Cilengitide (EMD 121974) for Recurrent Glioblastoma Multiforme (Brain Tumor)

Study Overview
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Brief Summary
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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).

Official Title
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A Multicenter, Open-label, Randomized, Uncontrolled, Phase IIa Trial in Subjects With Recurrent Glioblastoma Multiforme to Investigate the Clinical Activity, Safety, and Tolerability of Cilengitide (EMD 121,974) Administered as a Single Agent.

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Cilengitide 500 mg
* Drug: Cilengitide 2000 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cilengitide 500 Milligram (mg)<br> | Drug: Cilengitide 500 mg<br>* 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.<br>* Other names: EMD 121974;|
| Experimental: Cilengitide 2000 mg<br> | Drug: Cilengitide 2000 mg<br>* 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.<br>* Other names: EMD 121974;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the start of treatment up to 6 years | 
| 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. | From the start of treatment until disease progression (assessed up to a maximum of 6 years) | 
| 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. | From the start of treatment until death (assessed up to a maximum of 6 years) | 
| 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. | From the start of treatment up to 1 year | 
| Maximum Observed Plasma Concentration (Cmax) | Cmax is the maximum observed plasma concentration of cilengitide after administration. | Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2 | 
| Time to Reach Maximum Plasma Concentration (Tmax) | Tmax is the time to reach the maximum plasma concentration (Cmax) of cilengitide. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| Terminal Half-life (t1/2) | The t1/2 is the time taken to eliminate half the amount of cilengitide. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Pre-dose, 1, 1.5, 2, 3, 4, 8, 24 hours post-infusion on Day 1 of Week 1 in Cycle 1 and 2 | 
| 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. | From the start of treatment up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain cancer, Brain tumor