Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status

EMD Serono265 enrolled

Overview

CORE is a Phase 2 clinical trial in newly diagnosed glioblastoma in subjects with an unmethylated O6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) gene promoter in the tumor tissue. The MGMT gene promoter is a section of deoxyribonucleic acid (DNA) that acts as a controlling element in the expression of MGMT. Methylation of the MGMT gene promoter has been found to appear to be a predictive marker for benefit from temozolomide (TMZ) treatment. In a safety run-in period in dedicated study centers, the safety and tolerability of Cilengitide given as an intense treatment in combination with the first part of standard therapy will be assessed. Thereafter the trial will investigate the overall survival and progression-free survival in subjects receiving two different regimens of Cilengitide in combination with standard treatment versus standard treatment alone.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

265

Conditions

Glioblastoma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Newly diagnosed histologically proven supratentorial glioblastoma (World Health Organization \[WHO\] Grade IV, including glioblastoma subtypes, for example, gliosarcoma). The histological diagnosis has to be obtained from a neurosurgical resection of the tumor or by an open biopsy (stereotactic biopsy is not allowed) 2. Tumor tissue specimens from the glioblastoma surgery or open biopsy (formalin-fixed paraffin-embedded) must be available for MGMT gene promoter status analysis and central pathology review 3. Proven unmethylated MGMT gene promoter status (that is, cut-off ratio less than (\<) 2 by means of applied test to determine MGMT gene promoter status) 4. Males or females greater than or equal to (\>=) 18 years of age 5. Interval of \>= 2 weeks but less than or equal to (=\<) 7 weeks after surgery or biopsy before first administration of study treatment 6. Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI) performed within \< 48 hours after surgery 7. Stable or decreasing dose of steroids for \>= 5 days prior to randomization 8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 9. Has to meet 1 of the following recursive partitioning analysis (RPA) classifications: * Class III (Age \< 50 years and ECOG PS 0) * Class IV (meeting one of the following criteria: a) Age \< 50 years and ECOG PS 1 or b) Age \>= 50 years, underwent prior partial or total tumor resection, Mini Mental State Examination \[MMSE\] \>= 27) * Class V (meeting one of the following criteria: a) Age \>= 50 years and underwent prior partial or total tumor resection, MMSE \< 27 or b) Age \>= 50 years and underwent prior tumor biopsy only) 10. Other protocol defined inclusion criteria could apply Exclusion Criteria: 1. Prior chemotherapy within the last 5 years 2. Prior RTX of the head (except for low dose RTX for tinea capitis) 3. Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of cilengitide 4. Prior systemic anti-angiogenic therapy 5. Placement of Gliadel® wafer at surgery 6. Planned surgery for other diseases 7. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment 8. History of malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for \>= 5 years are eligible for this study 9. History of coagulation disorder associated with bleeding or recurrent thrombotic events 10. Clinically manifest myocardial insufficiency (New York Heart Association \[NYHA\] III, IV) or history of myocardial infarction during the past 6 months; or uncontrolled arterial hypertension 11. Inability to undergo Gd-MRI 12. Concurrent illness, including severe infection (for example, human immunodeficiency virus), which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety 13. Subject is pregnant (positive serum beta human chorionic gonadotropin \[b-HCG\] test at screening) or is currently breast-feeding, anticipates becoming pregnant/impregnating their partner during the study or within 6 months after study participation, or subject does not agree to follow acceptable methods of birth control, such as hormonal contraception, intra-uterine pessar, condoms or sterilization, to avoid conception during the study and for at least 6 months after receiving the last dose of study treatment 14. Current alcohol dependence or drug abuse 15. Known hypersensitivity to the study treatment 16. Legal incapacity or limited legal capacity 17. Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule 18. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such 19. Other protocol defined exclusion criteria could apply

Outcomes

Primary Outcomes

Overall Survival (OS) Time

The OS time is defined as the time (in months) from randomization to death or last day known to be alive. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.

Time frame: Time from randomization to death or last day known to be alive, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013)

Secondary Outcomes

Progression Free Survival (PFS) Time - Investigator and Independent Read

The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read is the assessment of all imaging by the treating physician at the local trial site. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC).

Time frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013)

Maximum Observed Plasma Concentration (Cmax)

The Cmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.