Actr-84. D-termined: a Phase 1 Trial in Newly Diagnosed High Grade Glioma With Temozolomide, Radiation, and Minocycline Followed by Adjuvant Minocycline/temozolomide
Year: 2017
Type: conference-abstract
Abstract: Activated microglia in high grade gliomas secrete TNF, which activates NF-kappaB. Activation of NF-kB promotes transition to the mesenchymal phenotype of GBM, which is associated with increased radiation-resistance and poorer prognosis. Minocycline is a tetracycline-derivative capable of blocking microglia activation and release of TNF. Minocycline is known to cross the blood-brain barrier and has been shown in vitro and in vivo to inhibit GBM proliferation. D-TERMINED was a single arm, open label phase I trial sponsored by the Musella Foundation enrolling people with newly diagnosed grade 3 or 4 glioma with a 3 + 3 dose escalation followed by a 14 patient dose expansion cohort. All patients received standard chemoradiation with temozolomide plus continuous oral minocycline. Primary objectives were to define the MTD and adverse event rate of minocycline with radiation and temozolomide; secondary objectives included PFS. Efficacy was assessed by the percent of people whose PFS exceeded the predicted median PFS based on RTOG RPA class. Nine evaluable patients were enrolled to the dose escalation component, and the MTD was defined as 150mg PO BID. A total of 20 patients were treated at 150mg PO BID. All patients treated at 150mg PO BID had GBM. At the 150mg PO BID dose, one person (5%) had grade 3 nausea and dizziness, and two people (10%) had temozolomide interruptions for grade 3–4 thrombocytopenia. 11 of 20 patients treated at 150mg BID exceeded expected PFS, 55% (95% CI 32%-77%), which does not meet the prescribed efficacy endpoint of 70%. Minocycline can be safely combined with radiation and temozolomide in newly diagnosed high grade glioma. A signal of efficacy was not seen. Further investigation of minocycline in unselected high grade glioma is not warranted, though biomarkers of NF-kappaB activation and mesenchymal phenotype are being investigated.
Source: Neuro-Oncology
Institutions: University of Utah, Huntsman Cancer Institute
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767319623