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

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

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

Study Overview

• Status: Completed
• Conditions: Biliary Tract Cancer; Extrahepatic Bile Duct Carcinoma; Non-Resectable Hepatocellular Carcinoma; Adenocarcinoma Metastatic; Adenocarcinoma of the Biliary Tract; Adenocarinoma Locally Advanced; Intrahepatic Bile Duct Carcinoma
• Intervention / Treatment: Drug: Arm NaI-IRI + 5-FU + Leucovorin (Arm A); Drug: Arm Cisplatin + Gemcitabine (Arm B)

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

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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
Other: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival [PFS]	approx. 25 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall progression free survival according to RECIST 1.1	Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)	approx. 54 months
3-years overall survival	3-years overall survival	approx. 36 months
Disease control rate according to RECIST 1.1		approx. 54 months
Objective tumor response rate (ORR) according to RECIST 1.1	Proportion of patients with an objective response according to RECIST 1.1	approx. 54 months
Toxicity/Safety according to CTC-AE-criteria		approx. 54 months
Health related quality of life	EORTC QLQ-BIL21	approx. 54 months
Health related quality of life	EORTC QLQ-C30	approx. 54 months
Health related quality of life	Hospital Anxiety and Depression Scale (HADS-D)	approx. 54 months
Retrospective correlation of resectability in accordance with a central surgical board compared to local surgical review	Tumor resectability in accordance with a retrospective central surgical board compared to local surgical review	approx. 54 months
Retrospective central radiological review		approx. 54 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory biomarkers analysis	cfDNA exome sequencing, transcriptome, miRNA-arrays prior to and after start of treatment and upon progress	approx. 54 months
Establishment of Predictive/Prognostic biomarker profiles for advanced cholangiocarcinoma		approx. 54 months
Tumor Evolution under systemic therapy		approx. 54 months

Collaborators and Investigators

• Sponsor: AIO-Studien-gGmbH
• Collaborators: Servier; Institut für Klinisch-Onkologische Forschung der Krankenhaus Nordwest GmbH
• Investigators: Principal Investigator: Thomas J. Ettrich, Dr., Klinik für Innere Medizin I, Universitätsklinikum Ulm

Publications and helpful links

General Publications

• Perkhofer L, Berger AW, Beutel AK, Gallmeier E, Angermeier S, Fischer von Weikersthal L, Goetze TO, Muche R, Seufferlein T, Ettrich TJ. Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study. BMC Cancer. 2019 Oct 23;19(1):990. doi: 10.1186/s12885-019-6142-y.
• Ettrich TJ, Modest DP, Sinn M, Striefler JK, Opitz B, Goetze T, Gallmeier E, Angermeier S, Fischer von Weikersthal L, Jacobasch L, Waldschmidt D, Niedermeier M, Sohm M, Berger AW, Manzini G, Fehrenbach U, Auer TA, Hosse C, Vogele D, Sookthai D, Schaaf M, Muche R, Hinke A, Seufferlein T, Perkhofer L. Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315). J Clin Oncol. 2024 Sep 10;42(26):3094-3104. doi: 10.1200/JCO.23.01566. Epub 2024 Jun 6.

Helpful Links

• AIO - Working Group for Medical Oncology from the German Cancer Society
• AIO-Studien-gGmbH

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2018
• Primary Completion (Actual): January 1, 2022
• Study Completion (Actual): January 31, 2025

Study Registration Dates

• First Submitted: January 23, 2017
• First Submitted That Met QC Criteria: February 3, 2017
• First Posted (Estimated): February 7, 2017

Study Record Updates

• Last Update Posted (Estimated): October 1, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Biliary Tract Cancer; NaI-IRI
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Carcinoma; Bile Duct Diseases; Biliary Tract Neoplasms; Cholangiocarcinoma; Bile Duct Neoplasms; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Enzymes and Coenzymes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Gemcitabine; Fluorouracil; Leucovorin
• Other Study ID Numbers: AIO-YMO/HEP-0315; 2016-002467-34 (EudraCT Number); O16-33004 (Other Identifier: Baxalta GmbH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No