Phase 1 Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Effects of CM93 in Subjects With Recurrent Glioblastoma (rGBM) Characterized by Epidermal Growth Factor Receptor (EGFR) Mutation or Amplification

This is a first-in-human study of CM93, an oral investigational drug, in adults with Epidermal Growth Factor Receptor-modified glioblastoma. The study is designed in three parts consisting of a dose-escalation phase, a dose-expansion phase and a window-of-opportunity surgical trial. The trial objectives are to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical effects of CM93 in this patient population.

开始日期2027-01-01

申办/合作机构

Crimson BioPharm, Inc.

NCT04629209 / Withdrawn临床2期IIT

A Phase II, Open Label Study of ONC201 in Adults With EGFR-low Glioblastoma

This is an open-label, two arm study. The trial will enroll a total of up to 36 patients. Arm A will enroll up to a total of 6 evaluable patients and Arm B will enroll up to a total of 30 evaluable patients. Arm A will explore the intra-tumoral ONC201 concentrations and pharmacodynamic activity in adult EGFR-low glioblastoma patients. Arm B will determine the radiographic efficacy of ONC201 in adult recurrent EGFR-low glioblastoma patients. All patients will be treated with oral ONC201 (625 mg) twice weekly, 2 consecutive days on and 5 days off per week schedule.

开始日期2024-06-28

申办/合作机构

University of Minnesota Masonic Cancer Center

[+1]

NCT06186401 / Recruiting临床1期IIT

Phase 1 Study of Autologous Anti-EGFRvIII synNotch Receptor Induced Anti-EphA2/IL-13R alpha2 CAR (E-SYNC) T Cells in Adult Participants With EGFRvIII+ Glioblastoma

This phase I trial tests the safety, side effects, and best dose of E-SYNC chimeric antigen receptor (CAR) T cells after lymphodepleting chemotherapy in treating patients with EGFRvIII positive (+) glioblastoma. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so the CAR T cells will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Lymphodepleting chemotherapy with cyclophosphamide and fludarabine before treatment with CAR T cells may make the CAR T cells more effective.

开始日期2024-04-30

申办/合作机构

The University of California, San Francisco

[+2]

100 项与 EGFR突变胶质母细胞瘤相关的临床结果

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100 项与 EGFR突变胶质母细胞瘤相关的转化医学

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0 项与 EGFR突变胶质母细胞瘤相关的专利（医药）

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项与 EGFR突变胶质母细胞瘤相关的文献（医药）

2024-08-01·Clinical Cancer Research

Bystander Effects, Pharmacokinetics, and Linker-Payload Stability of EGFR-Targeting Antibody-Drug Conjugates Losatuxizumab Vedotin and Depatux-M in Glioblastoma Models

Article

作者: Carlson, Brett L. ; Lefebvre, Didier R. ; Reilly, Edward B. ; Feldsien, Thomas M. ; Rathi, Sneha ; Bakken, Katrina ; Gupta, Shiv K. ; Le, Jiayan ; Porath, Kendra A. ; Eckel-Passow, Jeanette E. ; Hu, Zeng ; Decker, Paul A. ; Burgenske, Danielle M. ; Griffith, Jessica I. ; Jain, Sonia ; Sarkaria, Jann N. ; Pasa, Tugce I. ; Elmquist, William F. ; Vaubel, Rachael A.

AbstractPurpose:Antibody-drug conjugates (ADC) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given GBM’s molecular heterogeneity, the bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs with similar auristatin toxins, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), were compared in GBM patient-derived xenografts (PDX) and normal murine brain following direct infusion by convection-enhanced delivery (CED).Experimental Design:EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Nontumor-bearing mice were used to evaluate the pharmacokinetics (PK) and toxicity of ADCs using LC-MS/MS and immunohistochemistry.Results:CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs. 20–49 days with isotype control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221 with the cell-permeable monomethyl auristatin E (MMAE), compared with Depatux-M with the cell-impermeant monomethyl auristatin F. CED infusion of ABBV-221 into the brain or incubation of ABBV-221 with normal brain homogenate resulted in a significant release of MMAE, consistent with linker instability in the brain microenvironment.Conclusions:EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intratumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.

2024-03-01·Journal of Neuro-Oncology

Imaging predictors of 4q12 amplified and RB1 mutated glioblastoma IDH-wildtype

Article

作者: Dono, Antonio ; Tandon, Nitin ; Esquenazi, Yoshua ; Arevalo, Octavio ; Torres, Jose ; Riascos, Roy F ; Rodriguez-Quinteros, Juan Carlos ; Kamali, Arash ; Ballester, Leomar Y ; Nunez, Luis

INTRODUCTIONRecent studies have identified that glioblastoma IDH-wildtype consists of different molecular subgroups with distinct prognoses. In order to accurately describe and classify gliomas, the Visually AcceSAble Rembrandt Images (VASARI) system was developed. The goal of this study was to evaluate the VASARI characteristics in molecular subgroups of IDH-wildtype glioblastoma.METHODSA retrospective analysis of glioblastoma IDH- wildtype with comprehensive next-generation sequencing and pre-operative and post-operative MRI was performed. VASARI characteristics and 205 genes were evaluated. Multiple comparison adjustment by the Bejamin-Hochberg false discovery rate (BH-FDR) was performed. A 1:3 propensity score match (PSM) with a Caliper of 0.2 was done.RESULTS178 patients with GBM IDH-WT met the inclusion criteria. 4q12 amplified patients (n = 20) were associated with cyst presence (30% vs. 12%, p = 0.042), decreased hemorrhage (35% vs. 62%, p = 0.028), and non-restricting/mixed (35%/60%) rather than restricting diffusion pattern (5%), meanwhile, 4q12 non-amplified patients had mostly restricting (47.4%) rather than a non-restricting/mixed diffusion pattern (28.4%/23.4%). This remained statistically significant after BH-FDR adjustment (p = 0.002). PSM by 4q12 amplification showed that diffusion characteristics continued to be significantly different. Among RB1-mutant patients, 96% had well-defined enhancing margins vs. 70.6% of RB1-WT (p = 0.018), however, this was not significant after BH-FDR or PSM.CONCLUSIONSPatients with glioblastoma IDH-wildtype harboring 4q12 amplification rarely have restricting DWI patterns compared to their wildtype counterparts, in which this DWI pattern is present in ~ 50% of patients. This suggests that some phenotypic imaging characteristics can be identified among molecular subtypes of IDH-wildtype glioblastoma.

2023-12-01·Cancer Communications

Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma

Article

作者: Yang, Shixue ; Cui, Xiaoteng ; Kang, Chunsheng ; Zhao, Jixing ; Li, Guanzhang ; Wang, Qixue ; Zhou, Junhu ; Xiao, Menglin ; Yi, Kaikai ; Wang, Hu ; Fang, Chuan ; Zhan, Qi ; Tan, Yanli ; Tong, Fei ; Wang, Yunfei ; Yang, Chao ; Hong, Biao ; Jiang, Tao

AbstractBackgroundMetabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune‐escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR‐vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.MethodsClinical GBM specimens were selected for single‐cell RNA sequencing and untargeted metabolomics analysis. A metabolism‐associated RTK‐fatty acid‐gene signature was constructed and verified. MK‐2206 and MK‐803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo.ResultsGBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single‐cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl‐CoA synthetase short‐chain family member 3 (ACSS3), acyl‐CoA synthetase long‐chain family member 3 (ACSL3), and long‐chain fatty acid elongation‐related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF‐κB‐dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.ConclusionsOur findings not only uncovered the mechanism of metabolic reprogramming in EGFR‐activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

项与 EGFR突变胶质母细胞瘤相关的新闻（医药）

2024-07-31

·PipelineReview

Pinetree Therapeutics Closes $17 Million in Series A Funding to Advance AbReptor™ Protein Degradation Platform and Portfolio Programs

New investment supports continued development of multispecific antibody degraders for oncology and other therapeutic areas CAMBRIDGE, MA, USA I July 30, 2024 I Pinetree Therapeutics, Inc. (“Pinetree” or the “Company”), an emerging biotechnology company pioneering next-generation targeted protein degraders (TPD) to combat drug resistance in oncology and beyond, today announced the successful completion of a Series A funding round, raising $17 million from new and existing investors. The investment was co-led by STIC Investments and DSC Investment. New investors include Atinum Investment, Quantum FA, and S&S Investment, joining existing investors DSC Investment, Schmidt, and SGI Partners. The proceeds will be used to leverage the Company’s AbReptor™ antibody degrader platform to advance its novel multispecific TPD development programs across multiple tumor types and targets in several oncology indications, with potential application in other therapeutic areas. “We are pleased to announce the closing of this investment round to fuel Pinetree’s novel targeted degradation approach,” said Dr. Hojuhn Song, Founder and CEO of Pinetree. “Our best-in-class multispecific antibody platform, AbReptor™, leverages a novel mechanism of action to degrade surface and extracellular proteins to improve outcomes across therapeutics areas. This technology enables the development of effective and versatile protein degrader molecules, including our lead preclinical degrader candidate for EGFR-mutated cancers, for which we recently announced an exclusive option and global license agreement with AstraZeneca. With our first global partnership secured, this additional funding, and with the encouraging preclinical data generated to date from AbReptor™, we are excited to continue applying our scientific approach to advance additional candidates in oncology and other indications.” “We are proud to provide our continued support as part of an exceptional syndicate for Pinetree, whose promising AbReptor™ platform has yielded novel programs with the potential to address unmet medical needs in people living with a range of treatment-resistant diseases,” said Yohan Kim, Executive Director of DSC Investment. “Recent data from Pinetree’s degrader programs solidifies our confidence in the Company’s approach, and we look forward to continuing our support for Pinetree and its platform technology and pipeline.” AbReptor™ is a versatile antibody-based TPD platform that functions through co-engaging a surface-receptor or extracellular protein of interest together with another proprietary receptor target. Pinetree is advancing multiple preclinical candidates derived from its AbReptor™ TPD platform with potential in oncology and other therapeutics areas, including candidate degraders indicated for TKI-resistant tumors, immune checkpoint inhibitor-resistant tumors, and other disease targets. About Pinetree Therapeutics, Inc. Established to combat drug resistance in oncology and beyond, Pinetree’s platform technology, AbReptor™, is a best-in-class, transformative and modular antibody platform designed to degrade membrane-bound and extracellular proteins. Since its founding in 2019, Pinetree’s platform has brought about several compelling pre-clinical programs in oncology and other therapeutic areas. Please visit the Company’s website at pinetreetx.com and connect on LinkedIn for more information. SOURCE: PineTree Therapeutics

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