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

Primary Purpose

Glioblastoma Multiforme

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cilengitide 500 mg
Cilengitide 2000 mg
Sponsored by
EMD Serono
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring Brain cancer, Brain tumor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama at Birmingham
  • Barrow Neurological Institute
  • UCLA Medical Center
  • Denise Damek
  • Northwestern University
  • Indiana University Medical Center
  • Massachusetts General Hospital
  • University of Massachusetts
  • Henry Ford Health System
  • Washington University
  • Memorial Sloan Kettering Cancer Center
  • Duke University Medical Center
  • Good Samaritan Hospital/Tri Health Hatton Center
  • Baylor University Medical Center at Dallas
  • University of Texas MD Anderson Cancer Center
  • University of Vermont/Fletcher Allen Healthcare
  • University of Virginia Health System

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cilengitide 500 Milligram (mg)

Cilengitide 2000 mg

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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 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.
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.
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.
Maximum Observed Plasma Concentration (Cmax)
Cmax is the maximum observed plasma concentration of cilengitide after administration.
Time to Reach Maximum Plasma Concentration (Tmax)
Tmax is the time to reach the maximum plasma concentration (Cmax) of cilengitide.
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.
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.
Terminal Half-life (t1/2)
The t1/2 is the time taken to eliminate half the amount of cilengitide.
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.
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.
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.
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.
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.

Full Information

First Posted
October 7, 2004
Last Updated
January 18, 2019
Sponsor
EMD Serono
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1. Study Identification

Unique Protocol Identification Number
NCT00093964
Brief Title
Cilengitide (EMD 121974) for Recurrent Glioblastoma Multiforme (Brain Tumor)
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
October 13, 2004 (Actual)
Primary Completion Date
October 28, 2005 (Actual)
Study Completion Date
October 21, 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
EMD Serono

4. Oversight

Data Monitoring Committee
No

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme
Keywords
Brain cancer, Brain tumor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
81 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cilengitide 500 Milligram (mg)
Arm Type
Experimental
Arm Title
Cilengitide 2000 mg
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Cilengitide 500 mg
Other Intervention Name(s)
EMD 121974
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cilengitide 2000 mg
Other Intervention Name(s)
EMD 121974
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percentage of Subjects With Progression-free Survival
Description
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
Secondary Outcome Measure Information:
Title
Percentage of Subjects With Overall Response Rate
Description
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
Title
Time to Disease Progression
Description
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)
Title
Overall Survival Time
Description
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)
Title
Percentage of Subjects With 1-year of Survival Rate
Description
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
Title
Maximum Observed Plasma Concentration (Cmax)
Description
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
Title
Time to Reach Maximum Plasma Concentration (Tmax)
Description
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
Title
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity After Administration (AUC 0-infinity)
Description
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
Title
Apparent Terminal Rate Constant (Lambda z)
Description
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
Title
Terminal Half-life (t1/2)
Description
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
Title
Mean Residence Time of Drug in the Body (MRT)
Description
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
Title
Total Body Clearance (CL) of Drug From Plasma/Cerebro Spinal Fluid (CSF)
Description
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
Title
Apparent Volume of Distribution During the Terminal Phase (Vz)
Description
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
Title
Apparent Volume of Distribution at Steady State (Vss)
Description
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
Title
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Responsible
Organizational Affiliation
EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294-3280
Country
United States
Facility Name
Barrow Neurological Institute
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Facility Name
UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Denise Damek
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80010
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana University Medical Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Massachusetts
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Good Samaritan Hospital/Tri Health Hatton Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45206
Country
United States
Facility Name
Baylor University Medical Center at Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Vermont/Fletcher Allen Healthcare
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05401
Country
United States
Facility Name
University of Virginia Health System
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22903
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
18981465
Citation
Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008 Dec 1;26(34):5610-7. doi: 10.1200/JCO.2008.16.7510. Epub 2008 Nov 3.
Results Reference
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Cilengitide (EMD 121974) for Recurrent Glioblastoma Multiforme (Brain Tumor)

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