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

I Brana, R Berger, T Golan, P Haluska, J Edenfield, J Fiorica, J Stephenson, L P Martin, S Westin, P Hanjani, M B Jones, K Almhanna, R M Wenham, D M Sullivan, W S Dalton, A Gunchenko, J D Cheng, L L Siu, J E Gray, I Brana, R Berger, T Golan, P Haluska, J Edenfield, J Fiorica, J Stephenson, L P Martin, S Westin, P Hanjani, M B Jones, K Almhanna, R M Wenham, D M Sullivan, W S Dalton, A Gunchenko, J D Cheng, L L Siu, J E Gray

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.

Figures

Figure 1
Figure 1
Time on treatment for the patients in the dalotuzumab+MK-2206 and dalotuzumab+ridaforolimus (A) and dalotuzumab+MK-0752 arm (B).
Figure 2
Figure 2
Dalotuzumab (MK-0646) (A), MK-2206 (B), and MK-0752 (C) pharmacokinetic profile. Ridaforolimus pharmacokinetic profile was not evaluable as a large proportion of samples were obtained post-dose instead of pre-dose.

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