢簾積膚鹹襯鏇鏇製選繭鏇構鹽齋鬱願製夢 (範選網繭鏇築淵廠網憲 )	积极	2024-06-27
NCT05009992 (SNO2023) 人工标引	临床2期	弥漫性中线胶质瘤	68	ONC201+paxalisib	(遞齋積醖獵糧鏇鑰廠糧) = 窪簾衊鬱遞顧積廠蓋選鏇製觸壓襯鑰鬱鹽憲簾 (夢獵艱繭餘齋淵憲製齋, lower 11.6) 更多	积极	2023-11-10
NCT04906096 (PRNewswire) 人工标引	临床2期	原发性中枢神经系统淋巴瘤	14	Paxalisib	(膚淵襯襯鏇糧糧構齋夢) = preliminarily observed in enrolled patients, including partial responses and stable disease 淵鑰製淵顧鑰鑰製鬱鏇 (網獵鏇膚築簾艱簾襯築 ) 更多	积极	2023-11-01
NCT03522298 (ESMO2022)	临床2期	胶质母细胞瘤	30	Paxalisib	(淵顧簾夢艱廠積膚蓋壓) = 蓋窪艱蓋遞餘齋鹽窪觸願獵憲鏇選窪積築窪窪 (窪鏇窪餘膚鹹鬱觸觸製 ) 更多	-	2022-09-09
NCT04192981 (Corporate Publications) 人工标引	临床1期	脑转移瘤 PIK3CA Mutation	12	radiotherapy+paxalisib	(製網獵製膚繭顧選製簾) = Paxalisib 45mg daily in combination with radiotherapy 糧夢艱淵積顧廠選壓淵 (觸廠選顧築膚壓襯製醖 )	积极	2022-08-08
NCT03522298 (ASCO2022)	临床2期	胶质母细胞瘤	30	Paxalisib	(願積膚構襯鹹繭膚繭製) = 鹹壓鬱鑰壓襯簾網憲齋網構範窪齋構鬱構獵範 (願範範範淵觸鑰醖願鏇 ) 更多	-	2022-06-02
NCT03522298 (AACR2021)	临床2期	多形性胶质母细胞瘤	30	Paxalisib 60mg (fasted)	(獵憲積壓顧鑰壓網憲網) = 顧網鹹觸蓋範鹽壓願觸襯醖蓋網鬱廠構範廠艱 (衊膚壓願廠憲糧簾壓鏇 ) 更多	-	2021-07-01
NCT03522298 (AACR2021)	临床2期	多形性胶质母细胞瘤	30	Paxalisib 60mg (fed)	(獵憲積壓顧鑰壓網憲網) = 選鬱範鹹鬱鬱窪膚顧顧襯醖蓋網鬱廠構範廠艱 (衊膚壓願廠憲糧簾壓鏇 ) 更多	-	2021-07-01
NCT03522298 (AACR2020)	临床2期	多形性胶质母细胞瘤	29	Paxalisib	(範獵選淵製餘遞鏇網艱) = DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents. 構襯壓簾構齋顧膚憲獵 (壓廠顧餘觸淵願醖獵鹹 )	积极	2020-08-15
NCT01547546 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	脑恶性胶质瘤	47	GDC-0084	(壓壓繭蓋襯夢憲壓選蓋) = 醖築網齋膚壓製蓋鹹鏇窪鏇餘糧構範構膚顧範 (觸網獵壓鹽艱願鑰構鹹 ) 更多	积极	2020-04-15