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

Study Overview
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Brief Summary
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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.

Official Title
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Cilengitide in Subjects With Newly Diagnosed Glioblastoma and Unmethylated MGMT Gene Promoter - a Multicenter, Open-label Phase II Study, Investigating Two Cilengitide Regimens in Combination With Standard Treatment (Temozolomide With Concomitant Radiation Therapy, Followed by Temozolomide Maintenance Therapy). [The CORE Study]

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Cilengitide (2-times weekly)
* Drug: cilengitide (5-times weekly)
* Drug: Temozolomide
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) 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 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) Males or females greater than or equal to (>=) 18 years of age Interval of >= 2 weeks but less than or equal to (=<) 7 weeks after surgery or biopsy before first administration of study treatment Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI) performed within < 48 hours after surgery Stable or decreasing dose of steroids for >= 5 days prior to randomization Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 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) Other protocol defined inclusion criteria could apply Exclusion Criteria: Prior chemotherapy within the last 5 years Prior RTX of the head (except for low dose RTX for tinea capitis) Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of cilengitide Prior systemic anti-angiogenic therapy Placement of Gliadel® wafer at surgery 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; or uncontrolled arterial hypertension Inability to undergo Gd-MRI 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 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 Current alcohol dependence or drug abuse Known hypersensitivity to the study treatment Legal incapacity or limited legal capacity Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such 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 (2-times weekly) + Temozolomide + Radiotherapy<br> | Drug: Cilengitide (2-times weekly)<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 Week 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>* Radiation therapy (RTX) at a dose of 2 gray (Gy) per fraction will be given once daily, 5 days per week from Week 1 to 6, total dose 60 Gy.<br>|
| Experimental: Cilengitide (5-times weekly) + Temozolomide + Radiotherapy<br> | Drug: cilengitide (5-times weekly)<br>* Cilengitide 2000 milligram (mg) will be administered intravenously 5-times 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 Week 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>* Radiation therapy (RTX) at a dose of 2 gray (Gy) per fraction will be given once daily, 5 days per week from Week 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 Week 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>* Radiation therapy (RTX) at a dose of 2 gray (Gy) per fraction will be given once daily, 5 days per week from Week 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, Jun 2009 until cut-off date, (07 Feb 2013) | 

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. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC). | 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. | Days 1 and 5 of Week 1 | 
| Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) | The Tmax and t1/2 for cilengitide were 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. | Days 1 and 5 of Week 1 | 
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) and Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) | The AUC (0-infinity) and AUC (0-24) for cilengitide were 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. | Days 1 and 5 of Week 1 | 
| Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) | The Cpre and CT for cilengitide were 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. | Days 1 and 5 of Week 1 | 
| Apparent Terminal Rate Constant | The apparent terminal rate constant 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. | Days 1 and 5 of Week 1 | 
| Mean Residence Time From Time 0 to Infinity (MRT [0-infinity]) | The MRT (0-infinity) 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. | Days 1 and 5 of Week 1 | 
| Plasma Clearance (CL) | The CL 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. | Days 1 and 5 of Week 1 | 
| Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss) | The Vz (after single dose) and Vss (after repeated doses) for cilengitide were 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. | Days 1 and 5 of Week 1 | 
| 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, Jun 2009 until cut-off date (07 Feb 2013) | 
| 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, Jun 2009 until cut-off date (07 Feb 2013) | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters |  | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) | 

 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