C123
Preliminary activity in adrenocortical tumour (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small molecule insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumours
S Alam1, C Carden1, M Langham2, S Frentzas1, S Dolly1, S Sandhu1, R Kristeleit1, T Yap1, I Casamayor1, T Matthews1, AW Stephens3, S Poondru3, E Kim2, SB Kaye.1
1Institute of Cancer Research, Royal Marsden Hospital, London, UK, 2MD Anderson Cancer Centre, Texas, USA, 3OSI Pharmaceuticals, Colorado, USA
Background
Insulin-like growth factor-I receptor (IGF-IR) plays an important role in tumour cell growth and survival. IGF-1R blockade increases apoptosis, chemosensitivity and reduces tumour growth in many preclinical models. OSI-906 is an oral IGF-1R, tyrosine kinase inhibitor.
Method
Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumour activity.
Results
33 pt have been treated (19M: 14F, median age 62 yrs) at 10, 20, 40, 80, 150, 300 and 450mg on days (d) 1-3 q14 d, and at 450mg d 1-5 q14d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 2 hyperglycaemia and grade 1 fatigue, nausea, rash, diarrhoea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5-8 hr; AUC0- 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses ≥ 80mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. In total, 14 pt were treated for > 12 weeks (w). Of 3 pt with ACC, 1 pt at 450mg had a partial response (68% reduction in primary and multiple lung metastases) and remains on treatment after 33+ w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w. 7 patients had stable disease for ≥ 24 weeks on treatment (2 ACC, 2 NSCLC, 1 chondrosarcoma, salivary duct carcinoma, and gastric cancer)
Conclusion
OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1-3 q14 d, with preliminary antitumour activity seen, particularly in ACC. Dose escalation with 3, 5 and 7 d schedules q14 d continues.
