title: Phase II study of TP300 in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma.
abstract: TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas.
  
  
  
  Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m2with intra-patient escalation to 10 mg/m2from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study.
  
  
  
  In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 - 82), performance status ECOG 0/1, with GC [14] or GOJ carcinoma [6] were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m2at cycle 2, 2 decreased to 6 mg/m2, and 3 continued on 8 mg/m2. There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 - 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI [1.6 - 4.9]), median time to progression (TTP) was 2.9 months (CI [1.4 - 4.2]). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders.
  
  
  
  This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response.
  
  
  
  EU-CTR 2009-012097-12 2009-09-03.
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, Lower Ground Floor, Old Anatomy Building, Charterhouse Square, London, UK, EC1M 6BQ. d.j.propper@qmul.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.affiliation: Chugai Pharmaceuticals Europe Ltd. Turnham Green, London, W4 1NN, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.affiliation: St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds, LS9 7TF, UK.
authors.forename: D Alan
authors.initials: DA
authors.lastname: Anthoney
authors.affiliation: Department Medical Oncology, Christie Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Wasat
authors.initials: W
authors.lastname: Mansoor
authors.affiliation: Cancer Research Clinical Trials Team, Old Clinical Investigations Building, City Hospital, Dudley Road, Birmingham, B18 7QH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ford
authors.affiliation: Northern Ireland Cancer Clinical Trials Unit, Belfast City Hospital, East Podium, C Floor, Belfast, BT9 7AB, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Eatock
authors.affiliation: West London Cancer Research Network, Coulter Suite, 1st Floor Mint Wing, St Mary's Hospital, Praed St, London, W2 1 NY, UK.
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Nihonbashi Muromachi 2-1-1, Chuo-ku, Tokyo, 103-8324, Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Inatani
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Nihonbashi Muromachi 2-1-1, Chuo-ku, Tokyo, 103-8324, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Saito
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Nihonbashi Muromachi 2-1-1, Chuo-ku, Tokyo, 103-8324, Japan.
authors.forename: Masaichi
authors.initials: M
authors.lastname: Abe
authors.affiliation: Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, G12 OYN, UK.
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000368:Aged; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D006576:Heterocyclic Compounds, 4 or More Rings; C558017:TP 300
keywords: Advanced Gastric or Gastro-oesophageal junction adenocarcinoma; Oesophago-gastric adenocarcinoma; Pharmacodynamics; Pharmacokinetics; Phase II study; Safety profile; Siewert Types II & III; Topoisomerase-I inhibitor