title: A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors.
abstract: LY3022859 is an anti-TGFβRII IgG1monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK).
  
  
  
  LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W.
  
  
  
  Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2(4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration.
  
  
  
  The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines).
  
  
  
  clinicaltrials.gov Identifier: NCT01646203.
authors.affiliation: South Texas Accelerated Research Therapeutics LLC, San Antonio, TX, 78229, USA. atolcher@start.stoh.com.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232, USA.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.|Merck KGaA, Darmstadt, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Cosaert
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: UT M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: South Texas Accelerated Research Therapeutics LLC, San Antonio, TX, 78229, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Amaya
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Shande
authors.initials: S
authors.lastname: Tang
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Kyla
authors.initials: K
authors.lastname: Driscoll
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kimbung
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: S R Prasad
authors.initials: SR
authors.lastname: Kambhampati
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Ivelina
authors.initials: I
authors.lastname: Gueorguieva
authors.affiliation: UT M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016207:Cytokines; C000620254:LY3022859; D018125:Receptors, Transforming Growth Factor beta
keywords: Monoclonal antibody; Solid tumors; TGFβ; TGFβ receptor; Therapy resistance