Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Multicentre, Phase II, Parallel-Group Trial of Vandetanib Monotherapy or Vandetanib in Combination With Gemcitabine Versus Gemcitabine Plus Vandetanib Matching Placebo in Subjects With Advanced Biliary Tract Cancer (Gallbladder Cancer, Cancer of the Extrahepatic Bile Duct, Intrahepatic Cholangiocarcinoma and Ampullary Carcinoma)
Brief Summary: The primary objective of the trial is to determine the efficacy of VANDETANIB monotherapy or VANDETANIB plus GEMCITABINE or PLACEBO plus GEMCITABINE in prolonging the progression-free survival (PFS) at the trial closure in patients with advanced (unresectable or metastatic) biliary tract cancer.


Options:
A: Inclusion Criteria:

* Histologically or cytologically-confirmed advanced (unresectable or metastatic) biliary tract cancer (gallbladder cancer, cancer of the extrahepatic bile duct, intrahepatic cholangiocarcinoma and ampullary carcinoma)
* Patients must have measurable or evaluable but non-measurable disease
* Chemotherapy-naïve (prior chemotherapy in the adjuvant setting completed more than 3 months before the trial entry is accepted).
* WHO performance status 0 to 2: patients must have a WHO PS ≤ 2

Exclusion Criteria:

* Patients must not have received prior systemic therapy for advanced (unresectable or metastatic) disease; prior chemotherapy in the adjuvant setting within 3 months before the trial entry is accepted
* Inadequate end-organ function or Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance wit
* Significant cardiovascular event (e.g. myocardial infarction, superior vena cava \[SVC\] syndrome, New York Heart Association \[NYHA\] classification of heart disease ³2) within 3 months before entry, or presence of cardiac disease that in the opinion of
* History of arrhythmia or QTc with Bazett's correction unmeasurable or ≥ 480 msec on screening ECG
B: Inclusion Criteria:

1. Adenocarcinoma of the biliary tract (gallbladder, intra and/or extrahepatic bile ducts, or ampulla of Vater):

   * Cytologically or histologically confirmed. In case of uncertain biliary tract origin (e.g., intrahepatic, peripheral cholangiocarcinomas), inclusion is possible if i) extensive search for primary (thoracic and abdominopelvic CT scan, colonoscopy, upper digestive endoscopy, serum PSA level for men or mammography for women, and FDG-PET if possible) is negative; and ii) histological examination is consistent with bile duct adenocarcinoma (IHC should ideally be performed and be consistent with biliary primary, e.g., positive for cytokeratin 7 and 19 and negative for cytokeratin 20).
   * not amenable to curative resection, or recurrent after resection (i.e., locally advanced or metastatic),
   * With at least one unidimensionally measurable target lesion in a non-irradiated, non-PDT-treated area (longest diameter 1 cm \[spiral CT scan\]), or 2 cm \[conventional CT scan\]).
   * With biliary obstruction controlled,
2. Age between 18 and 75 years.
3. World Health Organization (WHO) performance status of 0 or 1.
4. Life expectancy higher than 3 months.
5. No prior chemotherapy for advanced disease. Previous adjuvant chemotherapy is allowed (completed at least 6 months previously, if containing gemcitabine or platinum salts). Previous irradiation (external radiotherapy, brachytherapy) and PDT are allowed provided that there is at least one unidimensionally measurable target lesion in untreated area.
6. Bilirubin 3 times the upper limit of the normal range (ULN). Pts with jaundice or evidence of bile duct obstruction, in whom the biliary tree can be decompressed by endoscopic or percutaneous endoprothesis with subsequent reduction in bilirubin £ 3 ULN, will be eligible for the study.
7. Aminotransferases (AST, ALT) 5 ULN, INR \< 1.5 (following vitamin K1 injection in patients with current or recent history of jaundice or bile duct obstruction), creatinine 1.5 ULN, neutrophils 1.5 109/L, platelets 100 109/L, hemoglobin 9 g/dL (red blood cell transfusion if needed is allowed).
8. Written informed consent. Note: EGFR tumor status has to be known for every pt, but it is neither an inclusion/exclusion criterion nor a stratification factor. EGFR expression has to be assessed by IHC using biopsy or surgical material, at any time prior to inclusion into the study.

Exclusion Criteria:

1. Known central nervous system metastases.
2. Contraindication or history of grade 3-4 allergy reaction to one treatment component.
3. Surgery (except diagnostic biopsy), external radiotherapy, brachytherapy, or PDT within 30 days prior to start of treatment. Prior adjuvant chemotherapy is only allowed if completed at least 30 days previously (6 months if containing gemcitabine or platinum salts).
4. Participation in another clinical trial within 30 days prior to start of treatment.
5. Concomitant systemic chronic immunotherapy, chemotherapy, or antitumor hormone therapy.
6. Previous administration of EGFR inhibitors or EGF.
7. Active uncontrolled infection, peripheral neuropathy grade 2, acute or subacute bowel obstruction or history of inflammatory bowel disease, symptomatic coronary disease or myocardial infarction in the past 6 months, congestive heart failure (NYHA class II), interstitial pneumonitis or respiratory failure, or renal failure.
8. Pregnancy (or positive b-HCG dosage at baseline), breast-feeding, or lack of effective contraception in male or female pts of reproductive potential.
9. Other malignancies either currently active or in the last 5 years, except adequately treated in situ carcinoma of the cervix and basal or squamous cell skin carcinoma.
10. Legal incapacity or physical, psychological or mental status interfering with the pt's ability to terminate the study or to sign the informed consent.
C: Inclusion Criteria:

* A histopathological/cytological diagnosis of non-resectable or recurrent/metastatic biliary 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; Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; Platelet count ≥ x 109/L, \*prior transfusions for patients with low haemoglobin are allowed
* Adequate liver function : Total bilirubin ≤1.5 x upper limit of normal (ULN); ALT and/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 a calculated GFR ≥ 45 mL/min. If the calculated GFR is below 45 mL/min, isotope EDTA confirmation of adequate renal function is required
* Adequate biliary drainage, with no evidence of active uncontrolled infection (patients on long-term antibiotics are eligible provided signs of active infection have resolved)
* Women of child-bearing potential should have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued for 3 months 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-hypertensive therapy, or patients who are requiring maximal doses of calcium channel blockers to stabilise blood pressure
* Incomplete recovery (grade CTC \>1) from previous anti-cancer therapy (except haematological toxicity - see eligibility for adequate haematological function, or alopecia) or unresolved biliary tree obstruction
* Prior therapy with chemoradiotherapy (either adjuvant or in the locally advanced setting)
* Any evidence of severe or uncontrolled systemic diseases which, in the view of the investigator, 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 evidence of stable brain metastases are eligible providing that they are asymptomatic and either do not require corticosteroids or have been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids
* Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart 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 familial long 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 positive pregnancy 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 AstraZeneca staff 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 the first 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 in the view of the investigator makes it undesirable for the patient to participate in the trial
* Any psychiatric or other disorder (eg brain metastases) likely to impact on informed consent
* NB. Whilst not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, it is recommended that audiograms be carried out at baseline and prior to cycle 2.
D: Inclusion Criteria:

1. Pathologically proven biliary adenocarinoma
2. Age \> 18
3. Evaluable disease
4. ECOG performance status of 2 or better
5. No prior exposure to chemotherapy, but adjuvant chemotherapy (or chemoradiotherapy) completed 6 moths or more before study enrollment is allowed
6. Adequate bone marrow function A. WBCs \> 4,000/µL, absolute neutrophil count \[ANC\]\>1,500/µL B. Hemoglobin \>9.0 g/dL C. Platelets \> 100,000/µL
7. Adequate kidney function (creatinine\<1.5 mg/dL)
8. Adequate liver function (bilirubin\<1.5 mg/dL \[\< 2.5 mg/dL for obstructive jaundice with adequately decompressed bile duct obstruction\], transaminases levels\<3 times the upper normal limit, and serum albumin of \>2.5 mg/dL)
9. No serious medical or psychological condition that would preclude study treatment
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion Criteria:

1. Other tumor type than adenocarcinoma
2. Evidence of GI bleeding or GI obstruction
3. Presence or history of CNS metastasis
4. Pregnancy or breastfeeding
5. Other serious illness or medical conditions
6. Axial skeletal radiotherapy within 6 months
7. Neuropathy grade 2 or worse

Answer: A