Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase II, Open-label, Randomized Clinical Trial of Panitumumab Plus Gemcitabine and Oxaliplatin (GEMOX) Versus GEMOX Alone as First Line Treatment in Advanced Biliary Tract Adenocarcinoma
Brief Summary: This is a multi-centre phase II, open-label, randomized (1:1), parallel-arm, study of panitumumab in combination with chemotherapy (P-GEMOX) versus chemotherapy alone (GEMOX). Eligible subjects will be enrolled and randomized to receive first-line combination therapy consisting of panitumumab and GEMOX (experimental arm) or GEMOX alone (control arm).The ame of the Stuy is to evaluate the clinical activity of the P-GEMOX (Panitumumab and GEMOX) combination compared to GEMOX alone in patients with previously untreated surgically unresectable or metastatic biliary tract carcinoma (KRAS wild-type)and To evaluate the safety profile of the P-GEMOX combination; to assess the objective response rate; to assess overall survival; to study the correlation between biomarkers with activity and efficacy.


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. 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:

* 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.
D: 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.

Answer: C