title: Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma.
abstract: OBJECTIVE
  This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors.
  
  
  METHODS
  Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort.
  
  
  RESULTS
  Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC(0-24) and C(max) increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively).
  
  
  CONCLUSIONS
  The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas. dshong@mdanderson.org.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Sarah Cannon Research Institute at HealthONE, Denver, Colorado.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ly M
authors.initials: LM
authors.lastname: Nguyen
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Goldy C
authors.initials: GC
authors.lastname: George
authors.affiliation: Eisai Inc., Oncology, Woodcliff Lake, New Jersey.
authors.forename: Lucy
authors.initials: L
authors.lastname: Xu
authors.affiliation: Eisai Inc., Oncology, Woodcliff Lake, New Jersey.
authors.forename: Robert
authors.initials: R
authors.lastname: Shumaker
authors.affiliation: Eisai Inc., Oncology, Woodcliff Lake, New Jersey.
authors.forename: Min
authors.initials: M
authors.lastname: Ren
authors.affiliation: Former employees of Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mink
authors.affiliation: Mary Crowley Cancer Research Center, Dallas, Texas.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bedell
authors.affiliation: Former employees of Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: Corina
authors.initials: C
authors.lastname: Andresen
authors.affiliation: Eisai Inc., Oncology, Woodcliff Lake, New Jersey.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Sachdev
authors.affiliation: Former employees of Eisai Inc., Woodcliff Lake, New Jersey.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Brien
authors.affiliation: Mary Crowley Cancer Research Center, Dallas, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib