AZD2171 in Treating Patients With Recurrent Glioblastoma Multiforme

A Phase II Study of AZD2171 in Recurrent Glioblastoma

This phase II trial is studying how well AZD2171 works in treating patients with recurrent glioblastoma multiforme. AZD2171 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor

Study Overview

• Status: Completed
• Conditions: Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor
• Intervention / Treatment: Drug: cediranib maleate

Detailed Description

PRIMARY OBJECTIVE:

I. Determine the proportion of patients with recurrent glioblastoma multiforme (GM) who are alive and progression free 6 months after starting AZD2171 therapy.

SECONDARY OBJECTIVES:

I. Assess the biological effect of AZD2171 by using the following MRI techniques: dynamic contrast-enhanced imaging; arterial spin-labeling imaging; perfusion-weighted imaging; and diffusion- tensor imaging at serial time points.

II. Measure circulating endothelial and progenitor cells and plasma levels of tumstatin, (vascular endothelial growth factor (VEGF)-A and -D, sVEGF receptors, P1GF, platelet-derived growth factor (PDGF)-AA, PDGF-AB, PDGF-BB, Ang1, thrombospondin-1, and interleukin-8 as markers for response to antiangiogenic therapy in recurrent GM.

III. Correlate treatment outcomes with pre-AZD2171 tumor specimens with respect to microvascular density, basement membrane and pericyte coverage, and angiopoietin-1 and -2 expression to determine whether these immunohistochemical analyses can be predictive of the response to AZD2171.

IV. Measure polymorphisms of kdr/flk-1 gene and genetic analysis of HIF1-alpha, TP53, and endothelial nitric oxide synthase genes in the archival tumor specimens.

V. Determine the overall survival of patients with recurrent GM treated with AZD2171.

VI. Determine the radiographic response rate in patients with recurrent GM treated with AZD2171.

VII. Determine the safety of AZD2171 in this patient population.

OUTLINE: This is a multicenter study.

Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 12 months.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Criteria:

• AST/ALT =< 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance >= 60 mL/min

• Measurable contrast-enhancing tumor >= 1 cm in longest diameter by baseline MRI or CT scan:

  • Patient must have been on no steroids OR a stable dose of steroids for >= 5 days prior to baseline MRI or CT scan
  • Patients who are on steroids must be maintained on a stable corticosteroid regimen from baseline scan until the start of study treatment
• No intratumoral or peritumoral hemorrhage by MRI
• Karnofsky performance status >= 60%
• No other concurrent malignancy within the past 5 years except curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast
• Mini-mental status examination score >= 15
• Histologically confirmed glioblastoma multiforme
• Platelet count >= 100,000/mm3
• Hemoglobin >= 8 g/dL
• Bilirubin normal
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD2171
• Mean QTc =< 470 msec (with Bazett's correction) on screening electrocardiogram
• No history of familial long QT syndrome
• No greater than +1 proteinuria on 2 consecutive dipsticks taken >= 1 week apart unless first urinalysis shows no protein
• No uncontrolled intercurrent illness, including, but not limited to, any of the following:

Hypertension; Ongoing or active infection; Symptomatic congestive heart failure; Unstable angina pectoris; Cardiac arrhythmia; Psychiatric illness/social situations that would limit compliance with study requirements

• No known coagulopathy that increases the risk of bleeding
• No history of clinically significant hemorrhages
• Recovered from toxicity of prior therapy
• At least 3 months since prior radiation therapy, including cranial radiation therapy
• At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas)
• At least 3 weeks since prior molecularly-targeted agents
• At least 4 weeks since prior major surgery
• No more than 2 prior chemotherapy regimens or antineoplastic drugs
• More than 30 days since prior participation in an investigational trial
• At least 2 weeks since prior enzyme-inducing antiepileptic drugs (EIAEDs)
• No concurrent EIAEDs; Concurrent non-EIAEDs allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No concurrent vascular endothelial growth factor inhibitors:

Prior thalidomide or lenolidomide allowed

• No concurrent anticoagulants (e.g., warfarin) or antiplatelet agents including aspirin
• No other concurrent anticancer agents or therapies
• No concurrent grapefruit juice
• WBC >= 3,000/mm3
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Absolute neutrophil count >= 1,500/mm3

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral AZD2171 once daily on days 1-28.	Drug: cediranib maleate; Given orally; Other Names: AZD2171; Recentin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients alive and progression-free at 6 months	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiographic response proportion	Will be described with 95% confidence limits.	Up to 12 months
Overall survival	Will be described with 95% confidence limits.	Up to 12 months
Toxicity proportion	Will be described with 95% confidence limits.	Up to 12 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tracy Batchelor, Massachusetts General Hospital

Publications and helpful links

General Publications

• Emblem KE, Farrar CT, Gerstner ER, Batchelor TT, Borra RJ, Rosen BR, Sorensen AG, Jain RK. Vessel caliber--a potential MRI biomarker of tumour response in clinical trials. Nat Rev Clin Oncol. 2014 Oct;11(10):566-84. doi: 10.1038/nrclinonc.2014.126. Epub 2014 Aug 12.
• Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010 Jun 10;28(17):2817-23. doi: 10.1200/JCO.2009.26.3988. Epub 2010 May 10.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: March 21, 2006
• First Submitted That Met QC Criteria: March 21, 2006
• First Posted (Estimate): March 22, 2006

Study Record Updates

• Last Update Posted (Estimate): August 22, 2013
• Last Update Submitted That Met QC Criteria: August 14, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Gliosarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Cediranib
• Other Study ID Numbers: NCI-2009-00127; N02CO12400 (Other Grant/Funding Number: US NIH Grant/Contract Award Number); 05-254; CDR0000460079 (Registry Identifier: PDQ (Physician Data Query))