Cediranib Maleate With or Without Gefitinib in Treating Patients With Recurrent or Progressive Glioblastoma

Study Overview
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Brief Summary
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RATIONALE: Cediranib Maleate and gefitinib 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. It is not yet known whether cediranib maleate given together with gefitinib is more effective than cediranib maleate given alone in treating patients with recurrent or progressive glioblastoma. PURPOSE: This randomized phase II trial is studying the side effects of giving cediranib maleate together with gefitinib and to see how well it works compared with giving cediranib maleate together with a placebo in treating patients with recurrent or progressive glioblastoma.

Detailed Description
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OBJECTIVES: To compare progression-free survival, overall survival, radiological response, and safety and tolerability of cediranib maleate in combination with gefitinib versus cediranib maleate in combination with a placebo in patients with recurrent or progressive glioblastoma following standard front-line treatment. OUTLINE: This is a multicenter study. Patients receive cediranib maleate and gefitinib or cediranib maleate and a placebo once daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Blood and tissue samples are collected from some patients for genetic profiling and biomarker analysis. Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Official Title
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Multi-Center, Randomized, Double-Blind Phase II Study Comparing Cediranib (AZD2171) Plus Gefitinib (Iressa, ZD1839) With Cediranib Plus Placebo in Subjects With Recurrent/Progressive Glioblastoma (DORIC Trial)

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: cediranib maleate
* Drug: gefitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed glioblastoma Measurable disease by MRI Completed standard first-line treatment for glioblastoma including surgery (unless not received due to anatomical location), radiotherapy and temozolomide (last dose given at least 28 days prior to enrollment) No other prior treatment for glioblastoma except Gliadel or steroids Recurrent or progressive disease after standard first-line treatment No disease progression within 3 months of completion of radiotherapy No intra- or peri-tumoral hemorrhage PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Mini-mental status score ≥ 15 Life expectancy ≥ 12 weeks Serum bilirubin, ALT/AST, creatinine, and urine protein normal Adequate bone marrow reserve Not pregnant or nursing Normal ECG No history of familial long QT syndrome No absorption or swallowing difficulties No uncontrolled hypertension or cardiac ventricular arrhythmias No current or history of uncontrolled hypertension or requiring maximal doses of calcium channel blockers No severe or uncontrolled disease No history of lung disease No recent hemorrhage or hemoptysis No known hypersensitivity to cediranib maleate, gefitinib, or any excipients No history of other malignancies except adequately treated basal cell or squamous cell carcinoma or carcinoma in situ within the past 5 years, unless disease-free for 2 years with tissue diagnosis No known HIV positivity No known hepatitis B or C infection No unhealed surgical incision Not involved in planning or conducting this study PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior anticancer therapy, including radiotherapy At least 3 months since prior cranial radiation At least 30 days since prior investigational drugs At least 28 days since prior craniotomy At least 2 weeks since prior enzyme-inducing antiepileptic drugs At least 2 weeks since prior and no concurrent dexamethasone (> 8 mg/day) or equivalent At least 14 days since prior major surgery or brain biopsy No concurrent steroids OR on stable dose 5 days prior to baseline MRI No other concurrent anticancer therapy, except for steroids (dexamethasone only) No previous enrollment on the current study No prior inhibitors of angiogenesis, EGFR, or downstream targets No prior radiosurgery or brachytherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cediranib & Gefitinib<br>Cediranib maleate 30mg od orally and gefitinib 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. | Drug: cediranib maleate<br> <br> Drug: gefitinib<br> <br> |
| Placebo Comparator: Cediranbib & placebo<br>Cediranib maleate 30mg od orally and placebo 500mg od orally. Each cycle of treatment lasts 6 weeks. Treatment will continue until confirmation of progression, patient decision or the development of unacceptable toxicity (if there is radiological progression only treatment can continue if the investigator has the opinion that the patient is receiving benefit. | Drug: cediranib maleate<br> <br> Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) defined as the time from the date of randomisation to the date of first progression or death due to any cause, whichever one comes first. The progression definition will be based on modified RANO criteria (Wen 2010), such that progression will be defined as the earliest time that at least one of the following occurs: Clinical deterioration Failure to return for evaluation as a result of death or deteriorating condition Or, by retrospective radiographic central review: Any new lesion Increase in ≥25% of sum of the products of perpendicular diameters of enhancing lesions compared with baseline scan, on stable or increasing doses of steroids (dexamethasone) compared to baseline (T1 post-contrast scan) Clear progression of non-measureable disease Significant increase in T2/FLAIR non-enhancing lesion - on stable or increasing steroids (dexamethasone) compared with baseline or best response not caused by co-morbid events. | from the date of randomisation to the date of first progression or death due to any cause, until 6 months from the date the last patient finished trial treatment (the day after the date that the last trial drug was taken) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | from date of randomization to date of Death due to any cause. | 
| Radiographic Response Rate |  | from baseline scan to six week and 12 week scans | 
| Progression-free Survival Rate at 6 Months |  | from the date of randomisation to 6 months | 
| Steroid Use |  | from randomization to first increase in dexamethasone dose | 
| Time to Deterioration of Neurological Status |  | from date of randomization to the date of first neurological status worsening in comparison to baseline (first of 2 confirmatory reports at 2 consecutive visits, 6 weeks apart) as assessed by the clinician, or until date of death, whichever is first. | 
| Safety and Tolerability |  | from date of randomisation to death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, recurrent adult brain tumor