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

Primary Purpose

Glioblastoma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Phase 1 Dose Escalation
Phase 1b
Ancillary Study
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring glioblastoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Macitentan

Arm Description

Macitentan in combination with dose-dense temozolomide

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Number of patients with treatment-emergent adverse events (AEs) and serious AEs
for all study periods
Number of patients with AEs leading to premature discontinuation of study treatment
for all study periods
Incidence of treatment-emergent* marked laboratory abnormalities
for all study periods
Number of patients with treatment-emergent ECG abnormalities
for all study periods
Change from baseline in vital signs
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
for all study periods

Full Information

First Posted
December 20, 2011
Last Updated
May 4, 2016
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT01499251
Brief Title
Clinical Study on the Safety and Tolerability of Macitentan in Combination With Dose-dense Temozolomide in Patients With Recurrent Glioblastoma
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 Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Terminated
Why Stopped
Results did not clearly support continuing development in recurrent GBM
Study Start Date
January 2012 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Actelion

4. Oversight

Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma
Keywords
glioblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Macitentan
Arm Type
Experimental
Arm Description
Macitentan in combination with dose-dense temozolomide
Intervention Type
Drug
Intervention Name(s)
Phase 1 Dose Escalation
Other Intervention Name(s)
dose-dense temozolomide, Macitentan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Phase 1b
Other Intervention Name(s)
Macitentan, dose-dense temozolomide
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ancillary Study
Other Intervention Name(s)
dose-dense temozolomide, Macitentan
Intervention Description
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.
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Number of patients with treatment-emergent adverse events (AEs) and serious AEs
Description
for all study periods
Time Frame
Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.
Title
Number of patients with AEs leading to premature discontinuation of study treatment
Description
for all study periods
Time Frame
Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.
Title
Incidence of treatment-emergent* marked laboratory abnormalities
Description
for all study periods
Time Frame
Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.
Title
Number of patients with treatment-emergent ECG abnormalities
Description
for all study periods
Time Frame
Up to 30 days after discontinuation of macitentan
Title
Change from baseline in vital signs
Description
for all study periods: systolic and diastolic blood pressure [supine and standing], average of the two measurements and pulse rate.
Time Frame
Up to 30 days after discontinuation of macitentan
Title
Occurrence of at least grade 2 ALT and/or AST elevation
Description
for all study periods
Time Frame
Participants will be followed up for the duration of combination treatment, an expected average of 9-12 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Facility Information:
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34693288
Citation
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.
Results Reference
derived

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

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