Please select the eligibility criteria that correspond to the clinical trial below.
Title: Gemcitabine, Alone or in Combination With Cisplatin, in Patients With Advanced or Metastatic Cholangiocarcinomas and Other Biliary Tract Tumors: A Multicentre, Randomized Phase III Study
Brief Summary: RATIONALE: Drugs used in chemotherapy, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether gemcitabine is more effective with or without cisplatin in treating cholangiocarcinoma or biliary tract tumors.

PURPOSE: This randomized phase III trial is studying gemcitabine and cisplatin to see how well they work compared to gemcitabine alone in treating patients with unresectable locally advanced or metastatic cholangiocarcinoma or other biliary tract tumors.


Options:
A: 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.
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:

* 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
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: D