A phase II study of linsitinib (OSI-906) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC).

Abstract

197 Background: Novel agents capable of blocking AR ligand independent pathways responsible for the development of CRPC are needed. 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. OSI-906 is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of OSI-906 in men with CRPC a Simon two-staged 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 OSI-906 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 OSI-906 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: To date 18 pts have 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, 17/18 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%); prolong 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 OSI-906 is safe. No PSA responses or changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. OSI-906 plus an AA might provide synergistic activity in this setting. Clinical trial information: NCT01533246.

Growth factor and signaling pathways and their relevance to prostate cancer therapeutics

“…Although transient PSA declines were noted, the majority of patients discontinued therapy due to PSA progression after a median of 3 months of therapy. Notable side effects included fatigue, liver function test abnormalities, prolonged QT interval, nausea, and vomiting [80]. However, it is unclear whether the benefits that have been reported preliminarily in these early phase studies are significant enough to warrant larger clinical trials in the metastatic CRPC population.…”