Abstract B256: A novel targeted oral insulin-like growth factor 1 (IGF-1) receptor inhibitor in clinical phase I/II testing

Abstract

Abstract The overall objective was to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related insulin receptor and to test such a compound in cancer patients with solid tumors. IGF-1R belongs to a family of related receptors also including the insulin receptor (IR). The IGF-1R signaling pathway is crucial for the survival and growth of most types of cancer cells, but not of normal cells. The concept has general applicability with respect to many different cancers. AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 demonstrates strong and unique anti-tumor efficacy, including complete regression of established tumors in animals xenografted with human malignant cells, including breast cancer, prostate cancer, glioblastoma (intracerebral implants), malignant melanoma, sarcoma and multiple myeloma. AXL1717 did not show any effect in animals with IGF-1R negative xenografts. Preclinical testing showed excellent tolerability together with good oral bioavailability. AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7–28 days of increasing BID doses of AXL1717. The preliminary results as of September 3rd 2009 have identified possible Phase II dosages. Even though the study was not designed to evaluate tumor or biomarker response, 4 out of 6 patients have shown decreased density of IGF-1R on granulocytes. Two patients, with progressive non-small cell lung cancer, treated with AXL1717 as 3rd and 4th line treatment, respectively, were reported to have documented tumor necrosis. The preliminary results from the Phase I/II clinical trial indicate a recommended phase II dose with good tolerability and with an oral bioavailability resulting in an exposure several fold higher than the exposure resulting in complete regression of tumors in animals. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B256.