Please select the eligibility criteria that correspond to the clinical trial below.
Title: Nal-IRI With 5-fluorouracil (5-FU) and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Biliary-tract Cancer - An Open Label, Non-comparative, Randomized, Multicenter Phase II Trial
Brief Summary: AIO-YMO/HEP-0315 (NIFE) is an open label, non-comparative, randomized, multicenter phase II trial


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:

1. Written informed consent incl. participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Age ≥ 18 years at time of study entry
3. Histologically confirmed, non-resectable, locally advanced or metastatic adenocarcinoma of the intrahepatic or extrahepatic biliary tract
4. Protocol-specific staging guidelines have to be observed and non-resectability has to be confirmed by local tumor board
5. Measurable or assessable disease according to RECIST 1.1
6. ECOG performance status 0-1
7. Life expectancy of more than 3 months
8. If applicable, adequately treated biliary tract obstruction before study entry with total bilirubin concentration ≤ 2 x ULN
9. Adequate blood count, liver-enzymes, and renal function:

   * White blood cell count ≥ 3.5 x 10\^6/mL
   * Platelet count ≥ 100 x 10\^9/L (\>100,000 per mm3)
   * AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal
   * Serum Creatinine ≤ 1.5 x ULN and a calculated glomerular filtration rate ≥ 30 mL per minute
10. Patients not receiving therapeutic anticoagulation must have an INR \< 1.5 ULN and PTT \< 1.5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of randomization
11. No prior palliative chemotherapy for biliary tract cancer
12. No adjuvant treatment within 6 months prior to study entry
13. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

1. Active uncontrolled infection, chronic infectious diseases, immune deficiency syndromes
2. Premalignant hematologic disorders, e.g. myelodysplastic syndrome
3. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) within 6 months before enrollment
4. Prior (\>5 years) or concurrent malignancy (other than biliary-tract cancer) which either progresses or requires active treatment. Exceptions are: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or T1b prostate carcinoma, or superficial bladder tumor \[Ta, Tis and T1\].
5. Pre-existing lung disease
6. History or clinical evidence of CNS metastases

   Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria:
   1. are asymptomatic and
   2. have no requirement for steroids 6 weeks prior to start of study treatment. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases
7. History of hypersensitivity to any of the study drugs or any of the constituents of the products
8. Allogeneic transplantation requiring immunosuppressive therapy or other major immunosuppressive therapy
9. Severe non-healing wounds, ulcers or bone fractions
10. Evidence of bleeding diathesis or coagulopathy
11. Major surgical procedures, except open biopsy, nor significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgical procedure during the course of the study except for surgery of central intravenous line placement for chemotherapy administration.
12. Medication that is known to interfere with any of the agents applied in the trial.
13. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). \[Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessary (only hormonal devices), sexual abstinence or vasectomy of the partner\]. Women of childbearing potential must have a negative pregnancy test (serum β-HCG) at Screening.
14. Known Gilbert-Meulengracht syndrome
15. Known chronic hypoacusis, tinnitus or vertigo
16. Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
17. Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is of longer duration.
18. Previous enrollment or randomization in the present study (does not include screening failure).
19. Any other chemotherapy at study start
20. Involvement in the planning and/or conduct of the study
21. Patient who might be dependent on the sponsor, site or the investigator
22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
23. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts.
C: 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
D: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed biliary tract, gallbladder, or ampullary carcinoma

  * Intra- or extra-hepatic disease allowed
* Unresectable locally advanced, recurrent, or metastatic disease
* No brain metastases

PATIENT CHARACTERISTICS:

Performance status

* ECOG 0-2

Life expectancy

* At least 3 months

Hematopoietic

* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 10 g/dL (transfusion allowed)
* WBC ≥ 3,000/mm\^3

Hepatic

* AST and ALT ≤ 3 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
* Bilirubin ≤ 1.5 times ULN
* Alkaline phosphatase ≤ 3 times ULN (5 times ULN if liver metastases are present)
* Adequate biliary drainage
* No unresolved biliary tract obstruction

Renal

* Creatinine \< 1.5 times ULN
* Urea \< 1.5 times ULN
* Glomerular filtration rate (GFR) ≥ 45 mL/min

  * If GFR \< 60 mL/min, isotope EDTA confirmation of adequate renal function is required

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 3 months after study participation
* No active, uncontrolled infection
* No other severe or uncontrolled systemic disease
* No other malignancy within the past 5 years except nonmetastatic basal cell or squamous cell skin cancer or carcinoma in situ of the cervix treated by cone-biopsy or resection
* No psychiatric disorder that would preclude giving informed consent

PRIOR CONCURRENT THERAPY:

Chemotherapy

* At least 6 months since prior adjuvant chemotherapy
* No prior gemcitabine hydrochloride
* No prior cisplatin
* No prior systemic chemotherapy for locally advanced or metastatic disease except low-dose radiosensitizing chemotherapy in conjunction with radiotherapy

Radiotherapy

* Prior radiotherapy for localized disease allowed provided there is clear evidence of disease progression afterwards

Surgery

* Prior curative surgery allowed provided there is evidence of nonresectable disease relapse requiring systemic chemotherapy

Other

* Recovered from all prior therapies
* Prior photodynamic therapy (PDT) allowed provided it was given for localized disease only (with no evidence of metastatic disease) and resulted in subsequent disease progression after completion of therapy OR to relieve biliary obstruction in the presence of metastatic disease

  * PDT must have been completed ≥ 4 weeks ago
* At least 4 weeks since prior investigational agents
* No other concurrent, curative anticancer therapy

Answer: B