3 research outputs found

    Thymidylate synthase as a target for chemotherapy in childhood leukaemia

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    SIGLEAvailable from British Library Document Supply Centre-DSC:DXN019909 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

    A phase I and pharmacokinetic study of plitidepsin in children with advanced solid tumours: An Innovative Therapies for Children with Cancer (ITCC) study

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    Aims To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2 weeks (one cycle) to children with refractory or relapsed solid tumours. Methods Consecutive cohorts of patients were treated according to a standard ‘3 + 3’ design with escalating doses of plitidepsin at 4, 5 and 6 mg/m2. Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity. Results Thirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5 mg/m2. PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4 weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3 months. Conclusion Plitidepsin administered to children as a 3-h infusion every 2 weeks is received with manageable toxicity for children with cancer, and the RD is 5 mg/m2. Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting
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