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

Study Overview
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Brief Summary
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CENTRIC is a Phase 3 clinical trial assessing efficacy and safety of the investigational integrin inhibitor, cilengitide, in combination with standard treatment versus standard treatment alone in newly diagnosed glioblastoma subjects with a methylated 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 be a predictive marker for benefit from temozolomide (TMZ) treatment.

Official Title
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Cilengitide for Subjects With Newly Diagnosed Glioblastoma and Methylated MGMT Gene Promoter - A Multicenter, Open-label, Controlled Phase III Study, Testing Cilengitide in Combination With Standard Treatment (Temozolomide With Concomitant Radiation Therapy, Followed by Temozolomide Maintenance Therapy) Versus Standard Treatment Alone (CENTRIC)

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Cilengitide
* Drug: Temozolomide
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tumor tissue specimens from the glioblastoma surgery or open biopsy (formalin-fixed, paraffin-embedded block; stereotactic biopsy not allowed) must be available for MGMT status analysis and central pathology review Newly diagnosed histologically proven supratentorial glioblastoma (World Health Organization [WHO] Grade IV) Proven methylated MGMT gene promoter methylation status Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI) performed within less than (<) 48 hours after surgery (in case it was not possible to obtain a Gd-MRI within <48 hours post surgery, a Gd-MRI is to be performed prior to randomization) Stable or decreasing dose of steroids for greater than or equal to (>=) 5 days prior to randomization Eastern Cooperative Oncology Group performance score (ECOG PS) of 0-1 Meets 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) Other protocol defined inclusion criteria could apply Exclusion Criteria: Prior chemotherapy within the last 5 years Prior RTX of the head Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of cilengitide Prior systemic antiangiogenic therapy Placement of Gliadel® wafer at surgery Inability to undergo Gd-MRI. Planned surgery for other diseases History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment 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 History of coagulation disorder associated with bleeding or recurrent thrombotic events Clinically manifest myocardial insufficiency (New York Heart Association [NYHA] III, IV) or history of myocardial infarction during the past 6 months; uncontrolled arterial hypertension Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cilengitide + Temozolomide + Radiotherapy<br> | Drug: Cilengitide<br>* Cilengitide 2000 milligram (mg) will be administered intravenously twice weekly over 1 hour infusion from Weeks -1 to 77 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. If considered beneficial in the opinion of the Investigator, continuation of cilengitide treatment will be optional in subjects without disease progression and after Week 77 since start of treatment.<br>Drug: Temozolomide<br>* Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] will be administered intravenously once daily from Weeks 1 to 6. From Week 11 onwards, TMZ will be given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 or until disease progression.<br>Radiation: Radiotherapy<br>* Radiotherapy (RTX) at a dose of 2 gray (Gy) per fraction will be given once daily, 5 days per week from Weeks 1 to 6, total dose 60 Gy.<br>|
| Active Comparator: Temozolomide + Radiotherapy<br> | Drug: Temozolomide<br>* Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] will be administered intravenously once daily from Weeks 1 to 6. From Week 11 onwards, TMZ will be given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 or until disease progression.<br>Radiation: Radiotherapy<br>* Radiotherapy (RTX) at a dose of 2 gray (Gy) per fraction will be given once daily, 5 days per week from Weeks 1 to 6, total dose 60 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 from randomization to death or last day known to be alive, reported between day of first participant randomized, that is, Sep 2008 until cut-off date, (19 Nov 2012) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 and Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC). Investigator's assessed progression according to MacDonald criteria and IRC by Response Assessment in Neuro-Oncology Working Group (RANO) criteria using Gadolinium-enhanced magnetic resonance imaging. Investigator and IRC read: Progression is defined as greater than 25 percent increase in the sum of the product of the largest perpendicular diameters of enhancing tumor compared to the smallest prior sum, or Worsening of an evaluable lesion(s),or Marked increase in T2/FLAIR non-enhancing lesions (IRC only) or Any new lesion | Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Sep 2008 until cut-off date, (19 Nov 2012) | 
| Maximum Observed Plasma Concentration (Cmax) | The Cmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1. | Day 1 of Week -1 | 
| Time to Maximum Plasma Concentration (Tmax) | The Tmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1. | Day 1 of Week -1 | 
| Area Under the Plasma Concentration Curve From Time 0 to 6 Hours (AUC [0-6]) After Dose | The AUC (0-6) for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1. | Day 1 of Week -1 | 
| European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores | The EORTC QLQ-C30 is a questionnaire including following sub-scales: global health status, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). Scores are averaged for each scale and transformed to 0-100 scale; higher score indicates better quality of life on global health status and functional scales and worse quality of life on symptom scales and financial difficulty scale. | Up to 50 months | 
| European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores | The QLQ-BN20 is a questionnaire specifically designed as the QLQ-C30 supplement for the evaluation of quality of life in brain tumor participants. It includes 4 multi-item sub-scales: future uncertainty, visual disorder, motor dysfunction, communication deficits, and 7 single-item scales: headaches, seizures, drowsiness, itchy skin, hair loss, weakness of legs, and bladder control. All items are rated on a 4-point Likert-type scale ('1=not at all', '2=a little', '3=quite a bit' and '4=very much'), and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms. | Up to 50 months | 
| EuroQol 5-Dimensions (EQ-5D) Questionnaire Index | The EuroQuol-5D (EQ-5D) questionnaire is a measure of health status that provides a simple descriptive profile and a single index value. The optional part of the questionnaire was not applied. The EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 items are combined to generate health profiles. These profiles were converted to a continuous single index score using a one to one matching. The lowest possible score is -0.594 (death) and the highest is 1.00 (full health). | Up to 50 months | 
| Number of Participants With Change From Baseline in Work Status at End of Study | Number of participants with change from baseline in work status (working full time [FT], part-time [PT], unemployed/retired [U/R]) at end of study (EOS) (up to cut-off date, [19 Nov 2012]) was reported. For the category 'part-time', the following sub-categories were defined: part-time due to basic disease (PT1); part-time not due to basic disease (PT2); part-time reason not known (PT3). | Baseline, End of study (up to cut-off date, [19 Nov 2012]) | 
| Number of Participants With Adverse Events (AEs), Serious AEs, Treatment-Related AEs, Treatment-Related Serious AEs, AEs Leading to Death, Treatment Related AEs Leading to Death, AEs of Grade 3 or 4 and Treatment Related AEs of Grade 3 or 4 | An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. Treatment-emergent AEs are the events between first dose of study drug and up to 28 days after last dose of study treatment. A Serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-related AEs are the AEs which are suspected to be reasonably related to the study treatment (cilengitide, or radiotherapy, or temozolomide) as per investigator assessment. The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome. | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Sep 2008 until cut-off date (19 Nov 2012) | 
| Number of Participants With AEs Belonging to Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) Thromboembolic Events and Hemorrhage With NCI-CTC Toxicity Grade 3 or 4 | Thromboembolic events (standardized MedDRA query [SMQ]) Grade 3 or 4 AEs encompassed hemiparesis and cerebrovascular accident, pulmonary embolism, and deep vein thrombosis. Thromboembolic events (SMQ) of any grade and of Grade 3 or 4 were generally more frequent in the Cilengitide + Temozolomide/Radiotherapy group than in the Temozolomide/Radiotherapy group but were still in the expected range of this patient population The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome. | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Sep 2008 until cut-off date (19 Nov 2012) | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters |  | Up to 50 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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newly diagnosed Glioblastoma (WHO Grade IV), Cilengitide, Temozolomide, Radiotherapy