Macitentan in Combo With Dose-dense Temozolomide in Patients With Recurrent Glioblastoma
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Purpose
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 on the recommended macitentan and dose-dense temozolomide dosing schedule derived 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 The study will end when all patients (excluding those prematurely withdrawn or lost to follow-up) in each part of the study have completed a visit at month 12.
| Condition | Intervention | Phase |
|---|---|---|
|
Glioblastoma |
Drug: Phase 1 Dose Escalation Drug: Phase 1b Drug: Ancillary Study |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | 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 |
- determine the maximum tolerated dose of macitentan in combination with dose-dense temozolomide [ Time Frame: Phase I Dose Escalation period (Dose-Limiting Toxicity from Baseline to 28 days for each dose level) ] [ Designated as safety issue: Yes ]
- number of patients with premature treatment discontinuation, proportion of patients with PFS at 6 months and other measures [ Time Frame: participants will be followed up for the duration of combination treatment, an expected average of 9-12 months. ] [ Designated as safety issue: Yes ]Number of participants with Adverse Events leading to premature treatment discontinuation, number of patients with marked laboratory abnormalities, change from baseline in systolic & diastolic blood pressure and heart rate on a monthly basis until end of combination treatment. Exploratory Efficacy endpoint of proportion of patients with PFS at 6 months
| Estimated Enrollment: | 48 |
| Study Start Date: | December 2011 |
| Estimated Study Completion Date: | December 2014 |
| Estimated Primary Completion Date: | August 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Macitentan
Macitentan in combination with dose-dense temozolomide
|
Drug: Phase 1 Dose Escalation
macitentan 30, 60, 90 mg or higher in 30mg dose increments, not exceeding 150mg. Dose-dense temozolomide 150mg/m2 body surface area alternating 1 week on 1 week off. Other Names:
Drug: Phase 1b
macitentan given orally and daily at dose/schedule determined from the dose escalation period. dose-dense temozolomide 150mg/m2 body surface area alternating 1 week on 1 week off. Other Names:
Drug: Ancillary Study
macitentan dosed initally for 8-14 days prior to craniotomy, then treatment interrupted from time of craniotomy until 7 days before start of dose dense temozolomide therapy. dose-dense temozolomide 150mg/m2 body surface area alternating 1 week on 1 week off. Other Names:
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria
- Patients at least 18 years of age
- 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 (if applicable)
- KPS 60% or higher
- Adequate bone marrow function
Exclusion Criteria
- Histology other than astrocytoma grade IV or gliosarcoma
- Tumor foci below the tentorium or cranial vault
- Glioblastoma or gliosarcoma disease with leptomeningeal spread
- Elevated serum aspartate aminotransferase, alanine aminotransferase, or bilirubin
- Moderate to severe hepatic impairment
- Confirmed systolic blood pressure < 100 mmHg or diastolic blood pressure < 50 mmHg
- History of orthostatic hypotension
- Renal insufficiency
- 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
Contacts and Locations More Information
No publications provided
| Responsible Party: | Actelion |
| ClinicalTrials.gov Identifier: | NCT01499251 History of Changes |
| Other Study ID Numbers: | AC-055-115 |
| Study First Received: | December 20, 2011 |
| Last Updated: | June 27, 2012 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by Actelion:
|
glioblastoma |
Additional relevant MeSH terms:
|
Glioblastoma Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial |
Neoplasms, Nerve Tissue Temozolomide Dacarbazine Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses |
ClinicalTrials.gov processed this record on May 16, 2013