title: A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial.
abstract: BACKGROUND
  A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.
  
  
  METHODS
  This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.
  
  
  CONCLUSIONS
  Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.
authors.affiliation: a Department of Immunology , Genetics and Pathology, Uppsala University , Uppsala , Sweden.
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
authors.affiliation: b Axelar AB, Karolinska Institute Science Park , Solna , Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Harmenberg
authors.affiliation: c Department of Oncology , Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Frödin
authors.affiliation: d Department of Oncology , Hospital of Gävle , Gävle , Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bergström
authors.affiliation: e Section of Radiology, Department of Radiology , Oncology and Radiation Sciences, Uppsala University , Uppsala , Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wassberg
authors.affiliation: f Childhood Cancer Research Unit, Department of Women's and Children's Health , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Eksborg
authors.affiliation: g Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology , Cancer Centre Karolinska, Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.affiliation: h Department of Clinical Chemistry , Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.affiliation: b Axelar AB, Karolinska Institute Science Park , Solna , Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Jerling
authors.affiliation: b Axelar AB, Karolinska Institute Science Park , Solna , Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Abrahmsen
authors.affiliation: a Department of Immunology , Genetics and Pathology, Uppsala University , Uppsala , Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Hedlund
authors.affiliation: i Uppsala Clinical Research Center , Uppsala , Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Alvfors
authors.affiliation: b Axelar AB, Karolinska Institute Science Park , Solna , Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Ståhl
authors.affiliation: a Department of Immunology , Genetics and Pathology, Uppsala University , Uppsala , Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009503:Neutropenia / Q000139:chemically induced; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D011446:Prospective Studies; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin