Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC). Methods Patients received at 150 mg orally twice daily on a 28-day cycle. The primary endpoint was prostate specific (PSA) response at 12 weeks and correlative studies included circulating tumor cells (CTCs) and circulating endothelial cells (CECs). Results Seventeen patients, median age 68 (55-78) and pre-treatment PSA of 55.23 (2.46-277.60) were enrolled and completed 12 weeks of therapy. All but two patients discontinued therapy secondary to PSA progression, which met the predefined futility criteria and led to early termination of this study. Overall best response (RECIST v1.1) included a partial response in 1 patient and stable disease in 8 patients. Higher baseline CTCs were associated with higher pre-treatment PSA levels (Spearman r = 0.49, p = 0.04) but no correlation between PSA progression and CTCs/CECs were observed. Most common adverse events included fatigue, nausea/vomiting, AST/ALT changes and prolonged QT interval. Conclusions Single-agent linsitinib was safe and well tolerated but failed to show activity in men with mCRPC. These results highlight the complexity of using IGF-1R as a therapeutic target in this patient population. ClinicalTrials.gov NCT01533246.
Investigational new drugs. 2018 Feb 23 [Epub ahead of print]
Pedro Barata, Matthew Cooney, Allison Tyler, John Wright, Robert Dreicer, Jorge A Garcia
Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA., Seidman Cancer Center, University Hospitals, Case Comprehensive Cancer Center, Cleveland, OH, USA., Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA., Division Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA., Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave/CA60, Cleveland, OH, 44195, USA. .