title: A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas.
abstract: OBJECTIVE
  Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+advanced solid tumors or lymphomas.
  
  
  METHODS
  Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle.
  
  
  RESULTS
  Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months.
  
  
  CONCLUSIONS
  Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696-705. ©2016 AACR.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee. jinfante@tnonc.com.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Cassier
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.affiliation: University Medical Center Utrecht Cancer Center, Utrecht, the Netherlands.
authors.forename: Petronella O
authors.initials: PO
authors.lastname: Witteveen
authors.affiliation: University of Michigan, Ann Arbor, Michigan.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Matano
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Dobson
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Crystal
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Sudha
authors.initials: S
authors.lastname: Parasuraman
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000627:therapeutic use*; D001499:Bayes Theorem; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011687:Purines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D011687:Purines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C000589651:ribociclib