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

Phase 1TerminatedNCT02254954

Actelion30 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Glioblastoma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

Time frame: Start of treatment to week 10

Secondary Outcomes

Plasma concentrations of endothelin-1

Time frame: Baseline, Weeks 2, 6, and 10

Plasma concentrations of macitentan and its metabolite

Time frame: 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

Time frame: Week 4

Peak plasma concentration (Cmax) of macitentan during one dosing interval for subjects treated with doses of macitentan 150 mg or higher

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: Starting from first dose of concurrent therapy (i.e., macitentan, TMZ, RT) until the end of treatment plus 30 days of follow-up

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes