Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

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.

Cilengitide

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.

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.

Radiotherapy

Roger Stupp, Prof. Dr.

Andriy Markivskyy, MD

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.

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

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)

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.

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

The Cmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1.

The Tmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1.

The AUC (0-6) for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1.

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.

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.

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).

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).

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.

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.

European Organisation for Research and Treatment of Cancer - EORTC

Merck KGaA, Darmstadt, Germany

EMD Serono

Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77, Temozolomide (TMZ) 75 milligram per square meter \[mg/m\^2\] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m\^2 for consecutive 5 days every 4 weeks until Week 34 and radiotherapy (RTX) at a dose of 2 gray (Gy) per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 will be optional in participants without disease progression, If cilengitide treatment considered beneficial in the opinion of the Investigator,

Cilengitide + Temozolomide + Radiotherapy

TMZ 75 mg/m\^2 administered intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m\^2 for consecutive 5 days every 4 weeks until Week 34 and RTX at a dose of 2 Gy per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason.

Temozolomide + Radiotherapy

Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77, Temozolomide (TMZ) 75 milligram per square meter \[mg/m\^2\] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m\^2 for consecutive 5 days every 4 weeks until Week 34 and radiotherapy (RTX) at a dose of 2 Gray (Gy) per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 was optional in participants without disease progression, If considered beneficial in the opinion of the Investigator.

Total

Age, Continuous

Sex: Female, Male

Intent-to-treat (ITT) population included all the participants who were randomized to study treatment.

Merck KGaA Communication Center

ITT population included all the participants who were randomized to study treatment.

Overall Survival (OS) Time

PFS Time: Investigator read

PFS Time: Independent read

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

Analysis population included all participants of "Cilengitide + Temozolomide + Radiotherapy" group who received at least 1 cilengitide dose with plasma concentration data available on Day 1 of Week -1.

Maximum Observed Plasma Concentration (Cmax)

Time to Maximum Plasma Concentration (Tmax)

Analysis population included all participants of "Cilengitide + Temozolomide + Radiotherapy" group who received at least 1 cilengitide dose with plasma concentration data available on Day 1 of Week -1. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Area Under the Plasma Concentration Curve From Time 0 to 6 Hours (AUC [0-6]) After Dose

Global Health Status (n=71, 92)

Physical Functioning (n=71, 92)

Role Functioning (n=71, 92)

Emotional Functioning (n=71, 93)

Cognitive Functioning (n=70, 93)

Social Activity (n=71, 93)

Fatigue (n=71, 92)

Nausea and Vomiting (n=71, 93)

Pain (n=71, 93)

Dyspnoea (n=71, 92)

Insomnia (n=71, 91)

Appetite Loss (n=71, 92)

Constipation (n=71, 93)

Diarrhoea (n=70, 92)

Financial Difficulties (n=71, 93)

ITT population included all the participants who were randomized to study treatment. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure and 'n' signifies those participants who were evaluable for the specified category.

European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores

Future Uncertainty (n=68, 86)

Visual Disorder (n=68, 85)

Motor Dysfunction (n=68, 86)

Communication Deficit (n=68, 86)

Headaches (n=68, 86)

Seizures (n=68, 87)

Drowsiness (n=66, 87)

Itchy Skin (n=68, 86)

Hair Loss (n=66, 86)

Weakness of Legs (n=67, 85)

Bladder Control (n=67, 85)

European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores

ITT population included all the participants who were randomized to study treatment. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

EuroQol 5-Dimensions (EQ-5D) Questionnaire Index

Baseline: FT, EOS: FT

Baseline: FT, EOS: PT1

Baseline: FT, EOS: PT2

Baseline: FT, EOS: PT3

Baseline: FT, EOS: U/R

Baseline: PT1, EOS: FT

Baseline: PT1, EOS: PT1

Baseline: PT1, EOS: PT2

Baseline: PT1, EOS: PT3

Baseline: PT1, EOS: U/R

Baseline: PT2, EOS: FT

Baseline: PT2, EOS: PT1

Baseline: PT2, EOS: PT2

Baseline: PT2, EOS: PT3

Baseline: PT2, EOS: U/R

Baseline: PT3, EOS: FT

Baseline: PT3, EOS: PT1

Baseline: PT3, EOS: PT2

Baseline: PT3, EOS: PT3

Baseline: PT3, EOS: U/R

Baseline: U/R, EOS: FT

Baseline: U/R, EOS: PT1

Baseline: U/R, EOS: PT2

Baseline: U/R, EOS: PT3

Baseline: U/R, EOS: U/R

Baseline: Missing, EOS: FT

Baseline: Missing, EOS: PT1

Baseline: Missing, EOS: PT2

Baseline: Missing, EOS: PT3

Baseline: Missing, EOS: U/R

Baseline: Missing, EOS: Missing

Safety population included all the participants who received any dose of study treatment that is Cilengitide, Temozolomide or Radiotherapy. According to trial design safety data in trial arms (Cilengitide vs Control) were collected based on different visit frequency and different safety surveillance period.

Number of Participants With Change From Baseline in Work Status at End of Study

Serious AEs

Treatment-related AEs

Treatment-Related Serious AEs

AEs leading to death

Treatment-related AEs leading to death

AEs with NCI-CTC toxicity Grade 3 or 4

Treatment-related AEs of Grade 3 or 4

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

SMQ:Thromboembolic events

SMQ: Hemorrhage

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

Any clinically significant abnormal ECG and lab finding was planned to be reported as AE only so they have been captured in the below mentioned adverse event section.

Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters

Overall Study

Cilengitide (2-times weekly)

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.

cilengitide (5-times weekly)

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.

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.

Louis B. Nabors, Prof. Dr.

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.

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

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]

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

Safety population included all participants who received any dose of study treatment that is Cilengitide, Temozolomide or Radiotherapy. 1 participant who was randomized to cilengitide 5-times weekly, but who actually received Cilengitide 2-times weekly was allocated to the cilengitide 2-times weekly treatment group for the safety population

Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy

Cilengitide 2000 mg 5-times weekly over 1 hour intravenous infusion from Weeks -1 to 77, TMZ 75 mg/m\^2 intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m\^2 for consecutive 5 days every 4 weeks until Week 34 and RTX at a dose of 2 Gy per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 was optional in participants without disease progression, If considered beneficial in the opinion of the Investigator.

Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy

Gender

Day 1 (Single dose)

Day 5 (Repeated doses)

Only "Cilengitide (5-times) + Temozolomide + Radiotherapy" group was analyzed for this outcome measure as per planned analysis. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

Tmax: Day 1 (Single dose)

Tmax: Day 5 (Repeated doses)

t1/2: Day 1 (Single dose)

t1/2: Day 5 (Repeated doses)

Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2)

AUC (0-infinity): Day 1 (Single dose)

AUC (0-infinity): Day 5 (Repeated Doses)

AUC (0-24): Day 1 (Single dose)

AUC (0-24): Day 5 (Repeated doses)

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])

Cpre: Day 1 (Single dose)

Cpre: Day 5 (Repeated doses)

CT: Day 1 (Single dose)

CT: Day 5 (Repeated doses)

Only "Cilengitide (5-times) + Temozolomide + Radiotherapy" group was analyzed for this outcome measure as per planned analysis. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure. One participant had implausible pre-dose concentration.

Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT)

Apparent Terminal Rate Constant

Mean Residence Time From Time 0 to Infinity (MRT [0-infinity])

Plasma Clearance (CL)

Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss)

Treatment-related serious AEs

AEs of Grade 3 or 4

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

SMQ: Thromboembolic events

SMQ:Hemorrhage

Any clinically significant abnormal ECG and lab finding was planned to be reported as AE only so they have been captured in the below mentioned adverse event section

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status	NCT00689221	Glioblastoma	Cilengitide Temozolomide Radiotherapy	18 Years -	EMD Serono
Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status	NCT00813943	Glioblastoma	Cilengitide (2-... cilengitide (5-... Temozolomide Radiotherapy	18 Years -	EMD Serono

Spots Global Cancer Trial Database for newly diagnosed glioblastoma (who grade iv)