Phase II Study of AZD2171 (NSC#732208) in Patients With Malignant Mesothelioma

We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed malignant mesothelioma (MM) who had received <=1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.

Pretreatment evaluation included a medical history and physical exam, complete blood count and differential, chemistry panel, pregnancy test, and a computed tomography (CT) scan of the chest, abdomen, and pelvis if relevant. A history and physical exam were repeated every 14 days and laboratory evaluations including a complete blood count with differential, serum chemistry panel, and urinalysis were repeated every 7 days. Patients were provided with a blood pressure monitoring device and a diary to record their blood pressure readings twice daily.

Patients received a minimum of 2 cycles unless unacceptable toxicity or rapid clinical progression of disease occurred. Response was evaluated by CT imaging every two cycles. Confirmatory scans were to be obtained at least 4 weeks after initial documentation of an objective complete or partial response.

Cediranib was administered orally once daily on days 1 through 28 of a 28-day cycle. Cediranib was initially dosed at 45 mg daily, but due to substantial rates of toxicity the protocol was amended in June 2007 to decrease the starting dose to 30 mg daily. Cediranib was taken 1 hour (h) before or 2 h after meals. Only one dose modification was permitted. When the starting cediranib dose was 45 mg, dose level-1 was 30 mg daily. After the protocol amendment, dose level-1 was 20 mg daily. Further dose reductions were allowed at the discretion of the investigator only if the patient had received clinical benefit from cediranib for >3 months. Patients undergo blood collection periodically during study for biomarker and optional pharmacogenomic correlative studies. After completion of study treatment, patients are followed for up to 8 weeks.

Adverse effects were graded according to National Cancer Institute Common Toxicity Criteria version 3.0. The dose was reduced for grade 3 or greater non-hematologic toxicity attributable to cediranib or grade 4 hematologic toxicity if the toxicity lasted for >5 days and did not resolve to <=grade 2. Maximal antihypertensive therapy was defined as taking 4 antihypertensive agents for >2 weeks at full dosage. For patients on antihypertensive therapy who had an elevation in systolic blood pressure (SBP) >=140 mmHg or diastolic blood pressure (DBP) >=90 mmHg on 2 separate readings during a 48 h period, the dose of cediranib was maintained without interruption while the dosage of current antihypertensive therapy was increased or an additional antihypertensive agent was started. If 2 readings reported a SBP >=180 mmHg or a DBP >=105 mmHg during a 1 week period, cediranib was held and there was either an increase in the dosage of current antihypertensive therapy or an additional antihypertensive agent was added. Resumption of cediranib was allowed only after the blood pressure was <140/90 mmHg. If 2 blood pressure readings recorded an SBP >=160 mmHg or a DBP >=105 mmHg 1 h apart during a 48 hour period in a patient already on maximal antihypertensive therapy, cediranib was held and treatment was resumed at 1 dose level lower when the blood pressure was <160/105.