Glioblastoma
Conditions
Keywords
glioblastoma
Brief summary
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.
Interventions
DRUGMacitentan in combination with RT and TMZ
Escalating doses of macitentan in combination with RT and TMZ, and maintenance TMZ.
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| Plasma concentrations of endothelin-1 | Baseline, Weeks 2, 6, and 10 |
| 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 |
| 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 |
Countries
United States
Outcome results
None listed