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Brana I , Berger R , Golan T , Haluska P , Edenfield J , Fiorica J , Stephenson J , Martin LP , Westin S , Hanjani P , Jones MB , Almhanna K , Wenham RM , Sullivan DM , Dalton WS , Gunchenko A , Cheng JD , Siu LL , Gray JE
A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours
Br J Cancer. 2014 Nov 11;111(10) :1932-44
PMID: 25290091   
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Abstract
BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.
Notes
1532-1827 Brana, I Berger, R Golan, T Haluska, P Edenfield, J Fiorica, J Stephenson, J Martin, L P Westin, S Hanjani, P Jones, M B Almhanna, K Wenham, R M Sullivan, D M Dalton, W S Gunchenko, A Cheng, J D Siu, L L Gray, J E UM1 CA186686/CA/NCI NIH HHS/United States Clinical Trial, Phase I Journal Article Multicenter Study Research Support, Non-U.S. Gov't England Br J Cancer. 2014 Nov 11;111(10):1932-44. doi: 10.1038/bjc.2014.497. Epub 2014 Oct 7.