title: Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.
abstract: Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil.
  
  
  
  We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m2) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m2) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m2on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here.
  
  
  
  Between Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5-14·1). At 4 months, 40 (56%, 90% CI 45-66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40-68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3-4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3-4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group.
  
  
  
  Nab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial.
  
  
  
  GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France; Department of Hepato-Gastroenterology, Groupe hospitalier Pitié Salpêtrière, Paris, France. Electronic address: jean-baptiste.bachet@aphp.fr.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.affiliation: Department of Digestive Oncology, Hôpital Beaujon, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.affiliation: Department of Hepato-Gastroenterology, Hôpital Privé Jean Mermoz, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Desramé
authors.affiliation: Department of Methodology and Quality of Life in Oncology, INSERM UMR 1098, Hôpital Universitaire de Besancon, Paris, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Meurisse
authors.affiliation: Department of Oncology, Institut Franco-Britannique, Levallois-Perret, Paris, France.
authors.forename: Benoist
authors.initials: B
authors.lastname: Chibaudel
authors.affiliation: Department of Oncology, Hôpital Saint Antoine, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: André
authors.affiliation: Department of Oncology, Institut Saint Catherine, Avignon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Debourdeau
authors.affiliation: Department of Oncology, Hôpital Layne Mont de Marsan, Mont de Marsan, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Dauba
authors.affiliation: Department of Hepato-Gastroenterology, Hôpital Trousseau, Tours, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lecomte
authors.affiliation: CHU La Timone, Marseille, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.affiliation: Department of Oncology, CHU Henri Mondor, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tournigand
authors.affiliation: Department of Hepato-Gastroenterology, CHU Avicenne, Bobigny, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aparicio
authors.affiliation: Department of Oncology, Institut de cancérologie de L'Ouest Paul Papin, Angers, France.
authors.forename: Véronique Guerin
authors.initials: VG
authors.lastname: Meyer
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Taieb
authors.affiliation: Department of Hepato-Gastroenterology, CHU Robert Debré, Reims, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Volet
authors.affiliation: GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie), Paris, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Monier
authors.affiliation: Department of Methodology and Quality of Life in Oncology, INSERM UMR 1098, Hôpital Universitaire de Besancon, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bonnetain
authors.affiliation: Department of Oncology, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louvet
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D057194:Intention to Treat Analysis; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; D017239:Paclitaxel; D002955:Leucovorin; D005472:Fluorouracil; D000093542:Gemcitabine