Glioblastoma Multiforme
Conditions
Keywords
Brain cancer, Brain tumor
Brief summary
This study will investigate clinical activity, safety, and tolerability of the anti-angiogenic compound cilengitide (EMD 121974) in the treatment of first recurrence of glioblastoma multiforme (GBM).
Interventions
DRUGCilengitide 500 mg
Subjects will receive 1-hour intravenous infusion of 500 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
DRUGCilengitide 2000 mg
Subjects will receive 1-hour intravenous infusion of 2000 mg cilengitide twice weekly on Day 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent.
Sponsors
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent obtained before undergoing any study-related activities. * Males or females 18 years of age or older who can be treated in an outpatient setting. * Histologically proven GBM, which is recurrent or progressive following surgery or biopsy, external beam radiation therapy, and 1 previous regimen of systemic chemotherapy (Gliadel wafer therapy is not considered systemic chemotherapy). Malignancy is to be documented with a previous histopathological report. * Subjects initially diagnosed with other conditions similar to GBM (such as anaplastic astrocytoma \[AA\] or low grade glioma) that subsequently progressed to histologically proven GBM and have had surgery or biopsy, external beam radiation therapy, and 1 previous regimen of systemic chemotherapy for the original diagnosis are eligible if they meet all inclusion criteria. * GBM recurring only in the contralateral hemisphere must be histologically confirmed by biopsy. GBM recurring bilaterally does not need to be histologically confirmed by biopsy (i.e., if recurrence is ipsilateral and contralateral). * Archived tumor tissue specimens from the GBM surgery or biopsy must be available for central pathology review and exploratory analysis of angiogenic markers (e.g. αvβ3 and αvβ5 integrins). * Measurable disease (solid contrast-enhancing lesion greater than or equal to (\>=)1 cm in any dimension) evaluated by gadolinium-enhanced magnetic resonance imaging (Gd MRI) within 2 weeks prior to the first dose of EMD 121974. * At least 12 weeks have elapsed since the last radiation treatment, and at least 4 weeks have elapsed since the last chemotherapy dose (at least 6 weeks for nitrosourea-containing chemotherapy) prior to the first dose of EMD 121974. * If the subject underwent recent surgery, status must be \>=2 weeks post surgery or \>=1 week post biopsy, in stable condition, and maintained on a stable corticosteroid regimen for \>=5 days prior to first dose of EMD 121974. * Karnofsky Performance Score (KPS) of \>=70%. * Subjects with the potential for pregnancy or impregnating their partner must agree to follow acceptable methods of birth control to avoid conception during the study and for at least 6 months after receiving the last dose of study drug. * Women of childbearing potential must have a negative pregnancy test at screening. * Laboratory values (within 1 week prior to the first dose of EMD 121974, except for blood count and Prothrombin time (PT)/Partial thromboplastin time (PTT), which are to be within 72 hours of the first dose): Absolute neutrophil count \>=1500/millimeter (mm)\^3. Platelets \>=100,000/mm\^3. Creatinine less than or equal to (\<=) 1.5 milligram/deciliter (mg/dL) or creatinine clearance \>=60 mL/min. Hematocrit \>=30%. Prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits. Hemoglobin \>=10 mg/dL. Total bilirubin \<=1.5 times the upper limit of normal. Aspartate aminotransferase and alanine aminotransferase \<=2.5 times above upper limit of normal. * No more than 8 weeks have elapsed since recurrence was detected
Exclusion criteria
* Prior radiation therapy greater than (\>) 66 Gray. * Subject anticipates undergoing elective surgery, dental extraction, or invasive dental procedures. * History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment. * History of prior 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. * Concurrent illness, including severe infection, which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety. * Subject is pregnant, anticipates becoming pregnant within 6 months after study participation, or is currently breast-feeding. * Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of EMD 121974. * Prior antiangiogenic therapy. * Placement of Gliadel wafer at surgery for recurrence. * Unable to undergo Gd MRI. * Current known alcohol dependence or drug abuse. * Requiring concomitant chemotherapy. * Treatment with a prohibited concomitant medication. * Known hypersensitivity to the study treatment. * Legal incapacity or limited legal capacity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Progression-free Survival | Month 6 | Progression-free survival was defined as subjects who survived greater than or equal to (\>=) 180 days without disease progression. Disease progression was assessed as per independent central blinded radiology assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Residence Time of Drug in the Body (MRT) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | MRT is defined as the mean duration of time a drug molecule is present in the systemic circulation. |
| Percentage of Subjects With Overall Response Rate | From the start of treatment up to 6 years | Overall response rate was defined as percentage of subjects who had best response during the study which was either complete response (CR: disappearance of all tumors, no new lesions and stable or improved neurological examination) or partial response (PR: \>= reduction in the sum of the products of the largest perpendicular diameters compared to the baseline sum, no worsening of evaluable lesion and stable or improved neurological examination). CR or PR was confirmed within 31 days with a repeat neuroimaging. |
| Time to Disease Progression | From the start of treatment until disease progression (assessed up to a maximum of 6 years) | Time to disease progression was defined as the number of days between the first dose and the date of first assessment of progressive disease during the study or until death. Surviving subjects without progressive disease were censored at the time of the last visit and the subject was known to be non-progressing. Disease progression was assessed as per independent central blinded radiology assessment. |
| Overall Survival Time | From the start of treatment until death (assessed up to a maximum of 6 years) | Survival time was defined as the number of months between the date of randomization and the date of death or the last date the subject was known to be alive. |
| Percentage of Subjects With 1-year of Survival Rate | From the start of treatment up to 1 year | 1-year survival rate was defined as percentage of subjects who survived for \>=365 days with or without disease progression. Disease progression was assessed as per independent central blinded radiology assessment. |
| Maximum Observed Plasma Concentration (Cmax) | Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2 | Cmax is the maximum observed plasma concentration of cilengitide after administration. |
| Terminal Half-life (t1/2) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | The t1/2 is the time taken to eliminate half the amount of cilengitide. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | AUC 0-infinity is the area under the curve for the plot showing plasma concentration against time from time zero to the time of the last quantifiable concentration of cilengitide. |
| Apparent Terminal Rate Constant (Lambda z) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. |
| Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as dose divided by AUC0-infinity. |
| Apparent Volume of Distribution During the Terminal Phase (Vz) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | Vz was calculated as Dose/(AUC0-infinity multiplied by elimination rate constant \[lambda z\]) following single dose. |
| Apparent Volume of Distribution at Steady State (Vss) | Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2 | Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state. |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the start of treatment up to 6 years | An AE was any untoward medical occurrence in a subject which did not necessarily have a causal relationship with the study drug. A TEAE was any AE that started on or any time after the day of first dose of cilengitide during the treatment phase or within the safety follow-up after last dose of cilengitide. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly. |
| Time to Reach Maximum Plasma Concentration (Tmax) | Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2 | Tmax is the time to reach the maximum plasma concentration (Cmax) of cilengitide. |
Countries
United States
Participant flow
Recruitment details
First/Last subject in: 13 October 2004/28 October 2005. Data analysis cut-off: 21 October 2010
Participants by arm
| Arm | Count |
|---|---|
| Cilengitide 500 Milligrams (mg) Subjects received a 1-hour intravenous (i.v.) infusion of 500 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. | 41 |
| Cilengitide 2000 mg Subjects received a 1-hour intravenous (i.v.) infusion of 2000 mg cilengitide twice weekly on Days 1 and 4 of each week during every 4-week cycle, for a total of 8 infusions per cycle. Cycles were repeated without pause until progressive disease (PD), unacceptable adverse events (AEs), or withdrawal of consent. | 40 |
| Total | 81 |
Baseline characteristics
| Characteristic | Cilengitide 500 Milligrams (mg) | Cilengitide 2000 mg | Total |
|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 12.11 | 54.6 years STANDARD_DEVIATION 11.4 | 53.8 years STANDARD_DEVIATION 11.59 |
| Sex: Female, Male Female | 18 Participants | 12 Participants | 30 Participants |
| Sex: Female, Male Male | 23 Participants | 28 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 41 | 39 / 40 |
| serious Total, serious adverse events | 16 / 41 | 18 / 40 |
Outcome results
Primary
Percentage of Subjects With Progression-free Survival
Progression-free survival was defined as subjects who survived greater than or equal to (\>=) 180 days without disease progression. Disease progression was assessed as per independent central blinded radiology assessment.
Time frame: Month 6
Population: The intention-to-treat (ITT) population included all randomized subjects who had received at least 1 intravenous administration of cilengitide. Here,Number of participants analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilengitide 500 Milligrams (mg) | Percentage of Subjects With Progression-free Survival | 7.5 percentage of subjects |
| Cilengitide 2000 mg | Percentage of Subjects With Progression-free Survival | 15.0 percentage of subjects |
Secondary
Apparent Terminal Rate Constant (Lambda z)
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Apparent Terminal Rate Constant (Lambda z) | Cycle 1 | 0.320 Per hour (/h) | Standard Deviation 0.08 |
| Cilengitide 500 Milligrams (mg) | Apparent Terminal Rate Constant (Lambda z) | Cycle 2 | 0.325 Per hour (/h) | Standard Deviation 0.107 |
| Cilengitide 2000 mg | Apparent Terminal Rate Constant (Lambda z) | Cycle 1 | 0.204 Per hour (/h) | Standard Deviation 0.01 |
| Cilengitide 2000 mg | Apparent Terminal Rate Constant (Lambda z) | Cycle 2 | 0.211 Per hour (/h) | Standard Deviation 0.008 |
Secondary
Apparent Volume of Distribution at Steady State (Vss)
Vss is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2
Population: The PK population included the subjects who had received cilengitide and who had blood samples drawn in Week 1 and/or 5 that provided drug concentration for non-compartmental PK evaluation. Here, Number of participants analysed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Apparent Volume of Distribution at Steady State (Vss) | Cycle 1 | 17.4 Liter (L) | Standard Deviation 7.8 |
| Cilengitide 500 Milligrams (mg) | Apparent Volume of Distribution at Steady State (Vss) | Cycle 2 | 19.3 Liter (L) | Standard Deviation 8.3 |
| Cilengitide 2000 mg | Apparent Volume of Distribution at Steady State (Vss) | Cycle 1 | 23.3 Liter (L) | Standard Deviation 4.1 |
| Cilengitide 2000 mg | Apparent Volume of Distribution at Steady State (Vss) | Cycle 2 | 15.9 Liter (L) | Standard Deviation 0.9 |
Secondary
Apparent Volume of Distribution During the Terminal Phase (Vz)
Vz was calculated as Dose/(AUC0-infinity multiplied by elimination rate constant \[lambda z\]) following single dose.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The PK population included the subjects who had received cilengitide and who had had blood samples drawn in Week 1 and/or 5 that provided drug concentration for non-compartmental PK evaluation. Here, Number of participants analysed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Apparent Volume of Distribution During the Terminal Phase (Vz) | Cycle 1 | 20.3 Liter (L) | Standard Deviation 8.9 |
| Cilengitide 500 Milligrams (mg) | Apparent Volume of Distribution During the Terminal Phase (Vz) | Cycle 2 | 21.0 Liter (L) | Standard Deviation 6.8 |
| Cilengitide 2000 mg | Apparent Volume of Distribution During the Terminal Phase (Vz) | Cycle 2 | 22.1 Liter (L) | Standard Deviation 1.2 |
| Cilengitide 2000 mg | Apparent Volume of Distribution During the Terminal Phase (Vz) | Cycle 1 | 28.9 Liter (L) | Standard Deviation 5.5 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity)
AUC 0-infinity is the area under the curve for the plot showing plasma concentration against time from time zero to the time of the last quantifiable concentration of cilengitide.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity) | Cycle 1 | 92.7 Microgram per milliliter*hour (mcg/mL*h) | Standard Deviation 60.4 |
| Cilengitide 500 Milligrams (mg) | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity) | Cycle 2 | 84.6 Microgram per milliliter*hour (mcg/mL*h) | Standard Deviation 33.2 |
| Cilengitide 2000 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity) | Cycle 1 | 346.5 Microgram per milliliter*hour (mcg/mL*h) | Standard Deviation 50.3 |
| Cilengitide 2000 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity) | Cycle 2 | 429.3 Microgram per milliliter*hour (mcg/mL*h) | Standard Deviation 27.4 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
Cmax is the maximum observed plasma concentration of cilengitide after administration.
Time frame: Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2
Population: The pharmacokinetic (PK) population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 | 40.4 microgram per milliliter (mcg/mL) | Standard Deviation 24.4 |
| Cilengitide 500 Milligrams (mg) | Maximum Observed Plasma Concentration (Cmax) | Cycle 2 | 35.4 microgram per milliliter (mcg/mL) | Standard Deviation 20.6 |
| Cilengitide 2000 mg | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 | 105.7 microgram per milliliter (mcg/mL) | Standard Deviation 14.1 |
| Cilengitide 2000 mg | Maximum Observed Plasma Concentration (Cmax) | Cycle 2 | 169.7 microgram per milliliter (mcg/mL) | Standard Deviation 20.7 |
Secondary
Mean Residence Time of Drug in the Body (MRT)
MRT is defined as the mean duration of time a drug molecule is present in the systemic circulation.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The pharmacokinetic (PK) population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Mean Residence Time of Drug in the Body (MRT) | Cycle 1 | 2.76 Hour (h) | Standard Deviation 0.66 |
| Cilengitide 500 Milligrams (mg) | Mean Residence Time of Drug in the Body (MRT) | Cycle 2 | 2.92 Hour (h) | Standard Deviation 0.74 |
| Cilengitide 2000 mg | Mean Residence Time of Drug in the Body (MRT) | Cycle 1 | 3.98 Hour (h) | Standard Deviation 0.25 |
| Cilengitide 2000 mg | Mean Residence Time of Drug in the Body (MRT) | Cycle 2 | 3.42 Hour (h) | Standard Deviation 0.18 |
Secondary
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a subject which did not necessarily have a causal relationship with the study drug. A TEAE was any AE that started on or any time after the day of first dose of cilengitide during the treatment phase or within the safety follow-up after last dose of cilengitide. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly.
Time frame: From the start of treatment up to 6 years
Population: The safety population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 41 subjects |
| Cilengitide 500 Milligrams (mg) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 16 subjects |
| Cilengitide 2000 mg | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 39 subjects |
| Cilengitide 2000 mg | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 18 subjects |
Secondary
Overall Survival Time
Survival time was defined as the number of months between the date of randomization and the date of death or the last date the subject was known to be alive.
Time frame: From the start of treatment until death (assessed up to a maximum of 6 years)
Population: ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide 500 Milligrams (mg) | Overall Survival Time | 6.54 months |
| Cilengitide 2000 mg | Overall Survival Time | 9.91 months |
Secondary
Percentage of Subjects With 1-year of Survival Rate
1-year survival rate was defined as percentage of subjects who survived for \>=365 days with or without disease progression. Disease progression was assessed as per independent central blinded radiology assessment.
Time frame: From the start of treatment up to 1 year
Population: ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilengitide 500 Milligrams (mg) | Percentage of Subjects With 1-year of Survival Rate | 22.0 percentage of subjects |
| Cilengitide 2000 mg | Percentage of Subjects With 1-year of Survival Rate | 37.5 percentage of subjects |
Secondary
Percentage of Subjects With Overall Response Rate
Overall response rate was defined as percentage of subjects who had best response during the study which was either complete response (CR: disappearance of all tumors, no new lesions and stable or improved neurological examination) or partial response (PR: \>= reduction in the sum of the products of the largest perpendicular diameters compared to the baseline sum, no worsening of evaluable lesion and stable or improved neurological examination). CR or PR was confirmed within 31 days with a repeat neuroimaging.
Time frame: From the start of treatment up to 6 years
Population: ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide. Here,Number of participants analysed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilengitide 500 Milligrams (mg) | Percentage of Subjects With Overall Response Rate | 5.0 percentage of subjects |
| Cilengitide 2000 mg | Percentage of Subjects With Overall Response Rate | 12.5 percentage of subjects |
Secondary
Terminal Half-life (t1/2)
The t1/2 is the time taken to eliminate half the amount of cilengitide.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Terminal Half-life (t1/2) | Cycle 1 | 2.24 Hour (h) |
| Cilengitide 500 Milligrams (mg) | Terminal Half-life (t1/2) | Cycle 2 | 2.04 Hour (h) |
| Cilengitide 2000 mg | Terminal Half-life (t1/2) | Cycle 1 | 3.38 Hour (h) |
| Cilengitide 2000 mg | Terminal Half-life (t1/2) | Cycle 2 | 3.21 Hour (h) |
Secondary
Time to Disease Progression
Time to disease progression was defined as the number of days between the first dose and the date of first assessment of progressive disease during the study or until death. Surviving subjects without progressive disease were censored at the time of the last visit and the subject was known to be non-progressing. Disease progression was assessed as per independent central blinded radiology assessment.
Time frame: From the start of treatment until disease progression (assessed up to a maximum of 6 years)
Population: ITT population included all randomized subjects who had received at least 1 intravenous administration of cilengitide.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide 500 Milligrams (mg) | Time to Disease Progression | 1.81 months |
| Cilengitide 2000 mg | Time to Disease Progression | 1.91 months |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax)
Tmax is the time to reach the maximum plasma concentration (Cmax) of cilengitide.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The PK population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Time to Reach Maximum Plasma Concentration (Tmax) | Cycle 1 | 1.13 Hour (h) |
| Cilengitide 500 Milligrams (mg) | Time to Reach Maximum Plasma Concentration (Tmax) | Cycle 2 | 1.17 Hour (h) |
| Cilengitide 2000 mg | Time to Reach Maximum Plasma Concentration (Tmax) | Cycle 1 | 1.33 Hour (h) |
| Cilengitide 2000 mg | Time to Reach Maximum Plasma Concentration (Tmax) | Cycle 2 | 1.00 Hour (h) |
Secondary
Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF)
CL is a quantitative measure of the rate at which a drug substance is removed from the body, calculated as dose divided by AUC0-infinity.
Time frame: Pre-dose,1,1.5,2,3,4,8 and 24 hours post-infusion on Day 1 of Week 1 in Cycles 1 and 2
Population: The pharmacokinetic (PK) population: subjects who had received cilengitide and who had blood samples drawn in Week 1 that provided drug concentration for non-compartmental PK evaluation. Here,Overall Number of participants analyzed = subjects evaluable for this outcome and Number analyzed = subjects evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide 500 Milligrams (mg) | Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF) | Cycle 1 | 6.85 Liter per hour (L/h) | Standard Deviation 4.47 |
| Cilengitide 500 Milligrams (mg) | Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF) | Cycle 2 | 6.75 Liter per hour (L/h) | Standard Deviation 3.25 |
| Cilengitide 2000 mg | Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF) | Cycle 1 | 5.85 Liter per hour (L/h) | Standard Deviation 0.86 |
| Cilengitide 2000 mg | Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF) | Cycle 2 | 4.67 Liter per hour (L/h) | Standard Deviation 0.31 |