Monitoring for the growth of these lesions will clearly be a part of clinical ca

Monitoring for the growth of these lesions will clearly be a part of clinical care of patients being treated with vemurafenib going forward,however.Preclinical Data Vemurafenib pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1- sulfonamide] is an oral serine?threonine kinase inhibitor.Owing to the failure of prior BRAF inhibitors,a structureguided discovery approach was pursued to identify molecules containing a pyridoimidazolone compatible with the ATP pocket-binding domain of BRAF.PLX4720,a 7-azaindole derivative,was the initial result of PLX4032 clinical trial these investigations.This molecule established a new class of more specific kinase inhibitors with selectivity for mutant BRAFV600E.Subsequent studies showed marked effects on apoptosis,proliferation,and blockade of downstream ERK phosphorylation.These findings translated into inhibition of growth in V600E mutant melanoma cell lines,as well as tumor regression in xenograft models.Via this drug discovery approach,a panel of related small molecules was also discovered including PLX4032.PLX4720 and PLX4032 were evaluated simultaneously.Owing to a more advantageous pharmacokinetic profile in dogs and cynomolgus monkeys,vemurafenib was chosen to take forward into further clinical development.
Vemurafenib was shown to be highly specific for BRAFV600E with an inhibitory concentration at 50% of 31 nmol/L.In melanoma cell lines as well as melanoma and colon cancer xenografts,vemurafenib was observed to inhibit tumor growth in a dose-dependent fashion.Animal studies in rats and beagle dogs showed no significant toxicity at a 1,000 mg/kg/day Vandetanib on a 28-day dosing schedule or in longer studies with effective exposures tested up to 2,600 mmol/L in rats and 820 mmol/L in beagle dogs.Notably,the effective exposure described in rats is higher than that administered to human patients.Clinical Studies The initial phase I trial of vemurafenib included a 55- patient dose escalation followed by a dose expansion of 32 patients.All advanced solid tumor patients were eligible for participation in the dose escalation; however,tumors associated with a high incidence of BRAFV600E mutation made up the bulk of the accrual.Eligibility requirements of note included Eastern Cooperative Oncology Group performance status of 0 or 1 and the absence of brain metastases.Patients received daily drug dosing until the development of toxicity or progression of disease.Vemurafenib was initially developed in a crystalline formulation and administered at a starting dose of 200 mg daily.After 26 patients were treated,accrual was stopped because of poor pharmacokinetics.Serum sampling revealed that available drug levels were lower than required for efficacy based on preclinical modeling.

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