Trial Outcomes & Findings for Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status (NCT NCT00689221)

Last Updated: 2014-11-04

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

545 participants

Primary outcome timeframe

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)

Results posted on

2014-11-04

Participant Flow

First/last participant (informed consent): Sep 2008/Aug 2011. Clinical data cut-off: 19 Nov 2012, Study completion date: Aug 2013.

Enrolled: 3471 screened for eligibility; 2926 excluded (mainly due to unmethylated O6-methylguanine-DNA methyltransferase status and non-fulfillment of inclusion or exclusion criteria), 545 participants randomized.

Participant milestones

Participant milestones
Measure	Cilengitide + 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.	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.
Overall Study STARTED	272	273
Overall Study COMPLETED	233	237
Overall Study NOT COMPLETED	39	36

Reasons for withdrawal

Reasons for withdrawal
Measure	Cilengitide + 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.	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.
Overall Study Ongoing at cut-off date	39	36

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cilengitide + Temozolomide + Radiotherapy n=272 Participants 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.	Temozolomide + Radiotherapy n=273 Participants 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.	Total n=545 Participants Total of all reporting groups
Age, Continuous	56.8 years STANDARD_DEVIATION 11.00 • n=5 Participants	56.0 years STANDARD_DEVIATION 10.97 • n=7 Participants	56.4 years STANDARD_DEVIATION 10.98 • n=5 Participants
Sex: Female, Male Female	124 Participants n=5 Participants	130 Participants n=7 Participants	254 Participants n=5 Participants
Sex: Female, Male Male	148 Participants n=5 Participants	143 Participants n=7 Participants	291 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=272 Participants 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.	Temozolomide + Radiotherapy n=273 Participants 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.
Overall Survival (OS) Time	26.3 Months Interval 23.8 to 28.8	26.3 Months Interval 23.9 to 34.7

SECONDARY outcome

Timeframe: 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)

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

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

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=272 Participants 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.	Temozolomide + Radiotherapy n=273 Participants 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.
Progression Free Survival (PFS) Time - Investigator and Independent Read PFS Time: Investigator read	13.5 Months Interval 10.8 to 15.9	10.7 Months Interval 8.1 to 13.3
Progression Free Survival (PFS) Time - Investigator and Independent Read PFS Time: Independent read	10.6 Months Interval 8.2 to 13.4	7.9 Months Interval 5.9 to 12.5

SECONDARY outcome

Timeframe: Day 1 of Week -1

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

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=38 Participants 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.	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.
Maximum Observed Plasma Concentration (Cmax)	167363.2 nanogram per milliliter (ng/mL) Standard Deviation 368301.11	—

SECONDARY outcome

Timeframe: Day 1 of Week -1

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

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=38 Participants 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.	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.
Time to Maximum Plasma Concentration (Tmax)	1.029 hours Standard Deviation 0.401	—

SECONDARY outcome

Timeframe: Day 1 of Week -1

Population: 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.

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

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=37 Participants 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.	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.
Area Under the Plasma Concentration Curve From Time 0 to 6 Hours (AUC [0-6]) After Dose	295171.2 hour*ng/mL Standard Deviation 198050.62	—

SECONDARY outcome

Timeframe: Up to 50 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=71 Participants 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.	Temozolomide + Radiotherapy n=93 Participants 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.
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Dyspnoea (n=71, 92)	15.96 units on a scale Standard Deviation 28.09	13.04 units on a scale Standard Deviation 22.62
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Insomnia (n=71, 91)	20.66 units on a scale Standard Deviation 30.01	20.51 units on a scale Standard Deviation 26.65
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Appetite Loss (n=71, 92)	21.13 units on a scale Standard Deviation 30.47	15.94 units on a scale Standard Deviation 28.59
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Global Health Status (n=71, 92)	54.34 units on a scale Standard Deviation 25.58	55.43 units on a scale Standard Deviation 27.02
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Physical Functioning (n=71, 92)	65.70 units on a scale Standard Deviation 33.01	67.46 units on a scale Standard Deviation 31.19
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Role Functioning (n=71, 92)	56.34 units on a scale Standard Deviation 37.31	56.34 units on a scale Standard Deviation 35.19
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Emotional Functioning (n=71, 93)	67.49 units on a scale Standard Deviation 30.58	67.00 units on a scale Standard Deviation 27.29
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Cognitive Functioning (n=70, 93)	64.05 units on a scale Standard Deviation 29.16	65.41 units on a scale Standard Deviation 31.40
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Social Activity (n=71, 93)	56.34 units on a scale Standard Deviation 36.77	62.72 units on a scale Standard Deviation 35.73
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Fatigue (n=71, 92)	44.37 units on a scale Standard Deviation 33.07	39.73 units on a scale Standard Deviation 29.93
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Nausea and Vomiting (n=71, 93)	10.33 units on a scale Standard Deviation 20.77	7.71 units on a scale Standard Deviation 16.03
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Pain (n=71, 93)	22.30 units on a scale Standard Deviation 29.40	24.37 units on a scale Standard Deviation 28.93
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Constipation (n=71, 93)	18.78 units on a scale Standard Deviation 28.02	13.98 units on a scale Standard Deviation 25.69
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Diarrhoea (n=70, 92)	6.67 units on a scale Standard Deviation 18.48	4.35 units on a scale Standard Deviation 13.28
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Sub-scale Scores Financial Difficulties (n=71, 93)	27.23 units on a scale Standard Deviation 31.53	22.94 units on a scale Standard Deviation 31.46

SECONDARY outcome

Timeframe: Up to 50 months

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.

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=68 Participants 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.	Temozolomide + Radiotherapy n=87 Participants 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.
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Future Uncertainty (n=68, 86)	44.49 units on a scale Standard Deviation 29.70	39.31 units on a scale Standard Deviation 30.24
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Visual Disorder (n=68, 85)	12.99 units on a scale Standard Deviation 20.24	17.78 units on a scale Standard Deviation 23.77
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Motor Dysfunction (n=68, 86)	27.45 units on a scale Standard Deviation 30.62	23.39 units on a scale Standard Deviation 25.95
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Communication Deficit (n=68, 86)	26.14 units on a scale Standard Deviation 28.59	19.96 units on a scale Standard Deviation 27.89
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Headaches (n=68, 86)	25.98 units on a scale Standard Deviation 32.50	21.71 units on a scale Standard Deviation 26.45
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Seizures (n=68, 87)	9.31 units on a scale Standard Deviation 22.93	8.05 units on a scale Standard Deviation 20.94
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Drowsiness (n=66, 87)	38.38 units on a scale Standard Deviation 33.71	35.25 units on a scale Standard Deviation 31.07
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Itchy Skin (n=68, 86)	9.80 units on a scale Standard Deviation 20.00	13.57 units on a scale Standard Deviation 24.72
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Hair Loss (n=66, 86)	13.13 units on a scale Standard Deviation 22.55	15.12 units on a scale Standard Deviation 26.40
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Weakness of Legs (n=67, 85)	24.38 units on a scale Standard Deviation 34.12	20.39 units on a scale Standard Deviation 28.68
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Brain Module (EORTC QLQ-BN20) Sub-scale Scores Bladder Control (n=67, 85)	19.40 units on a scale Standard Deviation 29.67	10.20 units on a scale Standard Deviation 21.22

SECONDARY outcome

Timeframe: Up to 50 months

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).

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=69 Participants 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.	Temozolomide + Radiotherapy n=90 Participants 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.
EuroQol 5-Dimensions (EQ-5D) Questionnaire Index	0.598 units on a scale Standard Deviation 0.43	0.623 units on a scale Standard Deviation 0.36

SECONDARY outcome

Timeframe: Baseline, End of study (up to cut-off date, [19 Nov 2012])

Population: 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 (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).

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=263 Participants 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.	Temozolomide + Radiotherapy n=258 Participants 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.
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: FT, EOS: FT	3 participants	6 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: FT, EOS: PT1	2 participants	1 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: FT, EOS: PT2	1 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: FT, EOS: PT3	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: FT, EOS: U/R	24 participants	22 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT1, EOS: FT	3 participants	2 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT1, EOS: PT1	3 participants	1 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT1, EOS: PT2	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT1, EOS: PT3	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT1, EOS: U/R	9 participants	12 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT2, EOS: FT	0 participants	1 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT2, EOS: PT1	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT2, EOS: PT2	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT2, EOS: PT3	1 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT2, EOS: U/R	5 participants	4 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT3, EOS: FT	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT3, EOS: PT1	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT3, EOS: PT2	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT3, EOS: PT3	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: PT3, EOS: U/R	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: U/R, EOS: FT	5 participants	8 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: U/R, EOS: PT1	5 participants	7 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: U/R, EOS: PT2	1 participants	1 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: U/R, EOS: PT3	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: U/R, EOS: U/R	199 participants	191 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: Missing, EOS: FT	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: Missing, EOS: PT1	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: Missing, EOS: PT2	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: Missing, EOS: PT3	0 participants	0 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: Missing, EOS: U/R	1 participants	1 participants
Number of Participants With Change From Baseline in Work Status at End of Study Baseline: Missing, EOS: Missing	1 participants	1 participants

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=263 Participants 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.	Temozolomide + Radiotherapy n=258 Participants 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.
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 AEs	261 Participants	253 Participants
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 Serious AEs	138 Participants	115 Participants
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 Treatment-related AEs	229 Participants	222 Participants
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 Treatment-Related Serious AEs	55 Participants	47 Participants
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 AEs leading to death	11 Participants	9 Participants
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 Treatment-related AEs leading to death	3 Participants	3 Participants
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 AEs with NCI-CTC toxicity Grade 3 or 4	169 Participants	158 Participants
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 Treatment-related AEs of Grade 3 or 4	100 Participants	101 Participants

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Cilengitide + Temozolomide + Radiotherapy n=263 Participants 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.	Temozolomide + Radiotherapy n=258 Participants 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.
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 SMQ:Thromboembolic events	35 Participants	23 Participants
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 SMQ: Hemorrhage	4 Participants	4 Participants

SECONDARY outcome

Timeframe: Up to 50 months

Population: 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.

Outcome measures

Outcome data not reported

Adverse Events

Cilengitide + Temozolomide + Radiotherapy

Serious events: 138 serious events

Other events: 251 other events

Deaths: 0 deaths

Temozolomide + Radiotherapy

Serious events: 115 serious events

Other events: 240 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Serono, a division of Merck KGaA

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All manuscripts and materials relating to Study shall be submitted to Sponsor at least 60 days prior to submitting/presenting and allow Sponsor 60 days for review. If Sponsor requests, any confidential information shall be removed. In multi-center study, any publication shall not be made before the first multi-center publication; provided, however, that if no multi-center publication is made within 1 year from database lock, then Site may publish individually in accordance with this provision.
Publication restrictions are in place

Restriction type: OTHER