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

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.

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…In general, obtained data from allosteric inhibitors such as perifosine in different advance neoplasms [201,202] and nelfinavir in glioblastoma and locally advanced rectal cancers [203,204] indicate a favorable safety profile. Akt allosteric inhibitor MK2206 in combination with cytotoxic therapies [119,205] or in combination with other molecular targeting agents such as anti-IGF-1R antibody dalotuzumab [206] and EGFR kinase inhibitor erlotinib [119] was shown to be well-tolerated in phase I trials. For hematologic malignancies, a favorable safety profile and clinical activity against multiple myeloma has been demonstrated by Akt allosteric inhibitor afuresertib alone in phase I study (GSK2110183) [207].…”

IGF2 signaling and regulation in cancer

“…Several companies, including Imclone with cixutumumab, Amgen with ganitumab and Pfizer with figitumumab, developed humanized antibodies against IGF1R, but clinical trials have been disappointing so far (58). Few IGF1R antibodies are still being developed, such as dalotuzumab from Merck (59). Trials of combination therapies (IGF1R antibody together with standard chemotherapy or compounds such as Sorafenib, Everolimus and Cetuximab) are actively recruiting (clinicaltrials.gov).…”

Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade

“…This pathway (Fig. 1) is composed of three receptor tyrosine kinases - insulin-like growth factor-1 receptor (IGF-1R), insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor (INSR); three ligands – insulin, IGF-1, and IGF-2 (2, 3); and six serum Insulin-like Growth Factor Binding Proteins (IGFBP’s), which serve as regulators of the pathway by determining ligand bioavailability (4). The most prevalent of the IGFBP’s is IGFBP3 (5).…”

“…Elevated serum levels of IGF-1 and IGF-2 as well as overactivation of the mitogenic, anti-apoptotic, and pro-motility signaling cascades induced by IGF-1R have been implicated in many tumor types, including epithelial malignancies (breast, lung, colorectal, prostate, ovarian), mesenchymal tumors (osteosarcoma, rhabdomyosarcoma), and hematologic malignancies (1, 2, 17, 20, 21). Furthermore, IGF-1R pathway dysregulation acts as an oncogenic signal in the context of both initial tumorigenesis and resistance to cytotoxic and targeted anticancer therapies (2, 3, 22, 23). …”