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

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 The study will end when all patients (excluding those prematurely withdrawn or lost to follow-up) in each part of the study have completed a visit at month 12 and 30 days of safety follow-up.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

Resource links provided by NLM:

Drug Information available for: Temozolomide Macitentan

Genetic and Rare Diseases Information Center resources: Glioblastoma Glioma Neuroepithelioma

U.S. FDA Resources

Further study details as provided by Actelion:

Primary Outcome Measures:

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) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

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. ] [ Designated as safety issue: Yes ]
for all study periods
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. ] [ Designated as safety issue: Yes ]
for all study periods
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. ] [ Designated as safety issue: Yes ]
for all study periods
Number of patients with treatment-emergent ECG abnormalities [ Time Frame: Up to 30 days after discontinuation of macitentan ] [ Designated as safety issue: Yes ]
for all study periods
Change from baseline in vital signs [ Time Frame: Up to 30 days after discontinuation of macitentan ] [ Designated as safety issue: Yes ]
for all study periods: systolic and diastolic blood pressure [supine and standing], average of the two measurements and pulse rate.
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. ] [ Designated as safety issue: Yes ]
for all study periods


Estimated Enrollment:	75
Study Start Date:	January 2012
Study Completion Date:	April 2016
Primary Completion Date:	January 2016 (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 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

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 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

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01499251

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 History of Changes
Other Study ID Numbers:	AC-055-115
Study First Received:	December 20, 2011
Last Updated:	May 4, 2016
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 Macitentan Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Endothelin A Receptor Antagonists Endothelin Receptor Antagonists Endothelin B Receptor Antagonists

ClinicalTrials.gov processed this record on September 28, 2016