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Nal-IRI With 5-fluorouracil (5-FU) and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Biliary-tract Cancer (NIFE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03044587
Recruitment Status : Active, not recruiting
First Posted : February 7, 2017
Last Update Posted : May 3, 2021
Institut für Klinisch-Onkologische Forschung der Krankenhaus Nordwest GmbH
Information provided by (Responsible Party):

Brief Summary:
AIO-YMO/HEP-0315 (NIFE) is an open label, non-comparative, randomized, multicenter phase II trial

Condition or disease Intervention/treatment Phase
Adenocarcinoma Metastatic Biliary Tract Cancer Adenocarcinoma of the Biliary Tract Adenocarinoma Locally Advanced Non-Resectable Hepatocellular Carcinoma Intrahepatic Bile Duct Carcinoma Extrahepatic Bile Duct Carcinoma Drug: Arm NaI-IRI + 5-FU + Leucovorin (Arm A) Drug: Arm Cisplatin + Gemcitabine (Arm B) Phase 2

Detailed Description:
The primary objective is to determine whether a combination of 5-FU and nal-IRI prolongs progression-free survival in patients with locally advanced or metastatic adenocarcinoma of the biliary tract

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 93 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : January 24, 2018
Actual Primary Completion Date : September 5, 2020
Estimated Study Completion Date : July 2022

Arm Intervention/treatment
Experimental: Arm NaI-IRI + 5-FU + Leucovorin (Arm A)
Nal-IRI [Irinotecan liposome], 5-FU [5-Fluorouracil], Leucovorin Cycle q2w
Drug: Arm NaI-IRI + 5-FU + Leucovorin (Arm A)
Nal-IRI (80 mg/m2 as a 1.5 hour infusion), 5-FU (2400 mg/m2 as 46 hour infusion) and Leucovorin (400 mg/m2 as 0.5 hour infusion) Cycle q2w

Arm Cisplatin + Gemcitabine (Arm B, standard of care)
Cisplatin, Gemcitabine Cycle q3w
Drug: Arm Cisplatin + Gemcitabine (Arm B)
Cisplatin (25 mg/m2 as 1 hour infusion on D1, D8) and Gemcitabine (1000 mg/m2 as 0.5 hour infusion on D1, D8) Cycle q3w

Primary Outcome Measures :
  1. Progression-free survival [PFS] [ Time Frame: approx. 25 months ]

Secondary Outcome Measures :
  1. Overall progression free survival according to RECIST 1.1 [ Time Frame: approx. 54 months ]
    Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)

  2. 3-years overall survival [ Time Frame: approx. 36 months ]
    3-years overall survival

  3. Disease control rate according to RECIST 1.1 [ Time Frame: approx. 54 months ]
  4. Objective tumor response rate (ORR) according to RECIST 1.1 [ Time Frame: approx. 54 months ]
    Proportion of patients with an objective response according to RECIST 1.1

  5. Toxicity/Safety according to CTC-AE-criteria [ Time Frame: approx. 54 months ]
  6. Health related quality of life [ Time Frame: approx. 54 months ]

  7. Health related quality of life [ Time Frame: approx. 54 months ]

  8. Health related quality of life [ Time Frame: approx. 54 months ]
    Hospital Anxiety and Depression Scale (HADS-D)

  9. Retrospective correlation of resectability in accordance with a central surgical board compared to local surgical review [ Time Frame: approx. 54 months ]
    Tumor resectability in accordance with a retrospective central surgical board compared to local surgical review

  10. Retrospective central radiological review [ Time Frame: approx. 54 months ]

Other Outcome Measures:
  1. Exploratory biomarkers analysis [ Time Frame: approx. 54 months ]
    cfDNA exome sequencing, transcriptome, miRNA-arrays prior to and after start of treatment and upon progress

  2. Establishment of Predictive/Prognostic biomarker profiles for advanced cholangiocarcinoma [ Time Frame: approx. 54 months ]
  3. Tumor Evolution under systemic therapy [ Time Frame: approx. 54 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03044587

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Universitätsklinikum Ulm
Ulm, Germany, 89081
Sponsors and Collaborators
Institut für Klinisch-Onkologische Forschung der Krankenhaus Nordwest GmbH
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Principal Investigator: Thomas J. Ettrich, Dr. Klinik für Innere Medizin I, Universitätsklinikum Ulm
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: AIO-Studien-gGmbH Identifier: NCT03044587    
Other Study ID Numbers: AIO-YMO/HEP-0315
2016-002467-34 ( EudraCT Number )
O16-33004 ( Other Identifier: Baxalta GmbH )
First Posted: February 7, 2017    Key Record Dates
Last Update Posted: May 3, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AIO-Studien-gGmbH:
Biliary Tract Cancer
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Biliary Tract Neoplasms
Carcinoma, Ductal
Bile Duct Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Biliary Tract Diseases
Neoplasms, Ductal, Lobular, and Medullary
Bile Duct Diseases
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs