Abstract B74: A Phase I trial of vertical inhibition of IGF signaling using IMC-A12, an IGF1-R inhibitor, and AZD6244, a MEK 1/2 inhibitor, in patients with advanced solid tumors.
Authors: Wilky Breelyn A. , Rudek Michelle , Laheru Daniel , Cosgrove David , Donehower Ross , Nelkin Barry , Ball Douglas , Doyle L. Austin , Chen Helen , Ye Xiaobu , Azad Nilofer 
Published: August 2014

Abstract
Background: The IGF1 receptor activates key pro-survival signaling pathways critical in cancer including the RAS/RAF/MEK/ERK and PI3K/mTOR/AKT pathways. Despite this, clinical trials of single-agent IGF1-R antibodies have shown modest clinical benefit. In vitro data suggests that dual inhibition of IGF1-R and MEK synergistically decreases downstream pathway activation and increases apoptosis. Therefore, we performed a phase I clinical trial to test the safety and toxicity of combined IMC-A12 (anti-IGF1-R antibody) and AZD6244 (MEK 1/2 inhibitor).
Methods: Patients were required to have advanced solid tumors refractory to standard therapy with adequate performance status and end-organ function. Treatment consisted of AZD6244 hydrogen sulfate capsules orally twice daily, and IMC-A12 intravenously on days 1 and 15 of each 28-day cycle. The study was a 3+3 design, with a dose-finding cohort and an expansion cohort treated at the maximally tolerated dose. Pharmacokinetic studies were performed on all patients, while pre- and post-treatment biopsies for pharmacodynamic assessment of pathway activity were obtained from patients on the expansion cohort.
Results: 30 patients were enrolled on the study, 16 in the dose-finding cohort and 14 patients in the expansion cohort. The regimen was well-tolerated in most patients, and the most common study-drug related adverse events included rash, nausea/vomiting, diarrhea, and poor appetite/weight loss. Grade 3 or greater toxicities included nausea and vomiting, anemia, CVA, hypertension, hyperglycemia, and ophthalmologic symptoms (blurry vision, floaters, flashing lights, black dots/lines in field of vision, retinopathy). Three patients treated at dose level 2 (AZD6244 75 mg / IMC-A12 12 mg) developed dose-limiting toxicity of ophthalmologic symptoms; therefore the maximally tolerated combination dose was AZD6244 50 mg / IMC-A12 12 mg. 19 patients remained on study for at least 8 weeks and were evaluable for radiographic response. Two patients achieved a partial response (one unconfirmed), and 6 patients achieved progression-free survival of greater than 6 months. Two of the three patients with BRAF mutations showed prolonged progression-free survival on therapy. Pharmacokinetic analysis is ongoing. Paired pre- and on-treatment biopsies obtained in 5 patients showed significant suppression of phospho-ERK activity with treatment.
Conclusions: Vertical inhibition of IGF1-R mediated signaling aims to avoid compensatory escape mechanisms by inhibiting additional downstream targets within the RAS/RAF/MEK/ERK and/or PI3K/mTOR/AKT pathways. Our study of IMC-A12 and AZD6244 showed that the drug combination is safe and well-tolerated, with decreased phosphorylation of ERK indicating effective target inhibition. Further study is necessary to identify biomarkers for patients likely to benefit from this treatment approach, particularly with regards to patients possessing BRAF mutations.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B74.
Citation Format: Breelyn A. Wilky, Michelle Rudek, Daniel Laheru, David Cosgrove, Ross Donehower, Barry Nelkin, Douglas Ball, L. Austin Doyle, Helen Chen, Xiaobu Ye, Nilofer Azad. A Phase I trial of vertical inhibition of IGF signaling using IMC-A12, an IGF1-R inhibitor, and AZD6244, a MEK 1/2 inhibitor, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B74.