Nal-IRI and 5-FU Compared to 5-FU in Patients With Cholangio- and Gallbladder Carcinoma Previously Treated With Gemcitabine-based Therapies

is an open label, randomized, multicenter phase II trial

The primary objective is to assess the efficacy of nal-IRI in gemcitabine pre-treated patients with advanced, unresectable and metastatic cholangio- and gallbladder carcinoma eligible for treatments after failure to respond to a gemcitabine-based treatment

Eligibility Criteria:
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 or cytologically confirmed, non-resectable, locally advanced or metastatic cholangiocarcinoma or gall bladder carcinoma
4. Measurable or assessable disease according to RECIST 1.1
5. Documented disease progression after prior gemcitabine or gemcitabine containing therapy, in locally advanced or metastatic setting. Examples of permitted therapies include, but are not limited to:

   1. Single agent gemcitabine
   2. Any one gemcitabine-based regimen, with or without maintenance gemcitabine
6. ECOG performance status 0-1
7. Adequate blood count, liver-enzymes, and renal function:

   * ANC \> 1,500 cells/μL without the use of hematopoietic growth factors; and
   * Platelet count ≥ 100 x 10\^9/L (\>100,000 per mm³) and
   * Hemoglobin \> 9 g/dL (blood transfusions are permitted for patients with hemoglobin levels below 9 g/dL)
   * Serum total bilirubin ≤ 3x upper normal limit (ULN) (biliary drainage is allowed for biliary obstruction; elevated bilirubin should be caused by obstruction not impaired liver function as assessed by albumin and INR values):
   * Albumin levels ≥ 3.0 g/dL
   * 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
   * 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
8. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of treatment.
9. Subject is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

1. Active CNS metastases (indicated by clinical symptoms, cerebral oedema, steroid requirement, or progressive disease); patient should have been off steroids for at least 28 days prior to starting study therapy
2. Clinically significant gastrointestinal disorder including bleeding, inflammation, occlusion, or diarrhoea \> grade 1
3. History of any second malignancy in the last 5 years; subjects with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they have been continuously disease free for at least 5 years.
4. Active uncontrolled infection, chronic infectious diseases, immune deficiency syndromes or an unexplained fever \> 38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, patients with tumour fever may be enrolled), which in the investigator's opinion might compromise the patient's participation in the trial or affect the study outcome.
5. Premalignant hematologic disorders, e.g. myelodysplastic syndrome
6. Pre-existing lung disease
7. Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment
8. History of hypersensitivity to any of the study drugs or any excipient (nal-IRI, other liposomal products, fluoropyrimidines or leucovorin)
9. Allogeneic transplantation requiring immunosuppressive therapy or other major immunosuppressive therapy
10. Severe non-healing wounds, ulcers or bone fractions
11. Evidence of bleeding diathesis or coagulopathy
12. 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.
13. Medication that is known to interfere with any of the agents applied in the trial.
14. 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). \[Acceptable methods of contraception are:implants, injectable contraceptives, combined oral contraceptives, intrauterine pessaries (only hormonal devices), sexual abstinence or vasectomy of the partner\].
15. Known Gilbert-Meulengracht syndrome
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 5 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. Previous enrollment in the NIFE trial \[AIO-YMO/HEP-0315\]
20. Involvement in the planning and/or conduct of the study (applies to both Baxalta staff and/or staff of sponsor and study site)
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 § 40 Abs. 1 S. 3 Nr. 4 AMG.
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 \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].