15 every 28 days.138 Neutropenia was Green et al. Page 11 Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript determined to be DLT encountered at a dose of OSU-03012 AR-12 1,440mg/m2 with skin biopsies showing phenotypic evidence of aurora B kinase inhibition at doses �?40mg/m2. No MTD could be determined. Pharmacokinetic data determined a t1/2 of 10.4 hours and Vd approximating total body water. No objective responses were observed in any patient, but 6 patients experienced stable disease. No active clinical trials are currently registered in the United States.28 5.5 AMG 900 AMG 900 is an oral pan aurora kinase inhibitor with extreme potency for all 3 aurora kinases, but little off target inhibition.
139 Preclinical investigation JNJ 26854165 of single agent AMG 900 demonstrated inhibition of proliferation in 26 tumor cell lines of both solid and hematologic malignancies, including cell lines resistant to paclitaxel and other AKIs .139 The first in human phase I study in advanced solid tumors is currently ongoing.28 5.6 VE 465 A pan aurora kinase inhibitor related to MK0457, VE 465 inhibits a host of off target kinases beyond aurora kinases at clinically relevant doses.140 Preclinical tissue culture cells and murine xenograft models confirm activity in CML as single agent and with imatinib140, multiple myeloma 141, hepatocellular carcinoma142, ovarian cancer 143, and myeloid leukemia144. Currently, no studies in humans are ongoing.28 5.
7 AS703569/R 763 Discovered through cell based approach for drug design, AS703569 is an orally available aurora kinase that exhibits potent off target inhibition of FLT3, BCR Abl, VEGFR 2, IGFR, Akt.145 Preclinical investigation in cell cultures and murine xenografts demonstrates antiproliferative activity in solid organ and hematologic tumors including non small cell lung, breast, pancreas adenocarcinoma, colorectal adenocarcinoma, prostate, cervix, ovary, osteogenic sarcoma, biphenotypic leukemia, acute promyelocytic leukemia, ALL, AML, CML, and MM.145,146,147 The first phase I study of AS703569 in humans was conducted using a two arm, doseescalation scheme in patients with advanced solid malignancies.148 The first arm administered AS703569 on days 1 and 8 every 21 days and the second arm administered AS 703569 on days 1, 2 and 3 every 21 days as a single oral dose.
Fifteen patients were enrolled with the most common malignancies being uterine and breast carcinomas. At study publication, no DLT or MTD had been established and 1 patient experienced tumor progression while on study. A second study also evaluated 2 different dosing schedules in patients with hematological malignancies.149 Forty three total patients were assigned to receive AS703569 once daily on days 1 3 and 8 10 every 21 days or once daily on days 1 6 ever 21 days . The majority of patients had de novo AML or secondary AML . The MTD for both administration schedules was determined to be 37mg/m2/day, with mucositis and neutropenia serving as DLT. PK data determined a Tmax of 2 4 hours and t1/2 of 10 20 hours.
Activity was modest with schedule of administration on days 1 3 and 8 10 demonstrating greater number of objective responses in this small cohort. Several clinical trials in both solid and hematologic malignancies, including combination studies with chemotherapy are either ongoing or recently completed.28 Green et al. Page 12 Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript 6.0 Conclusions Aurora SMIs have been developed as anti cancer therapies since they target aberrant centrosome amplification and/or a defective spindle assembly checkpoint associated with chromosomal instability in many human solid and hematologic malignancies. Approximately 15 distinct chemotypes reversibly targeting the ATP binding site of Aurora A and/or B are in early clinical de