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

Phase 2

Completed

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

• Registration Number: NCT00679354
• Lead Sponsor: National Cancer Institute (NCI)

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.

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 Timeline

• Study First Submitted: 2008-05-14
• Study First Submitted QC: 2008-05-14
• Study First Posted: 2008-05-16
• Study Start: 2008-06
• Primary Completion: 2010-10
• Study Completion: 2011-07
• Results First Submitted: 2014-01-06
• Results First Submitted QC: 2014-01-06
• Results First Posted: 2014-02-20
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-06
• Last Update Posted: 2018-08-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (cilengitide)	laboratory biomarker analysis	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.
Treatment (cilengitide)	pharmacological study	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.
Treatment (cilengitide)	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.

Primary Outcome Measures

Name	Time	Method
Objective Response to Cilengitide	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

Name	Time	Method
Time to Death (TTD)	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.
Pharmacokinetic Parameter of Cilengitide in Plasma: Systemic Clearance (Cl)	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.
Time to Treatment Failure (TTF)	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.
Rate of Toxicity, Especially That of Symptomatic Intratumoral Hemorrhage (ITH) Assessed by Common Terminology Criteria for Adverse Events Version 4.0	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.
Pharmacokinetic Parameter of Cilengitide in Plasma: Elimination Rate Constant (Ke)	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.
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by AUC	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.
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCB1 and Relate to Cilengitide Disposition as Measured by Systemic Clearance	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.
Time to Tumor Progression (TTP)	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.
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by Systemic Clearance	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.
Pharmacokinetic Parameter of Cilengitide in Plasma: Volume of Central Compartment (Vc)	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.
Pharmacokinetic Parameter of Cilengitide in Plasma: Half-life (t1/2)	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.
Pharmacogenetic Polymorphism in Drug Transporter Gene ABCG2 and Relate to Cilengitide Disposition as Measured by AUC	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.

Trial Locations

Locations (20)

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

Children's Hospital Medical Center of Akron; 🇺🇸 Akron, Ohio, United States

T C Thompson Children's Hospital; 🇺🇸 Chattanooga, Tennessee, United States

Newark Beth Israel Medical Center; 🇺🇸 Newark, New Jersey, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

Palmetto Health Richland; 🇺🇸 Columbia, South Carolina, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

University of California San Francisco Medical Center-Parnassus; 🇺🇸 San Francisco, California, United States

CancerCare Manitoba; 🇨🇦 Winnipeg, Manitoba, Canada

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Midwest Children's Cancer Center; 🇺🇸 Milwaukee, Wisconsin, United States

Kaiser Permanente-Oakland; 🇺🇸 Oakland, California, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Lombardi Comprehensive Cancer Center at Georgetown University; 🇺🇸 Washington, District of Columbia, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

New York University Langone Medical Center; 🇺🇸 New York, New York, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States