Clinical Trial

. 2024 Jul 16;5(7):101630.

doi: 10.1016/j.xcrm.2024.101630. Epub 2024 Jul 1.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Manmeet S Ahluwalia¹, Ahmad Ozair², Michelle Rudek³, Xiaobu Ye⁴, Matthias Holdhoff³, Frank S Lieberman⁵, Anna F Piotrowski⁶, Burt Nabors⁷, Arati Desai⁷, Glenn Lesser⁸, Ru Chih Huang⁹, Steve Glenn¹⁰, Atulya A Khosla¹¹, David M Peereboom¹², Patrick Y Wen¹³, Stuart A Grossman³

Affiliations

¹ Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA; Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA. Electronic address: manmeeta@baptisthealth.net.
² Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁶ Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ Department of Hematology and Oncology, Wake Forest Medical Center, Winston, NC, USA.
⁹ Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Independent Consultant to Erimos Pharmaceuticals, Houston, TX, USA.
¹¹ Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
¹² Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA.
¹³ Department of Neurology, Harvard Medical School, Boston, MA, USA; Center for Neuro-Oncology, Dana Farber Cancer Institute, Boston, MA, USA.

PMID: 38955178
PMCID: PMC11293336
DOI: 10.1016/j.xcrm.2024.101630

Clinical Trial

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Manmeet S Ahluwalia et al. Cell Rep Med. 2024.

. 2024 Jul 16;5(7):101630.

doi: 10.1016/j.xcrm.2024.101630. Epub 2024 Jul 1.

Authors

Affiliations

¹ Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA; Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA. Electronic address: manmeeta@baptisthealth.net.
² Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁶ Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ Department of Hematology and Oncology, Wake Forest Medical Center, Winston, NC, USA.
⁹ Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Independent Consultant to Erimos Pharmaceuticals, Houston, TX, USA.
¹¹ Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
¹² Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA.
¹³ Department of Neurology, Harvard Medical School, Boston, MA, USA; Center for Neuro-Oncology, Dana Farber Cancer Institute, Boston, MA, USA.

PMID: 38955178
PMCID: PMC11293336
DOI: 10.1016/j.xcrm.2024.101630

Abstract

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Keywords: CNS cancer; EM-1421; NDGA; Sp1 transcription factor; astrocytoma (MeSH); brain malignancy; brain tumor; glioblastoma; glioma (MeSH); tetra-o-methyl nordihydroguaiaretic acid.

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Conflict of interest statement

Declaration of interests M.S.A. – grants: Seagen, AstraZeneca, BMS, Bayer, Incyte, Pharmacyclics, Novocure, MimiVax, and Merck. Consultation fees: Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Celularity, SDP Oncology, Apollomics, Prelude Therapeutics, Janssen, Tocagen, Voyager Therapeutics, ViewRay, Caris Life Sciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, AnHeart Therapeutics, Menarini Ricerche, Sumitomo Pharma Oncology, Autem therapeutics, GT Medical Technologies, Allovir, Equillium Bio., QV Bioelectronics, and Theraguix. Scientific Advisory Board memberships: Cairn Therapeutics, Pyramid Biosciences, Bugworks, and Modifi Biosciences. Data Safety and Monitoring Committee membership: VBI Vaccines. Stock shareholder: MimiVax, CytoDyn, Trisalus Lifesciences, and MedInnovate Advisors, LLC. D.M.P. – consulting or advisory role: Orbus Therapeutics, Sumitomo Dainippon Pharma Oncology, Inc., Stemline Therapeutics, and Novocure. Research funding: Pfizer (Inst), Novartis (Inst), NeOnc Technologies (Inst), Orbus Therapeutics (Inst), Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Pharmacyclics (Inst), Bayer (Inst), Karyopharm Therapeutics (Inst), Apollomics (Inst), Vigeo Therapeutics (Inst), Global Coalition for Adaptive Research (Inst), MimiVax (Inst), Ono Pharmaceutical (Inst), and Mylan (Inst). Equity ownership/stock options: Pfizer (Pharmaceuticals) and Gilead (Pharmaceuticals). M.H. – Data Safety Monitoring Board member: Parexel and Advarra. Institutional research funding: Novartis and Vanquish. P.Y.W. – research support: AstraZeneca, Black Diamond, Bristol Meyers Squibb, Celgene, Chimerix, Eli Lily, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines. Advisory board/consultant: AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. R.C.H. has patents related to the drug terameprocol and is affiliated with Erimos Pharmaceuticals, which holds rights to the drug. S.G. is an independent contractor/consultant to Erimos Pharmaceuticals, LLC with no ownership or other financial interest in Erimos Pharmaceuticals or its products.

Figures

None — For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.xcrm.2024.101630.

See this image and copyright information in PMC

References

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A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Affiliations

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials