The World's Most Bizarre Alogliptin Celecoxib Story

Binhibition. Elevation in liver function tests and myocardial infarction at dose level of 162mgm2day signified the DLT and established MTD as 108mgm2day as a 72hr continuousinfusion. Celecoxib Doses above 6mgm2day made predictable and reversible neutropenia andalopecia. Around 33% of patients knowledgeable hematological response, with CMLpatients benefiting probably the most.AT9283 was administered to 22 patients with advanced solid tumors, which includes squamouscell carcinoma and colorectal adenocarcinoma, as a 72hr continuous intravenous infusionover 5 doses levels, ranging from 1.512mgm2day, inside a normal 33 dose escalationdesign.99 Aurora B kinase inhibition was seen across all dose levels, as evidenced by skinand serum samples. The MTD was determined to be 9mgm2day as a 72hr continuousinfusion with DLT of febrile neutropenia.
The Celecoxib ideal response was stable disease achievedafter at the very least 6 cycles. A second phase I study in 33 patients with refractory solid tumorsadministered AT9283 with administration parameters and identical style as previouslydescribed.100 The MTD of 9mgm2day as a 72hr continuous infusion with DLT of febrileneutropenia were replicated. Seven patients were administered a single oral dose of 0.9mgm2 prior to starting IV, revealing an oral bioavailability of 27%. The bestresponse was partial response in 1patient with nonsmall cell lung cancer and stabledisease in 4 other patientsafter receiving a minimum of 6 cycles.4.4 PF03814735Preclinical studies of PF03814735 displayed broad activity in cell lines and murinexenografts of breast, colorectal, lung, and promyelocytic leukemia.
101 A single phase I studyin 20 patients with varying refractory solid tumors was conducted working with an accelerated doseescalationscheme.102 Soon after 20 patients received a median of 2 cycles ranging from 5100mgday orally5 days, the MTD was determined to be 80mgday5 days with a DLTof febrile neutropenia. Other adverse effects consist of gastrointestinal toxicity and fatigue. Noobjective Alogliptin responses were reported in this study and no subsequent studies are currentlyongoing.285.0 PanAurora Kinase Inhibitors5.1 VX680MK0457Discovered via a molecular screening campaign, VX680MK0457 also potentlyinhibits Src and GSK3, Flt3, JAK2, BCRAbland BCRAblatnanomolar concentrations.103 The inhibition of a wide array of kinases stems from theability to bind to nonaurora kinases in their inactive conformations and preventingactivation.
103 A lot of preclinical investigations with VX680MK0457 were performed incell lines andor xenografts in animal models showing high degree of antitumor activity.The tumor kinds investigated as singleagent included ovarian104, renal cell carcinoma105,thyroid106, HSP oral squamous cell107, CML108,109,110,AML111, and MM112.Phenotypic modifications induced by VX680MK0457 indicated that synergy may be obtainedby Alogliptin combining VX680MK0457 with HDACI. Vorinostat inhibits HDAC6 causingacetylation and disruption of heat shock protein 90. By inducing acetylation ofhsp90, vorinostat inhibits the chaperone function of hsp90 leading to depleted aurora kinaselevels in AML and CML cells.
113 Many preclinical studies combining vorinostat withVX680MK0457 demonstrated additive or synergistic activity in AML113,114, colorectalcancer114, pancreatic cancer114, CML113,115, PhALL116, and breast cancer117. Synergy was also seen when VX680MK0457 is combinedwith chemotherapy agents or erlotinib, an orallyavailable epidermal growth aspect receptorantagonist, in Celecoxib preclinical studies of AML, CML, PhALL, and lung cancer.118,119,120 Anearly phase III study in humans attempted to study not just the inhibitor effect of aurorakinase, but also the antiJAK2 effect by enrolling 15 patients which includes 6 with V617FmutantJAK2 myeloproliferative disease.121 All patients received MK0457 as a 5day continuous infusion each and every 23 weeks on a dose escalation schedule. Clinical correlatesof CD34and peripheral blood morphonuclear cells were described, too.
Final results weremixed, Alogliptin with 5 of 6 MPD patients displaying limited apoptosis and slight decrease in JAK2transcripts. Three of 6 CML patients displayed no cytogenetic response and 3exhibited a response. Notably, a single in the 6 CML patients received MK0457 while inlymphoid blast crisis and displayed substantial apoptosis. Within the 15 patients enrolled,virtually all of the in vitro markers for cell death were evident, but did not translate to in vivofindings.A different phase I study of 40 patients, which includes 16 CML patients,2 PhALL, 13 with AML and 10 with quickly progressing ortransforming MPD evaluated doseescalation of MK0457 as 5day continuous infusion.122Still in progress at time of publication, authors note that MTD was not reached regardless of using24mgm2day as a 5day continuous infusion, with only grade 1 nausea and alopeciaobserved. These interim outcomes note that all 11 T315I BCRAbl CML patients along with the T315IBCRAbl PhALL patient knowledgeable objective response. Six of 8 evaluable MPD patientsalso knowledgeable objective responses.A subsequent phase I