Overview
Refractory anaplastic astrocytoma (WHO grade III) and Glioblastoma multiforme (WHO grade IV) are primary malignant brain tumours with poor prognosis and limited treatment options. Despite considerable genetic heterogeneity, these tumours often have impaired DNA repair systems, rendering them initially sensitive to alkylating agents, although they invariably develop resistance to these agents over time. Temozolomide is an imidazotetrazine prodrug that is stable at acidic pH but undergoes spontaneous nonenzymatic hydrolysis at neutral or slightly basic pH; these properties allow for both oral and intravenous administration. Following initial hydrolysis, further reactions liberate a highly reactive methyl diazonium cation capable of methylating various residues on adenosine and guanine bases leading to DNA lesions and eventual apoptosis. Temozomolide as an adjunct to radiotherapy followed by maintenance dosing remains the standard of care for both Glioblastoma and refractory anaplastic astrocytoma. Temozolomide was granted FDA approval on August 11, 1999, as an oral capsule and subsequently on February 27, 2009, as an intravenous injection. It is currently marketed under the trademark TEMODAR® by Merck.
Indication
Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma.
Associated Conditions
- Advanced Melanoma
- High Grade Glioma: Glioblastoma (GBM)
- Primary Central Nervous System Lymphoma
- Refractory Ewing Sarcoma
- Refractory Neuroblastoma
- Soft Tissue Sarcoma
- Advanced Neuroendocrine tumor
- Newly diagnosed Anaplastic Astrocytoma (AA)
- Refractory Anaplastic astrocytoma
- Refractory, advanced Mycosis fungoides
- Refractory, advanced Sezary Syndrome
Research Report
A Comprehensive Monograph on Temozolomide: Pharmacology, Clinical Efficacy, and Mechanisms of Resistance
Executive Summary
Temozolomide is an oral and intravenous alkylating agent that has fundamentally altered the therapeutic landscape for patients with high-grade malignant gliomas. As an imidazotetrazine derivative, it functions as a prodrug, undergoing non-enzymatic conversion at physiological pH to a reactive species that methylates tumor cell DNA, inducing cytotoxic lesions that lead to apoptosis. Its excellent oral bioavailability and ability to penetrate the blood-brain barrier make it uniquely suited for treating central nervous system malignancies.
The clinical utility of Temozolomide was definitively established by the landmark 2005 phase III trial by Stupp et al., which demonstrated that adding concomitant and adjuvant Temozolomide to standard radiotherapy significantly improved median and long-term survival for patients with newly diagnosed glioblastoma (GBM). This regimen, now known as the "Stupp protocol," was rapidly adopted as the global standard of care. The drug has also proven its efficacy in anaplastic astrocytoma (AA), first in the refractory/recurrent setting and more recently as an adjuvant therapy for newly diagnosed, IDH-mutant tumors.
Clinical Trials
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Title | Posted | Study ID | Phase | Status | Sponsor |
|---|---|---|---|---|---|
2016/10/24 | Phase 1 | Completed | |||
2016/10/14 | Phase 2 | UNKNOWN | |||
2016/10/10 | Phase 2 | UNKNOWN | Bassam Abdulkarim | ||
2016/09/16 | Phase 1 | Completed | |||
2016/09/13 | Phase 2 | Completed | |||
2016/08/18 | Phase 1 | Completed | |||
2016/07/18 | Phase 2 | Withdrawn | |||
2016/07/14 | Phase 2 | UNKNOWN | Sun Yat-sen University | ||
2016/07/13 | Phase 1 | Withdrawn | |||
2016/06/24 | Phase 1 | Recruiting |
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