title: Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours.
abstract: BACKGROUND
  This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours.
  
  
  METHODS
  In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25).
  
  
  RESULTS
  The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed.
  
  
  CONCLUSIONS
  MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Hollebecque
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Anas
authors.initials: A
authors.lastname: Gazzah
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: Drug Development Department and Radiation Therapy Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Amellal
authors.affiliation: Inserm Unit 981, Gustave Roussy, Villejuif Cedex, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Farace
authors.affiliation: Boehringer Ingelheim, 14 rue Jean Antoine de Baif, 75013 Paris, France.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ould-Kaci
authors.affiliation: Boehringer Ingelheim, Reims, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Roux
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Kristell
authors.initials: K
authors.lastname: Marzin
authors.affiliation: Drug Development Department, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011799:Quinazolines; D000077716:Afatinib; C530716:nintedanib