title: A phase 1b trial of the combination of an all-oral regimen of capecitabine and erlotinib in advanced non-small cell lung cancer in Caucasian patients.
abstract: OBJECTIVE
  Erlotinib is active in advanced non-small cell lung cancer (aNSCLC) particularly in patients with EGFR-sensitizing mutations. The thymidylate synthase inhibitors are active in NSCLC, but capecitabine is not well studied. This study explored the safety and activity of this oral combination.
  
  
  METHODS
  This phase Ib trial used a 3 + 3 escalation design with a combination of erlotinib (100 mg daily) with increasing doses of capecitabine (500, 750 and 1000 mg/m(2) BD, 14/21 days), in first- and second-line aNSCLC of adenocarcinoma histology. The DLT was any drug-induced toxicity ≥grade (G)2 causing dose interruption or dose delay during the first 2 cycles.
  
  
  RESULTS
  Forty patients were recruited, and 1 patient had an EGFR mutation. Dose escalation stopped at capecitabine 1000 mg/m(2) with expansion to 6 patients due to unpredicted DLTs in 2/6 patients: G2 creatinine rise, G2 anaemia, G3 atrial fibrillation and G3 pneumonia. MTD was capecitabine 750 mg/m(2). First-line dose escalation at the MTD led to unpredicted DLTs in 3/4 patients (G3 troponin rise, G2 rash and G2 hyperbilirubinaemia). MTD expansion in the second-line setting was well tolerated. The most common drug toxicities were gastrointestinal (35 %), followed by skin disorders (28 %). The response rate was 3 % with a disease control rate of 34 %. Median progressive-free survival was 1.6 months (95 % CI 1.4-3.5), and median overall survival was 6.1 months (95 % CI 5.1-10.1).
  
  
  CONCLUSIONS
  The MTD for the combination of capecitabine and erlotinib is 750 mg/m(2) BD, 14/21 days, and 100 mg daily, respectively, which is lower than predicted. Capecitabine did not improve the efficacy of erlotinib in aNSCLC unselected for EGFR mutation.
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Shir Kiong
authors.initials: SK
authors.lastname: Lu
authors.affiliation: The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Minchom
authors.affiliation: The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Sharp
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Ranga
authors.initials: R
authors.lastname: Gunapala
authors.affiliation: The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Jaishree
authors.initials: J
authors.lastname: Bhosle
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK. Mary.O'Brien@rmh.nhs.uk.
authors.forename: Mary E R
authors.initials: ME
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000069287:Capecitabine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Adenocarcinoma; Capecitabine; Erlotinib; Non-small cell lung cancer; Phase 1