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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Macitentan in combination with RT and TMZ


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Macitentan in combination with RT & TMZ<br>Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ. | Drug: Macitentan in combination with RT and TMZ<br>* Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ.<br>* Other names: Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with dose-limiting toxicities observed during the first 10 weeks of study treatment (i.e., 6 weeks of concurrent therapy with macitentan, RT and TMZ and 4 weeks of monotherapy with macitentan). |  | Start of treatment to week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of endothelin-1 |  | Baseline, Weeks 2, 6, and 10 | 
| Plasma concentrations of macitentan and its metabolite |  | Baseline, Weeks 2 and 6 | 
| Area under the plasma concentration-time curve (AUCτ) for macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher |  | Week 4 | 
| Peak plasma concentration (Cmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher |  | Week 4 | 
| Time to reach peak plasma concentration (Tmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher |  | Week 4 | 
| Number of adverse events (per Common Terminology Criteria for Adverse Events [CTCAE] criteria, version 4.03]) leading to premature discontinuation of study treatment |  | Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up | 
| Number of subjects with marked laboratory abnormalities or abnormal electrocardiogram (ECG) findings |  | Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up | 
| Change from baseline in pulse rate, systolic & diastolic blood pressure |  | Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days follow-up | 
| Exploratory efficacy endpoint of proportion of subjects with progression free survival (PFS) at 6 and 12 months |  | 6 and 12 months after the start of treatment | 
| Number of adverse events (per CTCAE] criteria, version 4.03]) as a measure of safety and tolerability. |  | Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioblastoma