h MK 0457 and maintained hematologic response with no hematologic toxicity. The CML patient who clinically failed dasatinib showed marked improvement after the first cycle of MK 0457. Due to serious cardiac events, including QTc prolongation, all further Fostamatinib Syk inhibitor trials of VX 680/MK 0457 were terminated and drug development halted.28 5.2 PHA 739358 An analogue of PHA 680632 with enhanced inhibitory potency for all aurora kinases, danusertib potently inhibits all aurora kinases, BCR Abl, FGFR 1 and FLT3, in addition to almost 30 other kinases at clinically relevant doses.124,125 Notably, danusertib is a very potent inhibitor of VEGFR2/3 at doses used clinically. Preclinical activity from cell lines and xenograft models displayed high degree of activity in colorectal, breast, prostate, lung, ovary, and hepatocellular tumors, in addition to CML.
125,126,127 Based upon preclinical data, danusertib was studied as both bolus128 and continuous infusion administration129 in separate phase I studies. The bolus infusion study evaluated administration of 45mg/m2 intravenously BMY 7378 over 6 hours and 250mg/m2 intravenously over 3 hours with standard dose escalation in a heterogeneous population of patients with solid tumors.128 Colorectal adenocarcinoma and sarcoma accounted for approximately 50% of patients. The 3 hour infusion schedule was determined after interim analysis of 6 hr infusion cohort. The DLT for 6 hr infusion was identified at 330mg/m2, but DLT for 3 hr infusion was not identified, as neutropenia was dose limiting. PK and PD correlates favored 330mg/ m2 intravenously as a 6 hr infusion.
However, no complete or partial responses were observed in this cohort, with objective response observed in 6 of 30 evaluable patients. Authors recommend 330mg/m2 given over 6 hours on days 1, 8, 15 of a 28 day cycle should be used in phase II testing. The phase I study of danusertib administered as continuous infusion included 56 patients with advanced solid tumors.129 Green et al. Page 10 Recent Pat Anticancer Drug Discov. Author manuscript, available in PMC 2011 February 15. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript The initial cohort of 40 patients received escalating doses of danusertib without 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 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 inhib
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