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

A Phase 1/1b, Open-label Study in Patients With Recurrent Glioblastoma to Assess the Safety and Tolerability of Macitentan in Combination With Dose-dense Temozolomide

This is an open-label, single arm, Phase 1 study to assess the safety and tolerability of macitentan in combination with dose-dense temozolomide in adult patients with recurrent glioblastoma or gliosarcoma. The study is composed of three parts. A Phase 1 Dose Escalation Period with a traditional 3+3 design will determine the maximum tolerated dose of macitentan in combination with dose-dense temozolomide. A Phase 1b Period will expand the safety and tolerability data of two doses of macitentan and dose-dense temozolomide selected from the Dose Escalation Period and explore efficacy. An Ancillary Study will further evaluate the effects of macitentan on biomarkers in brain tumor tissue.

The study is planned to have a minimum duration of 12 months. The study will end when all patients (excluding those prematurely withdrawn or lost to follow-up) in each part of the study have completed a visit at month 12 and 30 days of safety follow-up.

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