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

• ClinicalTrials.gov Identifier: NCT01499251
• Recruitment Status: Terminated
• First Posted: December 26, 2011
• Last Update Posted: May 5, 2016
• Sponsor: Actelion
• Information provided by (Responsible Party): Actelion

Study Description

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 The study will end when all patients (excluding those prematurely withdrawn or lost to follow-up) in each part of the study have completed a visit at month 12 and 30 days of safety follow-up.

Condition or disease	Intervention/treatment	Phase
Glioblastoma	Drug: Phase 1 Dose Escalation; Drug: Phase 1b; Drug: Ancillary Study	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: January 2012
• Actual Primary Completion Date: January 2016
• Actual Study Completion Date: April 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: Macitentan; Macitentan in combination with dose-dense temozolomide

Drug: Phase 1 Dose Escalation; 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.; Other Names: dose-dense temozolomide; Macitentan; Drug: Phase 1b; 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.; Other Names: Macitentan; dose-dense temozolomide; Drug: Ancillary Study; 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.; Other Names: dose-dense temozolomide; Macitentan

Outcome Measures

Primary Outcome Measures :

1. To 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) ]

Secondary Outcome Measures :

1. Number of patients with treatment-emergent adverse events (AEs) and serious AEs [ Time Frame: Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months. ]
   for all study periods
2. Number of patients with AEs leading to premature discontinuation of study treatment [ Time Frame: Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months. ]
   for all study periods
3. Incidence of treatment-emergent* marked laboratory abnormalities [ Time Frame: Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months. ]
   for all study periods
4. Number of patients with treatment-emergent ECG abnormalities [ Time Frame: Up to 30 days after discontinuation of macitentan ]
   for all study periods
5. Change from baseline in vital signs [ Time Frame: Up to 30 days after discontinuation of macitentan ]
   for all study periods: systolic and diastolic blood pressure [supine and standing], average of the two measurements and pulse rate.
6. Occurrence of at least grade 2 ALT and/or AST elevation [ Time Frame: Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months. ]
   for all study periods

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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
• No other concurrent investigational agents

Contacts and Locations

Locations

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Actelion

More Information

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01499251
• Other Study ID Numbers: AC-055-115
• First Posted: December 26, 2011
• Last Update Posted: May 5, 2016
• Last Verified: May 2016

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; Macitentan; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin B Receptor Antagonists