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A Phase Ib/II Study of AZD2171 in Combination With Daily Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma Not Taking Enzyme-Inducing Anti-Epileptic Drugs


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

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Trial Information

A Phase Ib/II Study of AZD2171 in Combination With Daily Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma Not Taking Enzyme-Inducing Anti-Epileptic Drugs


PRIMARY OBJECTIVES:

I. To determine the safety profile and optimal dose of AZD2171 (cediranib) (15mg or 20mg or
30mg) in combination with temozolomide and radiation in patients with newly diagnosed
glioblastoma (Phase Ib) II. To determine median progression-free survival of patients with
newly diagnosed glioblastoma treated with AZD2171 in combination with temozolomide and
radiation (Phase II)

SECONDARY OBJECTIVES:

I. To determine the radiographic response proportion in newly diagnosed glioblastoma
patients with measurable disease. (Phase II) II. To determine the median overall survival.
(Phase II) III. To determine the "vascular normalization" window in newly diagnosed
glioblastoma patients by the application of serial, non-invasive, MRI parameters. (Phase II)
IV. To measure the glucose metabolism changes in a subset of newly diagnosed glioblastoma
patients by performing FDG PET studies. (Phase II) V. Measurement of circulating endothelial
and progenitor cells and plasma levels of VEGF-A; VEGF-B; VEGF-C; VEGF-D; sVEGFR1, sVEGFR2,
bFGF, PlGF, PDGF-AA; PDGF-AB; PDGF-BB; SDF1α; tumstatin; thrombospondin-1; interleukin-8;
collagen IV sICAM1, sVCAM1 as markers for response to AZD2171 in newly diagnosed
glioblastoma patients. (Phase II) VI. Correlation of treatment outcomes with pre-AZD2171
tumor specimens with respect to cell proliferation, apoptosis, microvascular density (MVD),
basement membrane and pericyte coverage, angiopoietin-1 and -2 expression to determine
whether these immunohistochemical analyses can be predictive of the response to AZD2171.
(Phase II)

OUTLINE: This is a phase I, dose-escalation study of cediranib followed by a phase II study.

Patients begin study treatment within 21-42 days after craniotomy or 14-21 days after
stereotactic biopsy.

PHASE Ib:

CHEMORADIOTHERAPY: Patients receive cediranib orally (PO) once daily and oral temozolomide
once daily for 6 weeks. Within 2-6 hours of dosing, patients undergo concurrent
intensity-modulated radiotherapy (IMRT) once daily, 5 days a week for 6 weeks. Cediranib
monotherapy: Patients receive cediranib PO once daily for 4 weeks (weeks 7-10). Cediranib
and temozolomide monthly therapy: Patients receive cediranib PO once daily for 24 weeks
(weeks 11-34) and temozolomide once daily, 5 days a week in weeks 11, 15, 19, 23, 27, and
31. Cediranib monotherapy: Patients receive a fixed-dose of cediranib once daily for 24
weeks (weeks 35-58).

PHASE II:

CHEMORADIOTHERAPY: Patients receive cediranib PO at the recommended phase II dose determined
in phase Ib, temozolomide PO, and undergo concurrent IMRT as in phase Ib (weeks 1-6).
Cediranib monotherapy: Patients receive cediranib PO (at the recommended phase II dose
determined in phase Ib) once daily for 4 weeks (weeks 7-10). Cediranib and temozolomide
monthly therapy: Patients receive cediranib PO (at the recommended phase II dose determined
in phase Ib) once daily for 24 weeks (weeks 11-34) and temozolomide once daily, 5 days a
week in weeks 11, 15, 19, 23, 27, and 31. Cediranib monotherapy: Patients receive a
fixed-dose of cediranib once daily for 24 weeks (weeks 35-58).

Patients undergo blood and urine sample collection at baseline and periodically during
study. Blood samples are measured for tumstatin, as well as other well established
biomarkers, including VEGF-A, -D, sVEGFR1, sVEGFR2, sICAM1, sVCAM1, PlGF, PDGF-AA, PDGF-AB,
PDGF-BB, thrombospondin-1, and IL-8 by electrochemiluminescence detection. Circulating
endothelial cell (CEC) assays are evaluated to assess the kinetics of CECs and progenitor
cells prior to and during antiangiogenic therapy with cediranib and chemoradiotherapy. Urine
samples are collected for proteomic analyses to evaluate serial change of growth factors
such as VEGF and PlGF and of matrix metalloproteinases in response to treatment with
cediranib. Archival tumor tissue is collected for analysis of tumor microvascular density,
basement membrane and pericyte coverage, angiopoietin-1 and -2 expression, tumor cell
proliferation, and apoptosis by immunostaining methods and immunoenzyme techniques.

Patients also undergo dynamic contrast enhanced (DCE)-MRI and T2-weighted or
perfusion-weighted MRI at baseline and periodically during study to monitor antiangiogenic
effect on tumor vasculature through parameters reflecting both tumor perfusion and
permeability; and diffusion tensor imaging to measure degree of water diffusion and
fractional anisotropy. A subset of patients undergo fludeoxyglucose F 18 positron emission
tomography (FDG-PET) periodically to monitor antiangiogenic effects on glucose utilization.

After completion of study treatment, patients are followed periodically for 1 year.


Inclusion Criteria:



- Histologically confirmed glioblastoma

- Newly diagnosed disease

- Scheduled to receive standard post-surgical (i.e., biopsy or resection) temozolomide
and radiotherapy

- Must have residual, contrast-enhancing tumor (≥ 1 centimeter in ≥ 1 dimension)

- Patients must be maintained on a stable corticosteroid regimen for 5 days prior to
their baseline scan and for 5 days prior to their first vascular MRI; the dose of
steroids should remain the same during the baseline vascular MRIs

- Archival tumor tissue available for molecular analysis

- No intratumoral hemorrhage or peritumoral hemorrhage by MRI

- Karnofsky performance status 60-100%

- Leukocytes ≥ 3,000/mcl

- Absolute neutrophil count ≥ 1,500/mcL

- Platelet count ≥ 100,000/mcL

- Hemoglobin ≥ 8 g/dL

- Total bilirubin normal

- AST/ALT ≤ 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Proteinuria ≤ 1+ on two consecutive dipsticks ≥ 7 days apart

- Mini-mental status examination score ≥ 15

- Must be able to tolerate MRI and must consent to participate in additional Vascular
Imaging Procedures per protocol

- CT scans cannot be substituted for MRI

- Mean QTc ≤ 500 msec (with Bazett's correction) by electrocardiogram

- No concurrent malignancy except curatively treated basal cell or squamous cell
carcinoma skin cancer or carcinoma in situ of the cervix or breast

- Patients with prior malignancies must be disease-free for ≥ 5 years

- No history of familial long QT syndrome or other significant ECG abnormality

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cediranib

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Hypertension (e.g., blood pressure > 140/90 mm Hg)

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would preclude study compliance

- No known coagulopathy that increases risk of bleeding

- No history of clinically significant hemorrhages in the past

- No New York Heart Association class III-IV heart disease

- No condition requiring concurrent drugs or biologics with proarrhythmic potential

- No other concurrent chemotherapy agents, investigational agents, or biologic therapy

- No prior chemotherapy, radiotherapy, or any experimental therapy for this disease

- No prior IV bevacizumab for any other medical condition

- No prior carmustine implant (Gliadel Wafer)

- No prior brachytherapy or radiosurgery for this disease

- More than 30 days since prior and no other concurrent investigational agents or
participation in an investigational therapeutic trial

- At least 2 weeks since prior and no concurrent enzyme-inducing anti-epileptic drugs
(EIAEDs)

- Concurrent non-EIAEDs allowed

- No concurrent CYP450-inducing anticonvulsants

- No concurrent anticoagulants (e.g., dalteparin, warfarin, or low-molecular weight
heparin)

- If patients require warfarin or other anticoagulants (e.g., low-molecular weight
heparin) while on study, then patient may continue treatment

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent VEGF inhibitors

- No concurrent pentamidine

- No concurrent herbal or nontraditional medications

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Safety profile and optimal dose of cediranib during chemoradiotherapy (Phase I)

Outcome Description:

A dose-limiting toxicity of cediranib is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications/temozolomide and occurs following the first dose of cediranib in the chemoradiation.

Outcome Time Frame:

Up to 30 days after the last dose

Safety Issue:

Yes

Principal Investigator

Tracy Batchelor

Investigator Role:

Principal Investigator

Investigator Affiliation:

Massachusetts General Hospital

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00267

NCT ID:

NCT00662506

Start Date:

April 2008

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Glioblastoma
  • Gliosarcoma

Name

Location

Beth Israel Deaconess Medical CenterBoston, Massachusetts  02215
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Dana-Farber Cancer InstituteBoston, Massachusetts  02115