Clinical Study on the Safety and Tolerability of Macitentan in Combination With Dose-dense Temozolomide in Patients With Recurrent Glioblastoma

Inclusion Criteria * Histologically confirmed glioblastoma multiforme or gliosarcoma * Recurrent disease with an: * interval of at least 3 months following initial radiotherapy and temozolomide * interval of at least 3 weeks between end of surgery for recurrent disease and start of protocol therapy for patients who have undergone surgery for recurrent disease * KPS 60% or higher * Adequate bone marrow function Women of childbearing potential must have a negative serum beta-HCG pregnancy test documented within 14 days prior to study initiation. * Women of childbearing potential must agree to use two reliable methods of contraception from screening and up to 30 days after discontinuation of study treatment. * Males not naturally or surgically sterile, who have a female partner of childbearing potential, must agree to use two reliable methods of contraception from screening and up to 30 days after discontinuation of study treatment. Exclusion Criteria * Histology other than astrocytoma grade IV (GBM or gliosarcoma) * Tumor foci below the tentorium or or beyond the cranial vault * Glioblastoma or gliosarcoma disease with leptomeningeal spread * Patients with a history of any other cancer, unless in complete remission, and off all therapy for that disease for a minimum of 5 years * Elevated serum aspartate aminotransferase, alanine aminotransferase, or bilirubin (unless there is medical justification for bilirubin elevation, and aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase are normal) * Moderate to severe hepatic impairment * Confirmed systolic blood pressure \< 100 mmHg or diastolic blood pressure \< 50 mmHg * History of orthostatic hypotension * Renal insufficiency or serum creatinine above the normal reference range * Prior chemotherapy for recurrent glioblastoma with nitrosourea compounds or bevacizumab * Prior focal radiotherapy * Severe, active co-morbidity (e.g. cardiac disease; respiratory disease; chronic hepatitis; hematological and bone marrow diseases; severe malabsorption) * No other active cancer * No concurrent cytochrome P450 3A4 inducers * No concurrent strong cytochrome P450 3A4 inhibitors * No other concurrent investigational agents