Martin Fassnacht1, Alfredo Berruti2, Eric Baudin3, Michael J Demeure4, Jill Gilbert5, Harm Haak6, Matthias Kroiss7, David I Quinn8, Elizabeth Hesseltine9, Cristina L Ronchi10, Massimo Terzolo11, Toni K Choueiri12, Srinivasu Poondru13, Tanya Fleege13, Ramona Rorig13, Jihong Chen13, Andrew W Stephens14, Francis Worden9, Gary D Hammer15. 1. Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; Central Laboratory, Research Unit, University Hospital Würzburg, Würzburg, Germany. 2. Department of Medic Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy. 3. Department of Nuclear Medicine and Endocrine Tumors, Institut Gustave Roussy, Villejuif, France. 4. Translational Genomics Research Institute, Phoenix, AZ, USA. 5. Vanderbilt School of Medicine, Nashville, TN, USA. 6. Department of Internal Medicine, Máxima Medical Centre, Eindhoven, Netherlands; Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; Maastricht University, Department of Health Services Research, and CAPHRI School for Public Health and Primary Care, Maastricht, Netherlands. 7. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. 8. Univeristy of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. 9. Endocrine Oncology Program-Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA. 10. Central Laboratory, Research Unit, University Hospital Würzburg, Würzburg, Germany. 11. Univerita degli Studi di Torino, Orbassano, Turin, Italy. 12. Dana-Farber Cancer Institute, Boston, MA, USA. 13. Astellas Pharma Global Development, Northbrook, IL, USA. 14. Piramal Imaging, Berlin, Germany. 15. Endocrine Oncology Program-Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: ghammer@umich.edu.
Abstract
BACKGROUND: Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. METHODS: In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. FINDINGS:Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 toplacebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. INTERPRETATION: Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. FUNDING: Astellas.
RCT Entities:
BACKGROUND:Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. METHODS: In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. FINDINGS: Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. INTERPRETATION:Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. FUNDING: Astellas.
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