Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase II Study of Gemcitabine Plus Oxaliplatin (GEMOX) With or Without Cetuximab in Locally Advanced and Metastatic Biliary Tract Cancer (BTC)
Brief Summary: The primary objective is to investigate the objective response rate in patients receiving GEMOX (gemcitabine plus oxaliplatin) plus cetuximab as first line treatment in advanced or metastatic unresectable BTC biliary tract cancer compared to patients receiving the same chemotherapy without cetuximab. The secondary objectives include the exploration of the effect of the multimodality strategy on progression-free and overall survival, biomarker prediction, and toxicity.


Options:
A: 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.
B: Inclusion Criteria:

* Histologically or cytologically documented surgically unresectable or metastatic biliary tract adenocarcinoma (KRAS wild-type) including gallbladder either at diagnosis or relapsing after surgery.
* Documented KRAS status either on primary tumor or metastasis. KRAS testing will be performed as per center procedure (no centralized analysis is required).
* Availability of a tumor biopsy for the study of tumor biomarkers potentially involved in the response/resistance mechanisms.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
* Estimated life expectancy of at least 3 months.
* Adequate bone marrow, hepatic, and renal function determined within 2 weeks prior to starting therapy, defined as:

  * absolute neutrophil count (ANC) ≥ 1.5 x 10E9 cells/L
  * platelet count ≥ 100 x 10E9 cells/L
  * total hemoglobin \> 9.0 g/dL
  * total bilirubin \< 2.0 x institutional upper limit of normal (ULN)
  * alanine aminotransferase (ALT), aspartate transaminase (AST) \< 2.5 x ULN - alkaline phosphatase \< 3.0 x ULN
  * creatinine \< 1.5 X ULN
  * magnesium ≥ LLN
  * calcium ≥ LLN
* Voluntary, written and dated informed consent.

Exclusion Criteria:

* Any previous chemotherapy or target therapy .
* Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
* Coexisting malignancies, except for basal or squamous cell carcinoma of the skin or other solid tumors curatively treated with no evidence of disease for ≥ 3 years.
C: 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.
D: Inclusion criteria:

* Cyto-/histological confirmed unresectable, locally advanced, or metastatic biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma or adenocarcinoma of gallbladder, but NOT other peri-ampulla Vateri or mixed tumor.
* At least one, not previously irradiated, measurable lesion according to RECIST (version 1.1).
* Eastern Cooperative Oncology Group (ECOG) performance score of 0-1.
* Aged no less than 20 years, at the time of acquisition of informed consent.
* Life expectancy \>= 3 months.
* Adequate organ and bone marrow function as defined below: WBC \>= 3.00 × 103/L and absolute neutrophil count \>= 1.50 × 103/L, Platelet count \>= 100 × 103/L, Hemoglobin level \>= 10 g/dL, Serum creatinine \<= 1.5 x Upper Normal Limit (UNL) and calculated GFR \>= 40mL/min, Serum bilirubin \<= 1.5 x UNL , ALT \<= 2.5x UNL.
* Ability to understand and willingness to sign written Informed Consent Form.

Exclusion criteria:

* Other anti-tumor agent such as systemic chemotherapy, immunotherapy or EGFR/VEGF-pathway-targeting therapy before the commencement of study treatment.
* Radiotherapy (except palliative irradiation of bone lesions) within 4 weeks before the commencement of study treatment.
* Other cancer or prior treatment for other carcinomas within the last five years, except cured non-melanoma skin cancer and treated in-situ cervical cancer.
* Known CNS metastasis.
* Major surgery within 4 weeks prior to start of study treatment (diagnostic biopsy, laparotomy, line placement is not considered as major surgery).
* Pre-existing peripheral neuropathy \>= grade 2.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction in the past 12 months, active gastrointestinal bleeding, central nervous system disorders or psychiatric illness/social situation that would limit compliance with study requirements or judged to be ineligible for the study by the investigator.
* Having received any investigational agents or participated in any investigational drug study within 4 weeks prior to study enrollment.
* Pregnant or breast-feeding female (a pregnancy test must be performed on all female patients who are of child-bearing potential before entering the study, and the result must be negative).
* Poor compliance.

Answer: D