title: A phase 1 'window-of-opportunity' trial testing evofosfamide (TH-302), a tumour-selective hypoxia-activated cytotoxic prodrug, with preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.
abstract: Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease. Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy. The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions, which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy. This drug has shown promising results in several clinical studies when combined with chemotherapy. Therefore, in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer.
  
  
  
  A phase I, non-randomized, single-centre, open-label, 3 + 3 trial with repeated hypoxia PET imaging, will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients. Investigated dose levels range from 120 mg/m2 to 340 mg/m2. Evofosfamide will be administered one week before the start of chemoradiotherapy (CROSS-regimen) and repeated weekly up to a total of six doses. PET/CT acquisitions with hypoxia tracer (18)F-HX4 will be made before and after the first administration of evofosfamide, allowing early assessment of changes in hypoxia, accompanied with blood sampling to measure hypoxia blood biomarkers. Oesophagectomy will be performed according to standard clinical practice. Higher grade and uncommon non-haematological, haematological, and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications. Secondary endpoints are reduction in hypoxic fraction based on (18)F-HX4 imaging, pathological complete response, histopathological negative circumferential resection margin (R0) rate, local and distant recurrence rate, and progression free and overall survival.
  
  
  
  This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy. The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies. The addition of non-invasive repeated hypoxia imaging ('window-of-opportunity') enables us to identify the biologically effective dose. We believe this approach could also be used for other hypoxia targeted drugs.
  
  
  
  ClinicalTrials.gov Identifier: NCT02598687 .
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ruben T H M
authors.initials: RT
authors.lastname: Larue
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. lien.vandevoorde@gmail.com.
authors.forename: Lien
authors.initials: L
authors.lastname: Van De Voorde
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Berbée
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Wouter J C
authors.initials: WJ
authors.lastname: van Elmpt
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ludwig J
authors.initials: LJ
authors.lastname: Dubois
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Kranthi M
authors.initials: KM
authors.lastname: Panth
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.|Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Sarah G J A
authors.initials: SG
authors.lastname: Peeters
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ann
authors.initials: A
authors.lastname: Claessens
authors.affiliation: Department of Nuclear Medicine, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands.
authors.forename: Wendy M J
authors.initials: WM
authors.lastname: Schreurs
authors.affiliation: Department of Pathology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands.
authors.forename: Marius
authors.initials: M
authors.lastname: Nap
authors.affiliation: Department of Medical Oncology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands.
authors.forename: Fabiënne A R M
authors.initials: FA
authors.lastname: Warmerdam
authors.affiliation: Department of Medical Oncology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands.
authors.forename: Frans L G
authors.initials: FL
authors.lastname: Erdkamp
authors.affiliation: Department of Surgery, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, The Netherlands.|Surgical Collaborative Network Limburg, Limburg, The Netherlands.
authors.forename: Meindert N
authors.initials: MN
authors.lastname: Sosef
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000628:therapy*; D015687:Cell Hypoxia / Q000187:drug effects; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging* / Q000628:therapy*; D016629:Esophagectomy; D005260:Female; D006801:Humans; D008297:Male; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D010752:Phosphoramide Mustards / Q000008:administration & dosage* / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D011300:Preoperative Care; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; C552526:TH 302
keywords: Dose limiting toxicity; Evofosfamide; Hypoxia imaging; Neoadjuvant chemoradiotherapy; Oesophageal cancer; Oesophagectomy; Window-of-opportunity trial