A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumours.
BACKGROUND
LY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.


METHODS
Patients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0.


RESULTS
Thirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n=22) began with 300 mg BID (n=2). Due to toxicity, this was scaled back to doses of 25mg (n=3), 50 mg (n=8), 100mg (n=3), and 200 mg (n=6) QD. Part B dose escalation (n=12) included 50 mg (n=3), 75 mg (n=3), and 100 mg (n=6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis.


CONCLUSIONS
The MTD was determined to be 75 mg BID or 100mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose.
START - South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
Anthony
A
Tolcher
UCLA Division of Hematology & Oncology, Santa Monica, CA, USA.
Jonathan
J
Goldman
START - South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
Amita
A
Patnaik
START - South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA.
Kyriakos P
KP
Papadopoulos
Eli Lilly and Company, Windlesham, Surrey, UK.
Paul
P
Westwood
Eli Lilly and Company, Indianapolis, IN, USA.
Claudia S
CS
Kelly
Eli Lilly and Company, Indianapolis, IN, USA.
William
W
Bumgardner
Eli Lilly and Company, Indianapolis, IN, USA.
Lillian
L
Sams
Eli Lilly and Company, Indianapolis, IN, USA.
Sandaruwan
S
Geeganage
Eli Lilly and Company, Indianapolis, IN, USA.
Tao
T
Wang
Eli Lilly and Company, Indianapolis, IN, USA.
Andrew R
AR
Capen
Eli Lilly and Company, Indianapolis, IN, USA.
Jianping
J
Huang
Eli Lilly and Company, Indianapolis, IN, USA.
Sajan
S
Joseph
Eli Lilly and Company, Indianapolis, IN, USA.
Joel
J
Miller
Eli Lilly and Company, Indianapolis, IN, USA.
Karim A
KA
Benhadji
Eli Lilly and Company, Indianapolis, IN, USA.
Les H
LH
Brail
UCLA Division of Hematology & Oncology, Santa Monica, CA, USA. Electronic address: lrosen@mednet.ucla.edu.
Lee S
LS
Rosen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002784:Cholesterol / Q000378:metabolism; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D002784:Cholesterol; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C588151:LY2584702
Cancer; LY2584702 tosylate; PI3 kinase; p70 S6 kinase (p70S6K)