title: Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies.
abstract: BACKGROUND
  SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.
  
  
  METHODS
  SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.
  
  
  RESULTS
  Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.
  
  
  CONCLUSIONS
  SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ, USA. dmahadevan@westclinic.com
authors.forename: D
authors.initials: D
authors.lastname: Mahadevan
authors.forename: E G
authors.initials: EG
authors.lastname: Chiorean
authors.forename: W B
authors.initials: WB
authors.lastname: Harris
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: A
authors.initials: A
authors.lastname: Stejskal-Barnett
authors.forename: W
authors.initials: W
authors.lastname: Qi
authors.forename: S P
authors.initials: SP
authors.lastname: Anthony
authors.forename: A E
authors.initials: AE
authors.lastname: Younger
authors.forename: D M
authors.initials: DM
authors.lastname: Rensvold
authors.forename: F
authors.initials: F
authors.lastname: Cordova
authors.forename: C F
authors.initials: CF
authors.lastname: Shelton
authors.forename: M D
authors.initials: MD
authors.lastname: Becker
authors.forename: J R
authors.initials: JR
authors.lastname: Garlich
authors.forename: D L
authors.initials: DL
authors.lastname: Durden
authors.forename: R K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002867:Chromones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007008:Hypokalemia / Q000139:chemically induced; D007262:Infusions, Intravenous; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011506:Proteins / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy; D058570:TOR Serine-Threonine Kinases; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011506:Proteins; C526549:SF 1126; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases