title: Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study.
abstract: BACKGROUND
  Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer.
  
  
  METHODS
  We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m(2) intravenously on day 1, cisplatin 60 mg/m(2) intravenously on day 1, capecitabine 625 mg/m(2) twice a day orally on days 1-21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550.
  
  
  RESULTS
  Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9-7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5-7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5-7·0) in both rilotumumab groups combined, and 4·2 months (2·9-4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49-0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38-0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45-0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3-4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none).
  
  
  CONCLUSIONS
  Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress.
  
  
  BACKGROUND
  Amgen Inc.
authors: University Hospital Southampton, Southampton, UK. Electronic address: tim.iveson@uhs.nhs.uk.
authors: Timothy
authors: T
authors: Iveson
authors: Johns Hopkins Cancer Center, Baltimore, MD, USA.
authors: Ross C
authors: RC
authors: Donehower
authors: State Institution of Public Health "Regional Clinical Oncology Dispensary", Krasnodar, Russia.
authors: Irina
authors: I
authors: Davidenko
authors: Russian Cancer Research Center, Moscow, Russia.
authors: Sergey
authors: S
authors: Tjulandin
authors: Central Clinical Hospital MSW, Warsaw Medical University, Warsaw, Poland.
authors: Andrzej
authors: A
authors: Deptala
authors: Mount Vernon Hospital, Northwood, UK.
authors: Mark
authors: M
authors: Harrison
authors: Indo-American Cancer Institute and Research Centre, Hyderabad, India.
authors: Somanath
authors: S
authors: Nirni
authors: Kidwai Memorial Institute of Oncology, Bangalore, India.
authors: Kuntegowdanahalli
authors: K
authors: Lakshmaiah
authors: University of Leicester, Leicester, UK.
authors: Anne
authors: A
authors: Thomas
authors: Amgen Inc, Thousand Oaks, CA, USA.
authors: Yizhou
authors: Y
authors: Jiang
authors: Amgen Inc, Thousand Oaks, CA, USA.
authors: Min
authors: M
authors: Zhu
authors: Amgen Inc, Thousand Oaks, CA, USA.
authors: Rui
authors: R
authors: Tang
authors: Amgen Inc, Thousand Oaks, CA, USA.
authors: Abraham
authors: A
authors: Anderson
authors: Amgen Inc, South San Francisco, CA, USA.
authors: Sarita
authors: S
authors: Dubey
authors: Amgen Inc, Thousand Oaks, CA, USA.
authors: Kelly S
authors: KS
authors: Oliner
authors: Amgen Inc, South San Francisco, CA, USA.
authors: Elwyn
authors: E
authors: Loh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D016001:Confidence Intervals; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000009:adverse effects / Q000627:therapeutic use; D004943:Esophagogastric Junction / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D015251:Epirubicin; C524459:rilotumumab; D000069287:Capecitabine; D002945:Cisplatin; D005472:Fluorouracil