LY294002 154447-36-6 NIH PA Author Manuscript The initial cohort of 40 patients

lid tumors .129 Green et al. Page 10 Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript The initial cohort of 40 patients received escalating doses of danusertib without LY294002 154447-36-6 granulocyte colony stimulating factor and subsequent 16 patients received G CSF support. The MTD was determined to be 500mg/m2 intravenously over 24 hours every 14 days with DLT being neutropenia. When danusertib was administered with G CSF support, the MTD was determined to be 750mg/m2 intravenously over 24 hours every 14 days due to renal damage at the next higher dose level. Non hematologic adverse events were generally mild and reversible, with the exception of hypertension, which occurred in 12 patients and reversible reduction in left ventricular ejection fraction by approximately 10% from baseline in 2 cases.
Pharmacodynamic correlates of skin biopsies revealed low grade phenotypic changes consistent with aurora B kinase inhibition starting at 500mg/m2 cohort. Stable disease was most frequently detected, occurring in 18 of 42 patients, with durable stabilization of disease detected PF-04217903 in 4 patients. Twenty three patients with CML and Ph+ ALL were enrolled in a phase I study of danusertib administered via 3 hr infusion daily for 7 consecutive days every 14 days.130 Fifteen of 23 patients harbored T315I BCR Abl mutation. The MTD was not determined at publication, but a single episode of syncope was observed at 90mg/m2 cohort. Three patients experienced cytogenic response and 5 demonstrated hematologic response.
Phase II studies are currently ongoing in both solid and hematologic tumors using both 6 hr infusion and 24 hour continuous infusion schedule.28 5.3 CYC 116 CYC 116 is a potent, orally administered inhibitor of all 3 aurora kinases, Flt3, and VEGFR 2.131,132 Preclinical models in both cell lines and murine xenografts indicate activity against leukemia, pancreatic, colorectal, prostate, glioma, thyroid, melanoma, breast, and non small cell lung cancers, with inhibition of angiogenesis playing a distinct role in overall anti tumor effect. Preclinical data have also demonstrated synergy with combining CYC 116 with chemotherapeutic agents or in combination with ionizing radiation.133,134 Of note, the preclinical study of CYC 116 with ionizing radiation demonstrated a distinctly potent anti tumor effect in Ras mutated colorectal adenocarcinoma cell lines over Ras wild type cell lines.
134 A phase I trial was completed in October 2009 in patients with advanced solid tumors with results forthcoming.28 5.4 SNS 314 SNS 314 displays high selectivity for aurora kinases, binding with high affinity. A unique feature to SNS 314 is lack of off target inhibitory effects.135 Where many other AKIs coinhibit BCR Abl, FLT3, and VEGFR, none of these kinases are inhibited by SNS 314 at clinically relevant doses. Preclinical studies of single agent SNS 314 in cell lines and murine models show anti tumor efficacy for tumors of colon, breast, prostate, lung, ovary and melanoma.136 Combination studies of SNS 314 with chemotherapy agents in colorectal adenocarcinoma cell lines displayed synergy, with antimicrotubule agents providing most substantial synergy.
137 This study evaluated SNS 314 with various chemotherapeutic agents, either concurrently or in sequence. This model showed additive effect with many agents, except when SNS 314 was used concurrently with nucleoside antagonists or carboplatin. When used sequentially, agents that were antagonistic as concurrent therapy yielded additive effect. Furthermore, administration of SNS 314 prior to docetaxel was more efficacious than docetaxel prior to SNS 314. This innovative model has not been utilized with other AKIs and it remains to be seen if the effect on efficacy translates to humans. A phase I study of 32 patients with advanced solid malignancies evaluated administration of SNS 314 by 3 hour infusion on days 1, 8, and