A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours.
BACKGROUND
LY2584702 tosylate (hereafter referred to as LY2584702) is an oral, selective ATP competitive inhibitor of p70 S6 kinase. Preclinical studies with LY2584702 demonstrated significant synergistic activity with erlotinib and everolimus. The primary objective was to determine a phase II dose and schedule. Secondary objectives included evaluation of safety, toxicity and pharmacokinetics of LY2584702 in combination with erlotinib or everolimus.


METHODS
Patients with advanced solid tumours were treated with a total daily dose of 50-200mg of LY2584702 in combination with erlotinib 150 mg once daily (Arm A) or everolimus 10mg once daily (Arm B). Dose escalation was based on 3+3 design and used the Common Terminology Criteria for Adverse Events Version 4.0.


RESULTS
Twenty-nine patients were enrolled, 17 in Arm A and 12 in Arm B. Dose limiting toxicities (DLTs) in cycle 1 were observed in Arm A in four patients and consisted of Grade 3 vomiting, hypophosphataemia, pulmonary embolism and decreased clotting factor V. No DLTs were observed in Arm B at cycle 1, and the most frequent treatment-emergent adverse events related to study drug were: fatigue, anorexia, diarrhoea, nausea and vomiting. Seven patients received ≥4 cycles (3 in A, 4 in B). Best overall response was stable disease. Exposure accumulation of LY2584702 occurred with BID (twice daily) dosing. Exposure of erlotinib increased when administered in combination with LY2584702.


CONCLUSIONS
LY2584702 was not well tolerated when administered with erlotinib, therefore this combination is not feasible. The combination with everolimus was better tolerated but yielded very limited clinical benefit.
Institut Gustave Roussy, Villejuif, France.
Antoine
A
Hollebecque
Institut Bergonié, Bordeaux, France.
Nadine
N
Houédé
University of Chicago, Chicago, IL, USA.
Ezra E W
EE
Cohen
Institut Gustave Roussy, Villejuif, France.
Christophe
C
Massard
Institut Bergonié, Bordeaux, France.
Antoine
A
Italiano
Eli Lilly and Company, Erl Wood, Windlesham, UK.
Paul
P
Westwood
Eli Lilly and Company, Indianapolis, IN, USA.
William
W
Bumgardner
Eli Lilly and Company, Indianapolis, IN, USA.
Joel
J
Miller
Eli Lilly and Company, Indianapolis, IN, USA.
Les H
LH
Brail
Eli Lilly and Company, Indianapolis, IN, USA.
Karim A
KA
Benhadji
Institut Gustave Roussy, Villejuif, France. Electronic address: jean-charles.soria@gustaveroussy.fr.
Jean-Charles
JC
Soria
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D000855:Anorexia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000069347:Erlotinib Hydrochloride; D000068338:Everolimus; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C588151:LY2584702; D020123:Sirolimus
Erlotinib; Everolimus; LY2584702 tosylate; p70 S6 kinase inhibitor