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A Phase Ib Study of Cediranib in Combination With Cilengitide in Patients With Recurrent Glioblastoma

Phase 1
18 Years
Open (Enrolling)
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

A Phase Ib Study of Cediranib in Combination With Cilengitide in Patients With Recurrent Glioblastoma


I. To determine the safety profile of cediranib (cediranib maleate) in combination with
cilengitide in patients with recurrent glioblastoma (Part A).


I. To estimate overall survival. II. To estimate the proportion of radiographic responses in
recurrent glioblastoma patients with measurable disease treated with cediranib and

III. To estimate the proportion of patients alive and progression free at 6 months (APF6) in
patients with recurrent glioblastoma treated at the safe dose as determined in Part A (Part

IV. To explore potential imaging techniques and biomarkers to capture the disease process
through treatment.

OUTLINE: This is a dose-escalation study of cediranib maleate. Patients are initially
enrolled in the dose-finding portion of the study (part A). Once the safe dose of cediranib
maleate is determined, additional patients are enrolled in the dose-expansion portion of the
study (part B).

Part A (dose finding): Patients receive cediranib maleate orally (PO) once daily on days
1-28 and cilengitide intravenously (IV) over 1 hour on days 1, 4, 8, 11, 15, 18, 22, and 25.
Treatment repeats every 28 days in the absence of disease progression or unacceptable

Part B (dose expansion): Patients are assigned to 1 of 2 groups according to prior anti-VEGF
therapy (yes vs no). Patients in both groups receive cediranib maleate (administered at the
safe dose determined in part A) and cilengitide as in part A.

After completion of study therapy, patients are followed up every 2 months.

Inclusion Criteria:

- Patients must have histologically proven glioblastoma which is progressive or
recurrent following radiation therapy and/or chemotherapy; patients with previous low
grade glioma who progressed after radiotherapy and/or chemotherapy and are biopsied
and found to have glioblastoma are eligible

- Patients must have measurable contrast-enhancing progressive or recurrent
glioblastoma by magnetic resonance imaging (MRI) imaging within two weeks of starting
treatment; patient must be able to tolerate MRIs; computed tomography (CT) scans
cannot be substituted for MRIs in this study

- Patients must have recovered from severe toxicity of prior therapy; an interval of at
least 3 months must have elapsed since the completion of the most recent course of
radiation therapy while at least 3 weeks must have elapsed since the completion of a
non-nitrosourea containing chemotherapy regimen and at least 6 weeks since the
completion of a nitrosourea containing chemotherapy regimen

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- White blood cell (WBC) >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8 g/dL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3 × institutional
upper limit of normal

- Creatinine within normal institutional limits OR

- Creatinine clearance >= 60 ml/min/1.73m^2 for patients with creatinine levels above
institutional normal

- Patients must be able to provide written informed consent

- Patients must have =< 2 recurrences/relapses of their tumor

- Women of childbearing potential must have a negative pregnancy test prior to study
entry; cediranib has been shown to terminate fetal development in the rat, as
expected for a process dependent on vascular endothelial growth factor (VEGF)
signaling; women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- Patients may not be breast-feeding a child

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must have a Mini-Mental State Exam score of >= 15

- Patients must not have received prior cilengitide or cediranib therapy for their

- ARM 1 OF THE DOSE EXPANSION COHORT ONLY, the last treatment regimen the patient
received must have included anti-VEGF treatment; a period of at least 28 days must
have elapsed since the last bevacizumab treatment or a period of at least 21 days
since the last short-acting anti-VEGF treatment, before treatment with
cediranib/cilengitide can begin ARM 2 OF THE DOSE EXPANSION COHORT ONLY: patients
must not have had prior anti-VEGF therapy

- Patients must not be on enzyme-inducing anti-epileptic drugs (EIAED); patients may be
on non-enzyme inducing anti-epileptic drugs (NEIAED) or not be taking any
anti-epileptic drugs

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness, which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety

- Patients with > 2 prior tumor recurrences/relapses

- Patients receiving concurrent investigational agents; patients may not be receiving
any other cancer related investigational agents

- Although the following medications are not contraindicated on this study, each should
be used with extreme caution due to potential nephrotoxic effects: vancomycin,
amphotericin, pentamidine

- Patients may not be on anti-coagulants (dalteparin, warfarin, etc)

- Patients with a mean QTc > 500 msec (with Bazett's correction) in screening
electrocardiogram or history of familial long QT syndrome or other significant
electrocardiogram (ECG) abnormality noted within 14 days of treatment are ineligible

- Greater than +1 proteinuria on two consecutive dipsticks taken no less than 7 days
apart; however, if the first urinalysis shows no protein, then a repeat urinalysis is
NOT required

- Patients with a New York Heart Association classification of III or IV

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cediranib or cilengitide

- Uncontrolled intercurrent illness including, but not limited to, hypertension (blood
pressure > 140/90 mm Hg), ongoing or active infection, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements

- Pregnant women are excluded from this study because cediranib is a VEGF inhibitor
with known abortifacient effects; breastfeeding should be discontinued if the mother
is treated with cediranib

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with

- Patients on enzyme-inducing AED (EIAED) are not eligible for treatment on this
protocol; patients previously treated with EIAED may be enrolled if they have been
off the EIAED for 14 days or more prior to the first dose of cediranib or cilengitide

- Patients whose MRI scan demonstrates intratumoral hemorrhage or peritumoral
hemorrhage are not eligible for treatment if deemed significant by the treating

- Patients must not have a known coagulopathy that increases risk of bleeding or a
history of clinically significant hemorrhages in the past

- Patients receiving concurrent VEGF inhibitors are prohibited from participating in
this study

- Patients with conditions requiring concurrent drugs or biologics with proarrhythmic

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety profile of cediranib maleate based on the incidence of dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Description:

The proportion of patients with serious or life threatening toxicities will be estimated along with 95% confidence intervals.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Elizabeth Gerstner

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Food and Drug Administration

Study ID:




Start Date:

March 2010

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Gliosarcoma



Johns Hopkins University Baltimore, Maryland  21205
Cleveland Clinic Foundation Cleveland, Ohio  44195
Henry Ford Hospital Detroit, Michigan  48202
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Massachusetts General Hospital Boston, Massachusetts  02114-2617
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Emory University Atlanta, Georgia  30322
Wake Forest University Health Sciences Winston-Salem, North Carolina  27157
Adult Brain Tumor Consortium Baltimore, Maryland  21231-1000