Abstract
Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean C(min) was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. (18)F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals.
Highlights
Signaling by the insulin-like growth factor (IGF) receptor plays a key role in regulating cellular metabolism, growth, and cell fate in response to changes in nutrient availability [1,2,3]
At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 mg/mL, clearance was constant, and serum exposures were approximately dose proportional
Decreases in tumor Insulin-like growth factor-1 receptor (IGF-1R), downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients
Summary
Signaling by the insulin-like growth factor (IGF) receptor plays a key role in regulating cellular metabolism, growth, and cell fate in response to changes in nutrient availability [1,2,3]. There are several lines of evidence that suggest that this receptor may play a role in the survival and proliferation of human tumors. Phase I PK/PD Study of Dalotuzumab in Advanced Cancer Patients. The results from this clinical study of single-agent dalotuzumab show that the humanized monoclonal antibody is well tolerated in patients with advanced cancer. One particular combination supported by preclinical evidence, dalotuzumab in combination with an mTOR inhibitor, may be beneficial because it prevents the paradoxical activation of the IGF-1R signaling pathway by mTOR inhibitors
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