Glioblastoma
Conditions
Keywords
Newly diagnosed Glioblastoma (WHO Grade IV), Cilengitide, Temozolomide, Radiotherapy
Brief summary
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.
Interventions
DRUGCilengitide (2-times weekly)
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.
DRUGcilengitide (5-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.
DRUGTemozolomide
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.
RADIATIONRadiotherapy
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.
Sponsors
Merck KGaA, Darmstadt, Germany
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
1. Newly diagnosed histologically proven supratentorial glioblastoma (World Health Organization \[WHO\] Grade IV, including glioblastoma subtypes, for example, gliosarcoma). The histological diagnosis has to be obtained from a neurosurgical resection of the tumor or by an open biopsy (stereotactic biopsy is not allowed) 2. Tumor tissue specimens from the glioblastoma surgery or open biopsy (formalin-fixed paraffin-embedded) must be available for MGMT gene promoter status analysis and central pathology review 3. Proven unmethylated MGMT gene promoter status (that is, cut-off ratio less than (\<) 2 by means of applied test to determine MGMT gene promoter status) 4. Males or females greater than or equal to (\>=) 18 years of age 5. Interval of \>= 2 weeks but less than or equal to (=\<) 7 weeks after surgery or biopsy before first administration of study treatment 6. Available post-operative gadolinium-enhanced magnetic resonance imaging (Gd-MRI) performed within \< 48 hours after surgery 7. Stable or decreasing dose of steroids for \>= 5 days prior to randomization 8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 9. Has to meet 1 of the following recursive partitioning analysis (RPA) classifications: * Class III (Age \< 50 years and ECOG PS 0) * Class IV (meeting one of the following criteria: a) Age \< 50 years and ECOG PS 1 or b) Age \>= 50 years, underwent prior partial or total tumor resection, Mini Mental State Examination \[MMSE\] \>= 27) * Class V (meeting one of the following criteria: a) Age \>= 50 years and underwent prior partial or total tumor resection, MMSE \< 27 or b) Age \>= 50 years and underwent prior tumor biopsy only) 10. Other protocol defined inclusion criteria could apply
Exclusion criteria
1. Prior chemotherapy within the last 5 years 2. Prior RTX of the head (except for low dose RTX for tinea capitis) 3. Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of cilengitide 4. Prior systemic anti-angiogenic therapy 5. Placement of Gliadel® wafer at surgery 6. Planned surgery for other diseases 7. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment 8. History of malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for \>= 5 years are eligible for this study 9. History of coagulation disorder associated with bleeding or recurrent thrombotic events 10. Clinically manifest myocardial insufficiency (New York Heart Association \[NYHA\] III, IV) or history of myocardial infarction during the past 6 months; or uncontrolled arterial hypertension 11. Inability to undergo Gd-MRI 12. Concurrent illness, including severe infection (for example, human immunodeficiency virus), which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety 13. Subject is pregnant (positive serum beta human chorionic gonadotropin \[b-HCG\] test at screening) or is currently breast-feeding, anticipates becoming pregnant/impregnating their partner during the study or within 6 months after study participation, or subject does not agree to follow acceptable methods of birth control, such as hormonal contraception, intra-uterine pessar, condoms or sterilization, to avoid conception during the study and for at least 6 months after receiving the last dose of study treatment 14. Current alcohol dependence or drug abuse 15. Known hypersensitivity to the study treatment 16. Legal incapacity or limited legal capacity 17. Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule 18. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such 19. Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Time | Time from randomization to death or last day known to be alive, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Days 1 and 5 of Week 1 | 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. |
| Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) | Days 1 and 5 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. |
| 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]) | Days 1 and 5 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. |
| Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) | Days 1 and 5 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. |
| Apparent Terminal Rate Constant | Days 1 and 5 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. |
| Progression Free Survival (PFS) Time - Investigator and Independent Read | Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013) | 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). |
| Plasma Clearance (CL) | Days 1 and 5 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. |
| Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss) | Days 1 and 5 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. |
| 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 | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) | 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. |
| 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 | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) | 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. |
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters | Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013) | — |
| Mean Residence Time From Time 0 to Infinity (MRT [0-infinity]) | Days 1 and 5 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. |
Countries
Germany, United States
Participant flow
Recruitment details
First/last participant (informed consent): Mar 2009/Sep 2011. Clinical data cut-off: 07 Feb 2013, Study completion date: Aug 2013.
Pre-assignment details
Enrolled: 294 screened for eligibility; 29 excluded (mainly due to non-fulfillment of inclusion or exclusion criteria), 265 participants randomized.
Participants by arm
| Arm | Count |
|---|---|
| Cilengitide (2-times Weekly) + 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. | 88 |
| Cilengitide (5-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. | 88 |
| 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. | 89 |
| Total | 265 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Ongoing at cut-off date | 5 | 5 | 3 |
Baseline characteristics
| Characteristic | Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | Temozolomide + Radiotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 54.6 years STANDARD_DEVIATION 9.63 | 55.2 years STANDARD_DEVIATION 10.44 | 54.5 years STANDARD_DEVIATION 11.64 | 54.8 years STANDARD_DEVIATION 10.57 |
| Gender Female | 38 Participants | 38 Participants | 34 Participants | 110 Participants |
| Gender Male | 50 Participants | 50 Participants | 55 Participants | 155 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 83 / 89 | 79 / 81 | 76 / 85 |
| serious Total, serious adverse events | 47 / 89 | 36 / 81 | 30 / 85 |
Outcome results
Primary
Overall Survival (OS) Time
The OS time is defined as the time (in months) from randomization to death or last day known to be alive. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.
Time frame: Time from randomization to death or last day known to be alive, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013)
Population: ITT population included all the participants who were randomized to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Overall Survival (OS) Time | 16.3 Months |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | Overall Survival (OS) Time | 14.5 Months |
| Temozolomide + Radiotherapy | Overall Survival (OS) Time | 13.4 Months |
p-value: 0.032895% CI: [0.484, 0.972]Log Rank
p-value: 0.377195% CI: [0.612, 1.204]Log Rank
Secondary
Apparent Terminal Rate Constant
The apparent terminal rate constant for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Apparent Terminal Rate Constant | Day 1 (Single dose) | 0.32 per hour | Standard Deviation 0.11 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Apparent Terminal Rate Constant | Day 5 (Repeated doses) | 0.32 per hour | Standard Deviation 0.11 |
Secondary
Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss)
The Vz (after single dose) and Vss (after repeated doses) for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss) | Vz | 24.7 liter | Standard Deviation 6.29 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Apparent Volume of Distribution During the Terminal Phase (Vz) and Apparent Volume of Distribution at Steady State (Vss) | Vss | 19.2 liter | Standard Deviation 8.54 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) and Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24])
The AUC (0-infinity) and AUC (0-24) for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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]) | AUC (0-infinity): Day 1 (Single dose) | 280944 hour*ng/mL | Standard Deviation 75720 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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]) | AUC (0-infinity): Day 5 (Repeated Doses) | 335263 hour*ng/mL | Standard Deviation 105435 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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]) | AUC (0-24): Day 1 (Single dose) | 269941 hour*ng/mL | Standard Deviation 82850 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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]) | AUC (0-24): Day 5 (Repeated doses) | 316137 hour*ng/mL | Standard Deviation 110425 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
The Cmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Maximum Observed Plasma Concentration (Cmax) | Day 1 (Single dose) | 108527 nanogram per milliliter (ng/mL) | Standard Deviation 27197 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Maximum Observed Plasma Concentration (Cmax) | Day 5 (Repeated doses) | 150873 nanogram per milliliter (ng/mL) | Standard Deviation 97220 |
Secondary
Mean Residence Time From Time 0 to Infinity (MRT [0-infinity])
The MRT (0-infinity) for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Mean Residence Time From Time 0 to Infinity (MRT [0-infinity]) | Day 1 (Single dose) | 2.8 hour | Standard Deviation 0.71 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Mean Residence Time From Time 0 to Infinity (MRT [0-infinity]) | Day 5 (Repeated doses) | 2.9 hour | Standard Deviation 0.97 |
Secondary
Number of Participants With Adverse Events (AEs), Serious AEs, Treatment-Related AEs, Treatment-Related Serious AEs, AEs Leading to Death, Treatment-Related AEs Leading to Death, AEs of Grade 3 or 4 and Treatment-Related AEs of Grade 3 or 4
An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. Treatment-emergent AEs are the events between first dose of study drug and up to 28 days after last dose of study treatment. A Serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-related AEs are the AEs which are suspected to be reasonably related to the study treatment (cilengitide, or radiotherapy, or temozolomide) as per investigator assessment. The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (Version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome.
Time frame: Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013)
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 70 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 88 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 47 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 13 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 8 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 2 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 of Grade 3 or 4 | 57 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 25 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 64 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 of Grade 3 or 4 | 47 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 4 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 8 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 2 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 80 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 19 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 36 Participants |
| Temozolomide + Radiotherapy | 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 | 30 Participants |
| Temozolomide + Radiotherapy | 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 | 1 Participants |
| Temozolomide + Radiotherapy | 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 | 56 Participants |
| Temozolomide + Radiotherapy | 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 | 5 Participants |
| Temozolomide + Radiotherapy | 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 of Grade 3 or 4 | 45 Participants |
| Temozolomide + Radiotherapy | 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 | 82 Participants |
| Temozolomide + Radiotherapy | 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 | 5 Participants |
| Temozolomide + Radiotherapy | 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 | 17 Participants |
Secondary
Number of Participants With AEs Belonging to Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) Thromboembolic Events and Hemorrhage With NCI-CTC Toxicity Grade 3 or 4
Thromboembolic events (standardized MedDRA query \[SMQ\]) Grade 3 or 4 AEs encompassed hemiparesis and cerebrovascular accident, pulmonary embolism, and deep vein thrombosis. Thromboembolic events (SMQ) of any grade and of Grade 3 or 4 were generally more frequent in the Cilengitide + Temozolomide/Radiotherapy group than in the Temozolomide/Radiotherapy group but were still in the expected range of this patient population The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome.
Time frame: Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013)
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 17 Participants |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | 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 | 3 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 10 Participants |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | 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 | 0 Participants |
| Temozolomide + Radiotherapy | 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 | 12 Participants |
| Temozolomide + Radiotherapy | 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 | 1 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) and Lab Parameters
Time frame: Time from first dose up to 28 days after last dose of study treatment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date (07 Feb 2013)
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
Secondary
Plasma Clearance (CL)
The CL for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Plasma Clearance (CL) | Day 1 (Single dose) | 125.7 milliliter per minute | Standard Deviation 29.93 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Plasma Clearance (CL) | Day 5 (Repeated doses) | 109.3 milliliter per minute | Standard Deviation 36.61 |
Secondary
Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT)
The Cpre and CT for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) | Cpre: Day 1 (Single dose) | 6372.7 ng/mL | Standard Deviation 21135.95 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) | Cpre: Day 5 (Repeated doses) | 286.0 ng/mL | Standard Deviation 319.05 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) | CT: Day 1 (Single dose) | 108045.5 ng/mL | Standard Deviation 27981.04 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Plasma Concentration at Pre-dose (Cpre) and Plasma Concentration at End of Infusion (CT) | CT: Day 5 (Repeated doses) | 157470.0 ng/mL | Standard Deviation 99849.26 |
Secondary
Progression Free Survival (PFS) Time - Investigator and Independent Read
The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read is the assessment of all imaging by the treating physician at the local trial site. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC).
Time frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, that is, Jun 2009 until cut-off date, (07 Feb 2013)
Population: ITT population included all the participants who were randomized to study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Progression Free Survival (PFS) Time - Investigator and Independent Read | PFS Time: Independent read | 5.6 Months |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Progression Free Survival (PFS) Time - Investigator and Independent Read | PFS Time: Investigator read | 6.4 Months |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | Progression Free Survival (PFS) Time - Investigator and Independent Read | PFS Time: Investigator read | 7.5 Months |
| Cilengitide (5-times Weekly) + Temozolomide + Radiotherapy | Progression Free Survival (PFS) Time - Investigator and Independent Read | PFS Time: Independent read | 5.9 Months |
| Temozolomide + Radiotherapy | Progression Free Survival (PFS) Time - Investigator and Independent Read | PFS Time: Independent read | 4.1 Months |
| Temozolomide + Radiotherapy | Progression Free Survival (PFS) Time - Investigator and Independent Read | PFS Time: Investigator read | 6.0 Months |
Secondary
Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2)
The Tmax and t1/2 for cilengitide were calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2. Cilengitide plasma concentrations were determined after dosing on Day 1 (single dose) and Day 5 (repeated doses) of Week 1.
Time frame: Days 1 and 5 of Week 1
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) | Tmax: Day 1 (Single dose) | 0.97 hours | Standard Deviation 0.34 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) | Tmax: Day 5 (Repeated doses) | 1.17 hours | Standard Deviation 0.34 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) | t1/2: Day 1 (Single dose) | 2.38 hours | Standard Deviation 0.8 |
| Cilengitide (2-times Weekly) + Temozolomide + Radiotherapy | Time to Maximum Plasma Concentration (Tmax) and Terminal Elimination Half-Life (t1/2) | t1/2: Day 5 (Repeated doses) | 2.44 hours | Standard Deviation 0.8 |