A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours
Résumé
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 \textgreater/=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. CONCLUSION: 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.
Mots clés
Humans
Female
Middle Aged
Adult
Male
Treatment Outcome
Aged
Time Factors
Drug Administration Schedule
Adaptor Proteins
Signal Transducing/metabolism
Anorexia/chemically induced
Antineoplastic Combined Chemotherapy Protocols/adverse
Area Under Curve
Diarrhea/chemically induced
Dose-Response Relationship
Drug
effects/pharmacokinetics
effects/pharmacokinetics/*therapeutic use
Fatigue/chemically induced
Metabolic Clearance Rate
Neoplasms/*drug therapy/metabolism/pathology
Protein Kinase Inhibitors/administration & dosage/adverse
Proto-Oncogene Proteins c-akt/metabolism
Pyrazoles/administration & dosage/adverse effects/pharmacokinetics
Pyrimidines/administration & dosage/adverse effects/pharmacokinetics
Quinazolines/administration & dosage/adverse effects
Ribosomal Protein S6 Kinases
70-kDa/*antagonists & inhibitors/metabolism
Sirolimus/administration & dosage/adverse effects/analogs & derivatives
Vomiting/chemically induced