Inhibition of the IGF pathway in metastatic castrate resistant prostate cancer (CRPC): Results from a phase II study of OSI-906 (linsitinib).

Abstract

e16022 Background: AR ligand independent pathways are responsible for the development of CRPC. IGF-1R and its ligands (IGF-1/IGF-2) play a key role in regulating growth, resistance to apoptosis, and invasion in PCa. IGF-1R is overexpressed in PCa and mediates resistance to ADT. Linsitinib is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of linsitinib in men with CRPC a Simon two-stage phase II study was conducted. Methods: Men with asymptomatic or mildly symptomatic Met CRPC were eligible. ECOG 0-1, adequate organ function, and no prior chemotherapy for CRPC were required. Pts received linsitinib at 150mg orally twice daily on a 28-day cycle. Endpoints included PSA response at 12 wks, safety, RECIST-defined response, time to PSA progression, and OS. Correlative studies explored the impact of linsitinib on AR signaling (androstenedione, DHEA, DHEA-sulfate, p-IGF-1R, p-IR), markers of PD (TGF-b1, IL-6, TNF-a, MCP-1), and CTC and CECs. Results: Eighteen pts were enrolled and completed 12 wks of therapy. Median age 68 (55-78); Median pre-treatment PSA was 55.23 (range 2.46-277.60); 41% of pts had bone-only disease, 29% soft-tissue only and 29% had both. Although transient PSA declines were noted (8/18), seventeen pts discontinued therapy sec PSA progression. RECIST-defined SD was observed in 8 pts. Pts received a median of 3 cycles of therapy (range 2-6+). Most common G1/2 AEs included AST/ALT changes observed in 41 and 18% of patients respectively, fatigue (59%); prolonged QT interval (35%) and nausea/vomiting (35%). No significant change in the number of CTC and CEC counts was observed. An association between pre-treatment PSA and pre-treatment CTC was observed (Spearman r=0.49, p=.04). No correlation between CTC changes and PSA progression was observed .Evaluation of other molecular markers of PD is underway. Conclusions: Treatment with linsitinib is safe however no PCa activity was seen. No changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. Linsitinib plus an AA might provide synergistic activity in this setting. Clinical trial information: NCT01533246.