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Phase I Study of GRN1005 in Recurrent Malignant Glioma
Abstract
PURPOSE: GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. METHODS: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved. RESULTS: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥ 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥ 200 mg/m(2). CONCLUSION: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m(2) every 3 weeks.
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“Besides on the BBB, LRP1 was also found to be highly expressed on glioma cells39–41.”
From Brain-targeted drug delivery by manipulating protein corona functions (2019) · cites this paper as [39]
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“Our study further suggests that regulation of LRP-1 cell surface expression and function, through gene silencing or pharmacological inhibition of catalytic MMP activity, might become very useful in enhancing the chemotherapeutic effects of An2–drug conjugates [46,68,69] by promoting their internalization in both low-grade- and high-grade gliomas.”
From MT1-MMP Expression Levels and Catalytic Functions Dictate LDL Receptor-Related Protein-1 Ligand Internalization Capacity in U87 Glioblastoma Cells (2022) · cites this paper as [46]
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Metadata
- Authors
- Drappatz, J., Brenner, A., Wong, E. T., Eichler, A., Schiff, D., Groves, M. D., Mikkelsen, T., Rosenfeld, S., Sarantopoulos, J., Meyers, C. A., Fielding, R. M., Elian, K., Wang, X., Lawrence, B., Shing, M., Kelsey, S., Castaigne, J. P., & Wen, P. Y.
- Affiliations
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2013-03-14
- Volume
- 19
- Issue
- 6
- Pages
- 1567-1576
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2111631341
- Cited by
- 190
- References
- 51
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 15 · 2023: 16 · 2022: 22 · 2021: 15 · 2020: 17 · 2019: 19 · 2018: 12 · 2017: 6 · 2016: 15 · 2015: 18 · 2014: 7 · 2013: 1
- FWCI
- 6.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- recurrent malignant glioma, peptide-drug conjugates, LDL receptor-related protein 1, blood-brain barrier penetration, paclitaxel, maximum tolerated dose, pharmacokinetics, dose-limiting toxicity
- MeSH terms
- Adult, Aged, Antineoplastic Agents, Blood-Brain Barrier, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Glioma, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Peptides, Paclitaxel, Maximum Tolerated Dose, Drug-Related Side Effects and Adverse Reactions
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