title: Mutation-targeted therapy with sunitinib or everolimus in patients with advanced low-grade or intermediate-grade neuroendocrine tumours of the gastrointestinal tract and pancreas with or without cytoreductive surgery: protocol for a phase II clinical trial.
abstract: BACKGROUND
  Finding the optimal management strategy for patients with advanced, metastatic neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas is a work in progress. Sunitinib and everolimus are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic low-grade or intermediate-grade pancreatic NETs. However, mutation-targeted therapy with sunitinib or everolimus has not been studied in this patient population.
  
  
  METHODS
  This prospective, open-label phase II clinical trial was designed to determine if mutation-targeting therapy with sunitinib or everolimus for patients with advanced low-grade or intermediate-grade NETs is more effective than historically expected results with progression-free survival (PFS) as the primary end point. Patients ≥18 years of age with progressive, low-grade or intermediate-grade locally advanced or metastatic NETs are eligible for this study. Patients will undergo tumour biopsy (if they are not a surgical candidate) for tumour genotyping. Patients will be assigned to sunitininb or everolimus based on somatic/germline mutations profile. Patients who have disease progression on either sunitinib or everolimus will crossover to the other drug. Treatment will continue until disease progression, unacceptable toxicity, or consent to withdrawal. Using the proposed criteria, 44 patients will be accrued within each treatment group during a 48-month period (a total of 88 patients for the 2 treatments), and followed for up to an additional 12 months (a total of 60 months from entry of the first patient) to achieve 80% power in order to test whether there is an improvement in PFS compared to historically expected results, with a 0.10 α level one-sided significance test.
  
  
  BACKGROUND
  The study protocol was approved by the institutional review board of the National Cancer Institute (NCI-IRB Number 15C0040; iRIS Reference Number 339636). The results will be published in a peer-reviewed journal and shared with the worldwide medical community.
  
  
  BACKGROUND
  NCT02315625.
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Neychev
authors.affiliation: Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Candice
authors.initials: C
authors.lastname: Cottle-Delisle
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Merkel
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Naris
authors.initials: N
authors.lastname: Nilubol
authors.affiliation: Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yao
authors.affiliation: Molecular Genetics Section, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Genetics and Endocrinology Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Marx
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D000293:Adolescent; D000328:Adult; D006801:Humans; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D065426:Cytoreduction Surgical Procedures; D004067:Digestive System Neoplasms / Q000188:drug therapy / Q000601:surgery; D018572:Disease-Free Survival; D000068338:Everolimus / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000601:surgery; D041981:Gastrointestinal Tract / Q000473:pathology; D005838:Genotype; D007211:Indoles / Q000627:therapeutic use; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000601:surgery; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000601:surgery; D011446:Prospective Studies; D011758:Pyrroles / Q000627:therapeutic use; D012107:Research Design; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib