Cediranib Versus Placebo Plus Cisplatin/Gemcitabine Chemotherapy for Patients With Advanced Biliary Tract Cancers

Inclusion Criteria:

• A histopathological/cytological diagnosis of non-resectable or recurrent/metastaticbiliary tract carcinoma (intra- or extra-hepatic), gallbladder or ampullary carcinoma

• Measurable disease on CT or MR scanning. Radiological assessments must be done within 4 weeks of randomisation

• ECOG performance status 0 or 1

• Age ≥ 18 and estimated life expectancy > 3 months

• Adequate haematological function: Haemoglobin ≥ 10g/dl*; WBC ≥ 3.0 x 109/L; Absoluteneutrophil count (ANC) ≥ 1.5 x 109/L; Platelet count ≥ x 109/L, *prior transfusionsfor patients with low haemoglobin are allowed

• Adequate liver function : Total bilirubin ≤1.5 x upper limit of normal (ULN); ALTand/or AST ≤ 2.5 x ULN (If liver metastases are present, ALT or AST < 5 x ULN)

• Alkaline phosphatase ≤ 5 x ULN

• Adequate renal function with serum urea and serum creatinine < 1.5 times ULN and acalculated GFR ≥ 45 mL/min. If the calculated GFR is below 45 mL/min, isotope EDTAconfirmation of adequate renal function is required

• Adequate biliary drainage, with no evidence of active uncontrolled infection (patientson long-term antibiotics are eligible provided signs of active infection haveresolved)

• Women of child-bearing potential should have a negative pregnancy test prior to studyentry AND be using an adequate contraception method, which must be continued for 3months after completion of chemotherapy

Exclusion Criteria:

• Significant haemorrhage (>30 mL bleeding/episode in previous 3 months) or haemoptysis (>5 mL fresh blood in previous 4 weeks)

• Patients with history of poorly controlled hypertension with resting blood pressure >150/100 mmHg in the presence or absence of a stable regimen of anti-hypertensivetherapy, or patients who are requiring maximal doses of calcium channel blockers tostabilise blood pressure

• Incomplete recovery (grade CTC >1) from previous anti-cancer therapy (excepthaematological toxicity - see eligibility for adequate haematological function, oralopecia) or unresolved biliary tree obstruction

• Prior therapy with chemoradiotherapy (either adjuvant or in the locally advancedsetting)

• Any evidence of severe or uncontrolled systemic diseases which, in the view of theinvestigator, makes it undesirable for the patient to participate in the trial (e.g.unstable or uncompensated respiratory, cardiac, hepatic or renal disease)

• Untreated unstable brain or meningeal metastases. Patients with radiological evidenceof stable brain metastases are eligible providing that they are asymptomatic andeither do not require corticosteroids or have been treated with corticosteroids, withclinical and radiological evidence of stabilisation at least 10 days afterdiscontinuation of steroids

• Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 weekapart unless urinary protein <1.5 g in a 24-hour period

• History of significant gastrointestinal impairment, as judged by the Investigator,that would significantly affect the absorption of cediranib

• Mean QTc with Bazetts correction >470 msec in screening ECG or history of familiallong QT syndrome

• Recent (<14 days) major thoracic or abdominal surgery prior to entry into the study,or a surgical incision that is not fully healed

• Pregnant or breast-feeding women or women of childbearing potential with a positivepregnancy test prior to receiving study medication

• Known hypersensitivity to cediranib or any of its excipients

• Known risk of the patient transmitting HIV, hepatitis B or C via infected blood

• Involvement in the planning and conduct of the study (applies to both AstraZenecastaff or staff at the study site(s)

• Previous enrolment or randomisation of treatment in the present study

• Treatment with an investigational (non-registered) drug within 30 days prior to thefirst dose of cediranib

• Other concomitant anti-cancer therapy (except steroids)

• Incomplete recovery from previous surgery or unresolved biliary tract obstruction

• Patients undergoing current treatment with curative intent

• History of prior malignancy that will interfere with the response evaluation (exceptions include in-situ carcinoma of the cervix treated by cone-biopsy/resection,non-metastatic basal and/or squamous cell carcinomas of the skin, any early stage (stage I) malignancy adequately resected for cure greater than 5 years previously)

• Any evidence of severe or uncontrolled systemic diseases or laboratory finding that inthe view of the investigator makes it undesirable for the patient to participate inthe trial

• Any psychiatric or other disorder (eg brain metastases) likely to impact on informedconsent

• NB. Whilst not excluded, patients with significant impaired hearing must be made awareof potential ototoxicity and may choose not to be included. If included, it isrecommended that audiograms be carried out at baseline and prior to cycle 2.