title: Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors.
abstract: OBJECTIVE
  This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway.
  
  
  METHODS
  Patients with advanced, solid tumors received daily oral TAK-441 (50-1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1.
  
  
  RESULTS
  Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration-time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors).
  
  
  CONCLUSIONS
  TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling.
authors.affiliation: UCLA Hematology and Oncology, Santa Monica, California. JWGoldman@mednet.ucla.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goldman
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Curtis
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
authors.affiliation: Takeda Pharmaceuticals International Co., Deerfield, Illinois.
authors.forename: Asit
authors.initials: A
authors.lastname: Parikh
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts.
authors.forename: James
authors.initials: J
authors.lastname: Partyka
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts.
authors.forename: Helene
authors.initials: H
authors.lastname: Faessel
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts.
authors.forename: Esha
authors.initials: E
authors.lastname: Gangolli
authors.affiliation: UCLA Hematology and Oncology, Santa Monica, California.
authors.forename: Sally
authors.initials: S
authors.lastname: Stewart
authors.affiliation: UCLA Hematology and Oncology, Santa Monica, California.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D019233:Retreatment; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; C577980:TAK-441; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1