GDC-0879 All patients received MK 0457 as a 5 day continuous infusion

.121 All patients received MK 0457 as a 5 day continuous infusion every 2 3 weeks on a dose escalation schedule. Clinical correlates of CD34+ and peripheral blood morphonuclear cells were described, as well. Results were Green et al. Page 9 Expert GDC-0879 Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript mixed, with 5 of 6 MPD patients displaying limited apoptosis and slight decrease in JAK2 transcripts. Three of 6 CML patients displayed no cytogenetic response and 3 exhibited a response. Notably, one of the 6 CML patients received MK 0457 while in lymphoid blast crisis and displayed substantial apoptosis. In the 15 patients enrolled, virtually all of the in vitro markers for cell death were evident, but did not translate to in vivo findings.
Another phase I study of 40 patients, including 16 CML patients , 2 Ph+ ALL , 13 with AML and 10 with rapidly progressing or transforming MPD evaluated dose escalation of MK 0457 as 5 day continuous infusion.122 Still in progress at time of publication, authors note that GSK1904529A MTD was not reached despite using 24mg/m2/day as a 5 day continuous infusion, with only grade 1 nausea and alopecia observed. These interim results note that all 11 T315I BCR Abl CML patients and the T315I BCR Abl Ph+ALL patient experienced objective response. Six of 8 evaluable MPD patients also experienced objective responses. A subsequent phase I study in refractory CML and Ph+ ALL patients studied the effect of combining dasatinib, a second generation BCR Abl inhibitor, with MK 0457 in 3 patients .
123 All patients received dasatinib 70mg orally twice daily for 3 consecutive months. Patients who achieved major hematologic response received MK 0457 dosed at 64mg/m2/hr for 6 hours twice weekly. Patients who did not achieve MHR after 3 months of dasatinib received MK 0457 at a dose of 240mg/m2/day as continuous infusion for 5 days administered every 4 weeks. Both Ph+ ALL patients received biweekly treatment with 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 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 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 so