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

Abstract Background Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. Methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. Discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. Trial registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

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Multicenter phase II study of docetaxel and oxaliplatin combination in patients with locally advanced or metastatic biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.e15150 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. e15150-e15150

Author(s):

Eun-Kee Song ◽

Hye-Suk Han ◽

Ki Hyeong Lee ◽

Kyu Taek Lee ◽

Sang Byung Bae ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Phase Ii Study ◽

Locally Advanced ◽

Tract Cancer ◽

Multicenter Phase

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A randomised phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapy

European Journal of Cancer ◽

10.1016/j.ejca.2021.06.019 ◽

2021 ◽

Vol 154 ◽

pp. 288-295

Author(s):

In Sil Choi ◽

Ki Hwan Kim ◽

Ju Hyun Lee ◽

Koung Jin Suh ◽

Ji-Won Kim ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Phase Ii Study ◽

Locally Advanced ◽

First Line ◽

Tract Cancer

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A Multicenter Phase II Study of Gemcitabine, Capecitabine, and Bevacizumab for Locally Advanced or Metastatic Biliary Tract Cancer

American Journal of Clinical Oncology ◽

10.1097/coc.0000000000000347 ◽

2018 ◽

Vol 41 (7) ◽

pp. 649-655 ◽

Cited By ~ 14

Author(s):

Renuka V. Iyer ◽

Venkata K. Pokuri ◽

Adrienne Groman ◽

Wen W. Ma ◽

Usha Malhotra ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Phase Ii Study ◽

Locally Advanced ◽

Tract Cancer ◽

Multicenter Phase

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A single arm, prospective multicenter phase II study FOLFIRINOX in patients with advanced and recurrent biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.tps514 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. TPS514-TPS514 ◽

Cited By ~ 3

Author(s):

Naminatsu Takahara ◽

Hiroyuki Isayama ◽

Yousuke Nakai ◽

Tatsuya Ioka ◽

Masashi Kanai ◽

...

Keyword(s):

Disease Progression ◽

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Intravenous Infusion ◽

Tumor Response ◽

Phase Ii Study ◽

Phase Iii ◽

Open Label ◽

Tract Cancer

TPS514 Background: The current standard of care for patients with advanced biliary tract cancer (BTC) is gemcitabine and cisplatin (GC) combination chemotherapy. Despite intensive researches, no trials have proved better overall survival (OS) over GC. Recently, FOLFIRINOX provided a remarkable survival benefit over gemcitabine in patients with metastatic pancreatic cancer. Given the promising results of FOLFIRI and FOLFOX in patients with advanced BTC, FOLFIRINOX can be an attractive option in patients with advanced BTC as well. Methods: This is a single-arm, open-label, multi-center phase II study to evaluate the safety and efficacy of FOLFIRINOX in patients with advanced BTC. The major inclusion criteria are as follows; unresectable or recurrent BTC, histologically or cytologically confirmed adenocarcinoma, no prior chemotherapy or radiation therapy, age of 20-75 years, an ECOG PS of 0 or 1, at least one measurable lesion, adequate hematological, liver and renal function. The major exclusion criteria are as follows; UGT genetic polymorphisms of homozygous UGT1A1*6 or *28 or heterozygous UGT1A1*6 and *28, massive pleural effusion or ascites. FOLFIRINOX consists of oxaliplatin of 85 mg/m2, irinotecan of 180 mg/m2, leucovorin of 400 mg/m2 administered by intravenous infusion and fluorouracil of 400 mg/m2 by intravenous bolus and of 2,400 mg/m2 by continuous intravenous infusion every 2 weeks. The primary outcome is progression-free survival (PFS), and the secondary outcomes are OS, tumor response and safety. PFS and OS will be calculated from the date of enrollment until the date of documentation of disease progression or death in patients without disease progression and the date of death. Tumor response will be evaluated according to the RECIST version 1.1 every 2 months. Safety will be evaluated with the CTCAE version 4.0. A total of 35 patients will be required to provide 75% power to detect an increase in median PFS from 6 months provided by standard care of GC to 10 months in patients receiving FOLFIRINOX, with a 24 months of recruitment and 18 months of follow-up. A phase III trial will be considered when this study shows the lower limit of the 80% confidence interval for PFS is longer than 6 months. Clinical trial information: UMIN000020801.

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Clinical benefit and quality of life in patients with advanced biliary tract cancer receiving gemcitabine plus capecitabine (GemCap): Results from a multicenter phase II trial (SAKK 44/02)

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.15531 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 15531-15531

Author(s):

D. Gerber ◽

D. Dietrich ◽

D. Koeberle ◽

P. Saletti ◽

M. Borner ◽

...

Keyword(s):

Quality Of Life ◽

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Clinical Benefit ◽

Phase Ii Trial ◽

Tract Cancer ◽

Multicenter Phase

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A phase II study of gemcitabine as adjuvant treatment for biliary tract cancer after surgical resection.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.330 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 330-330 ◽

Cited By ~ 1

Author(s):

Sang Myung Woo ◽

Kyong-Ah Yoon ◽

Eun Kyung Hong ◽

Weon Seo Park ◽

Sung-Sik Han ◽

...

Keyword(s):

Biliary Tract ◽

Phase Ii ◽

Biliary Tract Cancer ◽

Vascular Invasion ◽

Phase Ii Study ◽

Cytidine Deaminase ◽

Hematologic Toxicity ◽

Open Label ◽

Extrahepatic Cholangiocarcinoma ◽

Tract Cancer

330 Background: The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. Methods: This clinical phase II study was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patents received gemcitabine 1000 mg/m2as an intravenous 30-min infusion on day 1, 8, and 15 for every 28 days. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry and eight SNPs in the CDA, hENT1, dCK, hCNT3 and RRM1 genes were evaluated. The relationship of each with patients’ clinical outcomes was assessed. Results: From January 2010 to July 2014, a total of 72 BTC patients (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma) were enrolled. At a median follow-up was 38.09 months (range: 4.14-68.29), 2-year recur- free survival (RFS) was 43% (95% CI, 33% to 57%). The most common grade 3 and 4 toxicity was neutropenia, which occurred in 8 patients (11%). There was one treatment-related death from pneumonitis. The Cox proportion hazard model was performed with the following nine variables; gross type, degree of tumor differentiation. pathologic T factor, N stage, vascular invasion, perineural invasion, lymphatic invasion, dosage, and each protein expression. In the multivariable model, DCK expression, vascular invasion, and lymph node metastasis, were significantly associated with RFS. None of the tested SNPs was significantly associated with RFS or with any hematologic or non-hematologic toxicity. Conclusions: Although the primary hypothesis of this study, defined as a 2-year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted. Clinical trial information: NCT01043172.

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