title: Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation.
  
  
  METHODS
  LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control-guided dose escalation.
  
  
  RESULTS
  Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6%] of 53 patients) and was the most common grades 3 to 4 event (in five [9%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels.
  
  
  CONCLUSIONS
  The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA.
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA.
authors.forename: Shyeilla V
authors.initials: SV
authors.lastname: Dhuria
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA.
authors.forename: Suman
authors.initials: S
authors.lastname: Sen
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA.
authors.forename: Scott
authors.initials: S
authors.lastname: Cameron
authors.affiliation: Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; E. Claire Dees, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Antony J. Olszanski, Fox Chase Cancer Center; Roger B. Cohen, Perelman School of Medicine, Philadelphia, PA; Shyeilla V. Dhuria and Suman Sen, Novartis Pharmaceuticals Corp, East Hanover, NJ; and Scott Cameron, Novartis Institutes for Biomedical Research, Cambridge, MA. roger.cohen@uphs.upenn.edu.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001682:Biological Availability; D016207:Cytokines / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019999:Pharmaceutical Solutions; D013577:Syndrome; D013607:Tablets; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D019999:Pharmaceutical Solutions; D013607:Tablets; D013844:Thiazoles