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

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ClinicalTrials.gov Identifier: NCT00093964
Recruitment Status : Completed
First Posted : October 11, 2004
Results First Posted : April 16, 2019
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
EMD Serono

Tracking Information
First Submitted Date  ICMJE October 7, 2004
First Posted Date  ICMJE October 11, 2004
Results First Submitted Date  ICMJE October 2, 2017
Results First Posted Date  ICMJE April 16, 2019
Last Update Posted Date April 16, 2019
Actual Study Start Date  ICMJE October 13, 2004
Actual Primary Completion Date October 28, 2005   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 18, 2019)
Percentage of Subjects With Progression-free Survival [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
Rate of 6-month Progression Free Survival
Change History Complete list of historical versions of study NCT00093964 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2019)
  • Percentage of Subjects With Overall Response Rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ 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 ]
    Cmax is the maximum observed plasma concentration of cilengitide after administration.
  • Time to Reach Maximum Plasma Concentration (Tmax) [ 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 ]
    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) [ 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 ]
    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) [ 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 ]
    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) [ 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 ]
    The t1/2 is the time taken to eliminate half the amount of cilengitide.
  • Mean Residence Time of Drug in the Body (MRT) [ 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 ]
    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) [ 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 ]
    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) [ 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 ]
    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) [ 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 ]
    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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
  • Response rate
  • Time to disease progression
  • survival time, safety, tolerability and PK
  • Rate of 1-year survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cilengitide (EMD 121974) for Recurrent Glioblastoma Multiforme (Brain Tumor)
Official Title  ICMJE 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.
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE
  • Drug: Cilengitide 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.
    Other Name: EMD 121974
  • Drug: Cilengitide 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.
    Other Name: EMD 121974
Study Arms  ICMJE
  • Experimental: Cilengitide 500 Milligram (mg)
    Intervention: Drug: Cilengitide 500 mg
  • Experimental: Cilengitide 2000 mg
    Intervention: Drug: Cilengitide 2000 mg
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 13, 2007)
81
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
80
Actual Study Completion Date  ICMJE October 21, 2010
Actual Primary Completion Date October 28, 2005   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00093964
Other Study ID Numbers  ICMJE EMD 121974-009
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party EMD Serono
Study Sponsor  ICMJE EMD Serono
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Responsible EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
PRS Account EMD Serono
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP