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

NCT01499251 | Terminated Phase 1

• 1 other identifier: AC-055-115
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

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 The study will end when all patients (excluding those prematurely withdrawn or lost to follow-up) in each part of the study have completed a visit at month 12 and 30 days of safety follow-up.

Conditions

Glioblastoma

Keywords

glioblastoma

Outcome Measures

Primary Outcomes (1)

• To determine the maximum tolerated dose of macitentan in combination with dose-dense temozolomide

  Phase I Dose Escalation period (Dose-Limiting Toxicity from Baseline to 28 days for each dose level)

Secondary Outcomes (6)

• Number of patients with treatment-emergent adverse events (AEs) and serious AEs

  Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.

• Number of patients with AEs leading to premature discontinuation of study treatment

  Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.

• Incidence of treatment-emergent* marked laboratory abnormalities

  Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.

• Number of patients with treatment-emergent ECG abnormalities

  Up to 30 days after discontinuation of macitentan

• Change from baseline in vital signs

  Up to 30 days after discontinuation of macitentan

Study Arms (1)

Macitentan

EXPERIMENTAL

Macitentan in combination with dose-dense temozolomide

Drug: Phase 1 Dose Escalation; Drug: Phase 1b; Drug: Ancillary Study

Interventions

Phase 1 Dose Escalation DRUG

Macitentan 30, 60, 90 mg or higher in 30 mg dose increments, given orally, up to 150 mg, then 225 mg, 300 mg and 375 mg, unless otherwise decided by the Safety Monitoring Committee. Dose-dense temozolomide 150 mg/m2 body surface area alternating 1 week on 1 week off.

Also known as: dose-dense temozolomide, Macitentan

Macitentan

Phase 1b DRUG

Macitentan given orally and daily at doses/schedule determined from the dose escalation period. Dose-dense temozolomide 150mg/m2 body surface area alternating 1 week on 1 week off.

Also known as: Macitentan, dose-dense temozolomide

Macitentan

Ancillary Study DRUG

Macitentan dosed initially 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 150 mg/m2 body surface area alternating 1 week on 1 week off.

Also known as: dose-dense temozolomide, Macitentan

Macitentan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Actelion: lead

Study Sites (1)

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Weathers SP, Rood-Breithaupt J, de Groot J, Thomas G, Manfrini M, Penas-Prado M, Puduvalli VK, Zwingelstein C, Yung WKA. Results of a phase I trial to assess the safety of macitentan in combination with temozolomide for the treatment of recurrent glioblastoma. Neurooncol Adv. 2021 Oct 2;3(1):vdab141. doi: 10.1093/noajnl/vdab141. eCollection 2021 Jan-Dec.

  PMID: 34693288 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

macitentan

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2011
• First Posted: December 26, 2011
• Study Start: January 1, 2012
• Primary Completion: January 1, 2016
• Study Completion: April 1, 2016
• Last Updated: May 5, 2016

Record last verified: 2016-05

Locations

US (1)