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Randomised Phase II Trial of Cediranib (AZD2171) Versus Placebo in Addition to Cisplatin/Gemcitabine Chemotherapy for Patients With Advanced Biliary Tract Cancers

Phase 2/Phase 3
18 Years
Open (Enrolling)
Biliary Tract Neoplasms

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Trial Information

Randomised Phase II Trial of Cediranib (AZD2171) Versus Placebo in Addition to Cisplatin/Gemcitabine Chemotherapy for Patients With Advanced Biliary Tract Cancers

Although there is currently no standard chemotherapy for patients with advanced biliary
tract cancers (ABC) the UK ABC-02 study (the largest study by far in this patient group,
n=410) is likely to define CisGem as the global standard of care for this disease based on a
significantly improved progression-free survival and overall survival compared to
gemcitabine alone.

Vascular endothelial growth factor (VEGF) is a pivotal stimulus of physiologic and
pathologic angiogenesis, including the sustained neo-vascularisation required to support
solid tumour growth. Human biliary tract carcinoma cells have higher expression of VEGF both
in cell lines and tissues (detected in 75.6% of 33 resected clinical specimens) and this is
associated with significantly higher levels of microvessel density and the presence of
intrahepatic metastases.

Cediranib is a highly potent inhibitor of VEGF receptor 2 tyrosine kinase and VEGF-induced
signalling in endothelial cells. It has been safely combined with a CisGem regimen in lung
cancer patients.

Aims This trial aims to evaluate the effect on progression-free survival of cediranib in
combination with CisGem chemotherapy compared to CisGem and placebo.

Summary of study Consenting patients with ABC (inoperable, locally advanced, recurrent or
metastatic) will receive CisGem chemotherapy and either cediranib (experimental arm) or
placebo (standard arm) orally. Treatment will continue until disease progression
(chemotherapy will stop at 24 weeks) with tumour reassessment by CT/MRI scans at 12-weekly
intervals. All patients will be followed up for survival analysis.

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

- 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

- 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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Time Frame:

six months

Safety Issue:


Principal Investigator

Juan Valle, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Christie Hospital NHS Foundation Trust


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:

ABC-03 09/0193



Start Date:

April 2011

Completion Date:

September 2014

Related Keywords:

  • Biliary Tract Neoplasms
  • Disease-Free Survival
  • Biliary Tract Neoplasms
  • Neoplasms