Cilengitide in Treating Younger Patients With Recurrent or Progressive High-Grade Glioma That Has Not Responded to Standard Therapy

Cilengitide (EMD 121974) (IND# 59073) in Recurrent or Progressive and Refractory Childhood High-Grade Glioma

This phase II trial studies how well cilengitide works in treating younger patients with recurrent or progressive high-grade glioma that has not responded to standard therapy. Cilengitide may stop the growth of tumor cells by blocking blood flow to the tumor.

Study Overview

• Status: Completed
• Conditions: Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Brain Tumor
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: cilengitide

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the objective response rate to cilengitide in younger patients with recurrent or progressive high-grade glioma that is refractory to standard therapy.

SECONDARY OBJECTIVES:

I. To estimate the distribution of time to progression, time to treatment failure, and time to death in these patients.

II. To estimate the rate of toxicity, especially symptomatic intratumoral hemorrhage, in these patients.

III. To evaluate the pharmacokinetics of cilengitide in plasma using a limited sampling strategy.

IV. To evaluate the pharmacogenetic polymorphisms in drug transporters (eg, breast cancer resistance protein [BCRP], P-glycoprotein [P-gp]) and relate to cilengitide disposition.

OUTLINE:

Patients receive cilengitide IV over 1 hour on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then periodically for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
• United States
  • California
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center-Parnassus
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Lombardi Comprehensive Cancer Center at Georgetown University
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Lurie Children's Hospital-Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health Richland
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T C Thompson Children's Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed primary central nervous system (CNS) high-grade glioma, including any of the following:

  • Glioblastoma multiforme
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma

  • High-grade astrocytoma not otherwise specified (i.e., anaplastic ganglioglioma, anaplastic mixed glioma, or anaplastic mixed glioneuronal tumors)

    • No diffuse pontine gliomas, gliomatosis cerebri, and primary spinal cord high-grade astrocytoma
  • Gliosarcoma
• Recurrent or progressive disease that is refractory to standard therapy

• Radiographically documented measurable disease

  • Lesion must be at least twice the thickness of the image from which it is derived (e.g., 10 mm for a 5 mm slice thickness)
• No diffuse pontine gliomas
• No evidence of prior CNS bleeding
• Karnofsky performance status (PS) 50-100% (patients > 16 years of age)
• Lansky PS 50-100% (patients =< 16 years of age)
• Life expectancy >= 8 weeks
• Absolute neutrophil count (ANC) >= 1,000/μL
• Platelet count >= 100,000/μL (transfusion independent)
• Hemoglobin >= 8.0 g/dL (red blood cell [RBC] transfusions allowed)

• Creatinine clearance or radioisotope glomerular filtration rate >= 70mL/min OR serum creatinine based on age/gender as follows:

  • 0.4 mg/dL (1 month to < 6 months of age)
  • 0.5 mg/dL (6 months to < 1 year of age)
  • 0.6 mg/dL (1 to < 2 years of age)
  • 0.8 mg/dL (2 to < 6 years of age)
  • 1.0 mg/dL (6 to < 10 years of age)
  • 1.2 mg/dL (10 to < 13 years of age)
  • 1.5 mg/dL (male) or 1.4mg/dL (female) (13 to < 16 years of age)
  • 1.7 mg/dL (male) or 1.4mg/dL (female) (>= 16 years of age)
• Total bilirubin =< 1.5 times upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times ULN for age
• No evidence of dyspnea at rest
• No exercise intolerance
• Pulse oximetry > 94%, if determination is clinically indicated
• Seizure disorder is allowed provided it is well-controlled with anticonvulsants
• No uncontrolled infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Recovered from all prior therapy
• No more than two prior treatments for high-grade glioma (i.e., one initial treatment and one treatment for relapse)
• More than 2 weeks since prior myelosuppressive chemotherapy (>= 6 weeks for nitrosoureas)
• At least 1 week since prior non-myelosuppressive chemotherapy, immunotherapy, or biologic therapy
• At least 2 weeks since prior local palliative radiotherapy (i.e., small port) to a symptomatic non-target lesion only
• At least 3 months since prior craniospinal radiotherapy
• At least 6 weeks since prior substantial bone marrow radiotherapy

• At least 6 months since prior allogeneic stem cell transplant (SCT) or rescue

  • Patients who have undergone prior allogeneic SCT and who have graft-versus-host disease (GVHD) must have controlled GVHD that is =< grade 2
• At least 1 month since prior autologous SCT
• More than 1 week since prior growth factors (> 3 weeks for pegfilgrastim [Neulasta®])
• No other concurrent anticancer therapy, including chemotherapy or immunomodulating agents
• No other concurrent experimental agents or therapies
• No concurrent alternative or complimentary therapies
• No concurrent homeopathic medicines
• No concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (aspirin)
• No concurrent steroids as anti-emetics
• Concurrent steroids for treatment of increased intracranial pressure allowed if on a stable or decreasing dose for >= 1 week before study entry
• Concurrent radiotherapy to localized painful lesions allowed provided >= 1 measurable lesion is not irradiated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment (cilengitide); Patients receive cilengitide IV over 1 hour on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: cilengitide; Given IV; Other Names: EMD 121974

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response to Cilengitide	Objective response is defined as a complete response or partial response at 4 weeks that is sustained for at least another 4 weeks, or a stable disease at 4 weeks that is sustained for at least 12 weeks while on stable or decreasing dose of corticosteroids, except when corticosteroids are being used to control hydrocephaly unrelated to tumor progression.	Up to 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Tumor Progression (TTP)	The distribution of TTP will be analyzed separately using product limit (PL) estimate.	Time from study enrollment to radiographically determined tumor progression or recurrence, assessed up to 5 years
Time to Treatment Failure (TTF)	The distribution of TTF will be analyzed separately using PL estimate.	Time from study enrollment to tumor progression, tumor recurrence, death from any cause, or occurrence of a second malignant neoplasm, assessed up to 5 years
Time to Death (TTD)	The distribution of TTD will be analyzed separately using PL estimate.	Time from study enrollment to death from any cause, assessed up to 5 years
Rate of Toxicity, Especially That of Symptomatic Intratumoral Hemorrhage (ITH) Assessed by Common Terminology Criteria for Adverse Events Version 4.0	Rate of individual toxicity including that of symptomatic ITH will be summarized in each course of treatment using standard descriptive statistical methods.	Up to 5 years
Pharmacokinetic Parameter of Cilengitide in Plasma: Volume of Central Compartment (Vc)	Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one Vc value per patient.	At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Pharmacokinetic Parameter of Cilengitide in Plasma: Elimination Rate Constant (Ke)	Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one Ke value per patient.	At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Pharmacokinetic Parameter of Cilengitide in Plasma: Half-life (t1/2)	Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one t1/2 value per patient.	At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Pharmacokinetic Parameter of Cilengitide in Plasma: Systemic Clearance (Cl)	Cilengitide plasma concentration-time data are fit to a compartmental pharmacokinetic model using MAP-Bayesian estimation as implemented in ADAPT II. For each patient, samples collected at different time points are used to derive one Cl value per patient.	At baseline and 1, 3, and 6 hours after the first dose of cilengitide
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by AUC	Cilengitide systemic exposure as measured by AUC is used in this genotype-phenotype analysis. The ABCB1 (P-glycoprotein; P-gp) Exon 26 genotype is coded as 0/1/2 based on the number of T alleles.	At baseline
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by Systemic Clearance	Cilengitide systemic exposure as measured by systemic clearance is used in this genotype-phenotype analysis. The ABCB1 (P-glycoprotein; P-gp) Exon 26 genotype is coded as 0/1/2 based on the number of T alleles.	At Baseline
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by AUC	Cilengitide systemic exposure as measured by AUC is used in this genotype-phenotype analysis. The ABCG2 (breast cancer resistance protein; BCRP) Exon 5 genotype is coded as 0/1/2 based on the number of G alleles.	At baseline
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by Systemic Clearance	Cilengitide systemic exposure as measured by systemic clearance is used in this genotype-phenotype analysis. The ABCG2 (breast cancer resistance protein; BCRP) Exon 5 genotype is coded as 0/1/2 based on the number of G alleles.	At baseline

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tobey MacDonald, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (ACTUAL): October 1, 2010
• Study Completion (ACTUAL): July 1, 2011

Study Registration Dates

• First Submitted: May 14, 2008
• First Submitted That Met QC Criteria: May 14, 2008
• First Posted (ESTIMATE): May 16, 2008

Study Record Updates

• Last Update Posted (ACTUAL): August 1, 2018
• Last Update Submitted That Met QC Criteria: July 6, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Glioma; Astrocytoma; Oligodendroglioma
• Other Study ID Numbers: NCI-2009-00339 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA098543 (U.S. NIH Grant/Contract); COG-ACNS0621; CDR0000595623; ACNS0621 (OTHER: CTEP)