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

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ClinicalTrials.gov Identifier: NCT00679354
Recruitment Status : Completed
First Posted : May 16, 2008
Results First Posted : February 20, 2014
Last Update Posted : August 1, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Childhood High-grade Cerebellar Astrocytoma Childhood High-grade Cerebral Astrocytoma Recurrent Childhood Anaplastic Astrocytoma Recurrent Childhood Anaplastic Oligoastrocytoma Recurrent Childhood Anaplastic Oligodendroglioma Recurrent Childhood Brain Tumor Recurrent Childhood Cerebellar Astrocytoma Recurrent Childhood Cerebral Astrocytoma Recurrent Childhood Glioblastoma Recurrent Childhood Visual Pathway and Hypothalamic Glioma Drug: cilengitide Other: laboratory biomarker analysis Other: pharmacological study Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cilengitide (EMD 121974) (IND# 59073) in Recurrent or Progressive and Refractory Childhood High-Grade Glioma
Study Start Date : June 2008
Actual Primary Completion Date : October 2010
Actual Study Completion Date : July 2011

Resource links provided by the National Library of Medicine


Arms and Interventions
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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.
 Drug: cilengitide
Given IV
Other Name: EMD 121974

Other: laboratory biomarker analysis
Correlative studies

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies


Outcome Measures
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Primary Outcome Measures :
  1. Objective Response to Cilengitide [ Time Frame: Up to 16 weeks ]
    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.


Secondary Outcome Measures :
  1. Time to Tumor Progression (TTP) [ Time Frame: Time from study enrollment to radiographically determined tumor progression or recurrence, assessed up to 5 years ]
    The distribution of TTP will be analyzed separately using product limit (PL) estimate.

  2. Time to Treatment Failure (TTF) [ Time Frame: 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 ]
    The distribution of TTF will be analyzed separately using PL estimate.

  3. Time to Death (TTD) [ Time Frame: Time from study enrollment to death from any cause, assessed up to 5 years ]
    The distribution of TTD will be analyzed separately using PL estimate.

  4. Rate of Toxicity, Especially That of Symptomatic Intratumoral Hemorrhage (ITH) Assessed by Common Terminology Criteria for Adverse Events Version 4.0 [ Time Frame: Up to 5 years ]
    Rate of individual toxicity including that of symptomatic ITH will be summarized in each course of treatment using standard descriptive statistical methods.

  5. Pharmacokinetic Parameter of Cilengitide in Plasma: Volume of Central Compartment (Vc) [ Time Frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide ]
    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.

  6. Pharmacokinetic Parameter of Cilengitide in Plasma: Elimination Rate Constant (Ke) [ Time Frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide ]
    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.

  7. Pharmacokinetic Parameter of Cilengitide in Plasma: Half-life (t1/2) [ Time Frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide ]
    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.

  8. Pharmacokinetic Parameter of Cilengitide in Plasma: Systemic Clearance (Cl) [ Time Frame: At baseline and 1, 3, and 6 hours after the first dose of cilengitide ]
    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.

  9. Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by AUC [ Time Frame: At baseline ]
    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.

  10. Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by Systemic Clearance [ Time Frame: At Baseline ]
    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.

  11. Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by AUC [ Time Frame: At baseline ]
    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.

  12. Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by Systemic Clearance [ Time Frame: At baseline ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00679354


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tobey MacDonald Children's Oncology Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00679354    
Obsolete Identifiers: NCT01648400
Other Study ID Numbers: NCI-2009-00339
NCI-2009-00339 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
COG-ACNS0621
CDR0000595623
ACNS0621 ( Other Identifier: Children's Oncology Group )
ACNS0621 ( Other Identifier: CTEP )
U10CA098543 ( U.S. NIH Grant/Contract )
First Posted: May 16, 2008    Key Record Dates
Results First Posted: February 20, 2014
Last Update Posted: August 1, 2018
Last Verified: July 2018
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Oligodendroglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
 Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue