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Khan K.H.,Drug Development Unit | Wong M.,Drug Development Unit | Rihawi K.,Drug Development Unit | Bodla S.,The Royal Marsden RM National Health Service NHS Foundation Trust | And 3 more authors.
Oncologist | Year: 2016

Background. Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management. Materials and Methods. Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their associationwith grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0)were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables. Results. A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%)andgrade2in61(20.5%)patients, respectively.Grade≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age <65 years (p = .03), history of diabetes (p=.003), and treatmentwith AKT and dual PI3K/mTOR inhibitors (p < .0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort. Conclusion. Hyperglycemia iscommonin patients treatedwith PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation. © AlphaMed Press 2016. Source

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