Clinical Study on Macitentan, RT and TMZ Concurrent Therapy Followed by Maintenance Macitentan and TMZ in Newly Diagnosed Glioblastoma

A Single-center, Open-label, Phase 1 Study of Macitentan, Radiotherapy and Temozolomide Concurrent Therapy Followed by Maintenance Therapy With Macitentan and Temozolomide in Subjects With Newly Diagnosed Glioblastoma

This is a prospective, single-center, open-label, 3+3 dose escalation Phase 1 safety study. Adults with newly diagnosed GBM or gliosarcoma will receive macitentan in addition to the standard of care treatment for GBM. The study consists of a screening period, a treatment period, and a 30-day safety follow up period. The treatment period includes 6 weeks of concurrent therapy (macitentan+RT+TMZ), 4 weeks of monotherapy (macitentan) and 12 cycles of maintenance therapy (macitentan+TMZ). The study will end when the last treated subject has completed study treatment and the 30-day safety follow-up period.

The planned duration of the study is approximately 34-38 months depending on the number of dose levels and cohorts of subjects enrolled. Subject participation in the study will be for approximately 16 months.

Inclusion Criteria:

• Subjects at least 18 years of age
• Histologically proven supratentorial GBM or gliosarcoma
• Use of effective contraception by women of childbearing potental.
• Use of effective contraception by fertile males with a female partner of childbearing potential.
• Interval of at least 3 weeks after biopsy or open surgery and able to begin study treatment.
• Result from a post-operative contrast-enhanced brain MRI within 72 hours after surgery or biopsy.
• Adequate bone marrow function
• Karnofsky Performance Score of at least 70.

Exclusion Criteria:

• Prior treatment for glioblastoma or gliosarcoma.
• Evidence of leptomeningeal spread of glibolastoma or gliosarcoma.
• Tumor foci below the tentorium or beyond the cranial vault.
• Evidence of recent hemorrhage on post-operative contrast enhanced brain MRI (except hemosiderin, resolving hemorrhage changes related to surgery, presence of punctuate hemorrhage in tumor).
• Aspartate aminotransferase or alanine aminotransferase > 3 times the upper limit of normal.
• Supine systolic blood pressure < 100 mmHg or diastolic blood pressure < 50 mmHg.
• Medical history of orthostatic hypotension.
• International normalized ratio > 1.5 on anticoagulant therapy, active bleeding on low molecular weight heparin, or chronic condition with a high risk of bleeding.
• Severe renal impairment.
• Severe hepatic impairment.
• Severe, active co-morbidity: (e.g. cardiac disease; respiratory disease; chronic hepatitis; hemtological and bone marrow diseases; severe malabsoprtion; human immunodeficiency virus).
• No concurrent strong CYP3A4 inducers or inhibitors.
• No investigational drug within 4 weeks of starting study treatment.
• Any life-threatening condition that could affect protocol compliance.