title: First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma.
abstract: OBJECTIVE
  TGFβ signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGFβ signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer.
  
  
  METHODS
  Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria.
  
  
  RESULTS
  In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥ 6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ≥ 6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events.
  
  
  CONCLUSIONS
  On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation.
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain. jrodon@vhio.net jrodon@vhebron.net.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Sepulveda-Sánchez
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Analia
authors.initials: A
authors.lastname: Azaro
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Braña
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Sicart
authors.affiliation: Eli Lilly and Company, Erl Wood, United Kingdom.
authors.forename: Ivelina
authors.initials: I
authors.lastname: Gueorguieva
authors.affiliation: Eli Lilly and Company, Erl Wood, United Kingdom.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Cleverly
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: N Sokalingum
authors.initials: NS
authors.lastname: Pillay
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Durisala
authors.initials: D
authors.lastname: Desaiah
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Shawn T
authors.initials: ST
authors.lastname: Estrem
authors.affiliation: Hospital Virgen del Rocío, Sevilla, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Holdhoff
authors.affiliation: Department of Neurology/Neurosurgery/and Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jaishri
authors.initials: J
authors.lastname: Blakeley
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; C557799:LY-2157299; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I