Dose finding study of oral PSC 833 combined with weekly intravenous etoposide in children with relapsed or refractory solid tumours (original) (raw)
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Pharmacokinetics of etoposide (VP16) in children and adolescents with refractory solid tumors
Cancer research, 1984
The clinical pharmacokinetics of etoposide were studied in eight pediatric patients with refractory solid tumors. The alpha-phase half-life, beta-phase half-life, volume of distribution, and elimination rate constant averaged 0.82 hr, 6.5 hr, 4.0 liters/sq m, and 0.25 hr-1, respectively. Noncompartmental parameters such as systemic clearance, mean residence time, and volume of distribution at steady-state averaged 20.9 ml/min/sq m, 7.8 hr, and 7.2 liters/sq m, respectively. A significant relationship between serum glutamic pyruvic transaminase and systemic clearance was observed, with patients having elevated serum glutamic pyruvic transaminase showing slower systemic clearance of etoposide. Systemic clearance, mean residence time, and beta-phase half-life of etoposide were significantly lower in those patients who had received cisplatin prior to their Phase II etoposide trial. The average pharmacokinetic values derived from these eight pediatric patients with solid tumors did not d...
Clinical trial of etoposide (VP-16) in children with recurrent malignant solid tumors
Investigational New Drugs, 1988
Etoposide (VP-16), 150 mg/M 2, given intravenously daily for 3 days every 3 weeks resulted in 3 complete responses and 6 partial responses in 154 patients with a spectrum of recurrent malignant solid tumors. There was evidence of disease control in an additional 37 patients (27 mixed responses and 10 stable disease). These responses occurred primarily in patients with Ewing's sarcoma, Hodgkin's disease, neuroblastoma and rhabdomyosarcoma. Most of the patients had every extensive prior therapy; however prior therapy with teniposide (VM-26), the congener of VP-16, did not seem to preclude responses to the latter drug. Myelosuppression was the principal form of toxicity. Neutropenia characterized by absolute neutrophil counts of 0.5 to 0.9 • 109/L occurred in one-half of the patients, and thrombopenia with platelet counts of < 25 to 49 • 109/L in one-fourth. These results demonstrate a favorable therapeutic index for VP-16 in several recurrent childhood solid tumors, supporting its use as a component of primary therapy for these diseases.
Etoposide for the treatment of paediatric tumours: What is the best way to give it?
European Journal of Cancer, 1996
Etoposide is one of the most important drugs available for the treatment of paediatric malignancies. Although there is evidence of schedule dependency for etoposide therapy in adults with small-cell lung cancer, the relevance of this observation to childhood cancers is uncertain. Prolonged parent-era1 or oral etoposide therapy has not yet shown a clear-cut advantage over intermittent treatment, and there are still no data to show that the administration of etoposide as a short intravenous (i.v.) daily infusion for 5 days does not represent acceptable therapy for primary disease. The pharmacokinetic variability seen with etoposide argues strongly for the use of pharmacologically guided dosing, and the introduction of etoposide phosphate will simplify both parenteral etoposide administration and the future evaluation of alternative etoposide schedules. Although the impact of molecular and cellular pharmacological investigations on the clinical use of etoposide has yet to be felt, the tools to perform these studies are now available and prospective trials can be designed. Such studies, performed in the setting of a pharmacologically guided trial to ensure control over pharmacokinetic variability, should identify the best way of treating children with etoposide. Copy
Child's Nervous System
Purpose The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. Methods Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. Results The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progress...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2000
Cyclophosphamide (CPA) has a broad spectrum of activity against solid tumors. Hepatic self-induction of the active metabolite 4-hydroxycyclophosphamide occurs after repeated administration. We evaluated the clinical efficacy of a window regimen that administers fractionated CPA in conjunction with etoposide (VP16) in children with advanced or refractory solid tumors. Seventeen children with advanced (n = 12) or refractory (n = 5) solid tumors were entered onto this phase II window study. The treatment regimen consisted of intravenous (IV) CPA 500 mg/m(2)/d and IV VP16 100 mg/m(2)/d. Both drugs were administered daily by short infusions for 5 consecutive days. A total of 34 courses were administered, with a median of two courses per patient. The median interval between chemotherapy courses was 21 days (range, 17 to 35 days). Thirty-three courses were assessable for toxicity, and all patients were assessable for response. No life-threatening toxicities were observed. The incidence of ...
Pharmacokinetics of carboplatin and etoposide in infant neuroblastoma patients
Cancer Chemotherapy and Pharmacology, 2010
Newcastle upon Tyne NE2 4HH UK Tel: (+44) 0191 246 4332 / 4412 Fax: (+44) 0191 246 4301 Email: G.J.Veal@ncl.ac.uk; Alan.Boddy@ncl.ac.uk peer-00568264, version 1 -Abstract Purpose Carboplatin and etoposide are commonly used chemotherapeutics for the treatment of many paediatric cancers. However, there are very limited published data concerning the pharmacokinetics of these agents in infants and very young children, for whom dose reductions are frequently implemented.
Pediatric Blood & Cancer, 2014
Background-We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies. Procedure-MK-2206 was administered either every other day (schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and posttherapy in PBMC and in tumors at diagnosis or recurrence. Results-Fifty patients [26 males, median age 12.6 years (range, 3.1-21.9)] with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (schedule 1 n=23; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m 2 ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/ m 2 ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m 2). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m 2 ; grade 3 rash in 1/6 patients at 120 mg/ m 2 , and grade 3 rash in 2/6 patients at 155 mg/m 2 .
Cancer research, 1993
Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The...
Neuro-Oncology, 2006
The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group-VETOPEC I, Baby Brain 91, and VETOPEC II-have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors