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

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)

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.

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.

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