Jan H M Schellens

Utrecht University, Utrecht, Utrecht, Netherlands

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Publications (740)2873.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Currently, no country-specific metastatic breast cancer (MBC) observational costing data are available for the Netherlands and Belgium. Our aim is to describe country-specific resource use and costs of human epidermal receptor 2 (HER-2)-positive MBC in the Netherlands and Belgium, making use of real-world data.The eligibility period for patient selection was from April 2004 to April 2010. Inclusion and retrospective data collection begins at the time of first diagnosis of HER-2-positive MBC during the eligibility period and ends 24 months post-index diagnosis of MBC or at patient death.We identified 88 eligible patients in the Netherlands and 44 patients in Belgium. The total costs of medical treatment and other resource use utilisation per patient was €48 301 in the Netherlands and €37 431 in Belgium. Majority of costs was related to the use of trastuzumab in both countries, which was 50% of the total costs in the Netherlands and 56% in Belgium respectively.Our study provides estimates of resource use and costs for HER-2-positive MBC in the Netherlands and Belgium. We noticed various differences in resource use patterns between both countries demonstrating caution is needed when transferring cost estimates between countries.
    European Journal of Cancer Care 12/2014; · 1.31 Impact Factor
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    ABSTRACT: Purpose:Since a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the maximum tolerated dose (MTD) to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. Experimental Design:We collected data on 1182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: a) patients treated within completed single agent studies where a maximum-administered-dose was defined; b) RECIST/survival data available. Results:72% of patients were included in trials with MTA (N=854) and 28% in trials with CTX (N=328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40-80%) had better survival compared to those receiving low or high dose (p=0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (p=0.003). Conclusions:While these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40-80% of MTD).
    Clinical cancer research : an official journal of the American Association for Cancer Research. 09/2014;
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    ABSTRACT: Background:Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC.Methods:One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m(-2)) on days 1-5 and 29-33, mitomycin C (MMC, 10 mg m(-2)) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m(-2) b.i.d. on weekdays), MMC (10 mg m(-2)) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity.Results:Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3-4) toxicity.Conclusions:Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC.British Journal of Cancer advance online publication 28 August 2014; doi:10.1038/bjc.2014.467 www.bjcancer.com.
    British journal of cancer. 08/2014;
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    ABSTRACT: Background The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to provide a motivating example of the application of CTS in the design of pediatric oncology clinical trials.ProcedureA pharmacokinetic (PK) model for vincristine in children was used to simulate concentration-time profiles. A continuous model for body surface area versus age was defined based on pediatric growth curves. Informative sampling time windows were derived using D-optimal design. The CTS framework was used to different magnitudes of clearance inhibition (10%, 25%, or 40%), sample size (30–500), the impact of missing samples or sampling occasions, and the age distribution, on the power to detect a significant inhibition effect, and in addition, the relative estimation error (REE) of the interaction effect.ResultsA minimum group specific sample size of 38 patients with a total sample size of 150 patients was required to detect a clearance inhibition effect of 40% with 80% power, while in the case of a lower effect of clearance inhibition, a substantially larger sample size was required. However, for the majority of re-estimated drug effects, the inhibition effect could be estimated precisely (REE < 25%) in even smaller sample sizes and with lower effect sizes.Conclusion This work demonstrated the utility of CTS for the evaluation of PK clinical trial designs in the pediatric oncology population. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 08/2014; · 2.35 Impact Factor
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    ABSTRACT: BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models. In vitro cell survival, drug accumulation, efflux and transport studies with BMS-275,183 were performed employing MDCKII (wild-type, MDR1, BCRP, MRP2) and LLCPK (wild-type and MDR1) cells. In vivo the pharmacokinetics and tissue distribution of BMS-275,183 after p.o. and i.v. administration were explored in Mdr1a/1b(-/-) and wild-type mice, in presence or absence of the PPI pantoprazole. Results In vitro, BMS-275,183 was found to be a good substrate for MDR1, a moderate substrate for MRP2 and not a substrate for BCRP. In vivo, oral bioavailability, plasma AUC0-6h and brain concentrations were significantly 1.5-, 4-, and 2-fold increased, respectively, in Mdr1a/1b(-/-) compared with wild-type mice (p < 0.001). However, oral co-administration of pantoprazole (40 mg/kg) did not alter the pharmacokinetics of BMS-275,183 in wild-type mice. Conclusions BMS-275,183 is efficiently transported by Pgp and to a lesser extent by MRP2 in vitro. Genetic deletion of Pgp significantly altered the pharmacokinetics and brain distribution of p.o. and i.v. administered BMS-275,183 in Mdr1a/1b-/- compared to wild-type mice. Oral co-administration of BMS-275,183 with pantoprazole did not affect the pharmacokinetics of BMS-275,183 in wild-type mice, suggesting no interaction with PPI at the dose employed.
    Investigational New Drugs 07/2014; · 3.50 Impact Factor
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    ABSTRACT: Purpose:This phase I expansion study assessed safety, pharmacodynamic effects and antitumor activity of RO4987655, a pure MEK inhibitor in selected advanced solid tumor patients. Experimental Design:We undertook a multicenter phase I two-part study (dose escalation, cohort expansion). Here we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice-daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK-phosphorylation and Ki-67 expression. BRAF- and KRAS-testing were implemented as selection criteria and broader tumor mutational analysis added. Results:95 patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant CRC. Most frequent adverse events were rash, acneiform dermatitis and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant CRC developed PD. Paired tumor biopsies demonstrated reduced ERK-phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. 69% showed decrease in fluorodeoxyglucose-uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS CRC) without therapeutic implications. Conclusions:Safety profile of RO4987655 was comparable to other MEK inhibitors. Single agent activity was observed in all entities except CRC. Evidence of target modulation and early biological activity were shown amongst all indications independent of mutational status.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
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    ABSTRACT: Pertuzumab is a recombinant humanized monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of HER2. Based on the positive opinion from the European Medicines Agency (EMA) on March 4, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. The demonstration of clinical benefit for pertuzumab was based on a single, phase III, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in previously untreated patients with locally advanced or metastatic HER2-positive breast cancer. In the primary analysis, median progression-free survival was 18.5 months in the pertuzumab group compared with 12.4 months in the placebo group (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.51-0.75; p < .0001). For the secondary endpoints, overall survival (HR: 0.66; 95% CI: 0.52-0.84; p = .0008) and objective response rate (80.2% vs. 69.3%) were also favored in the pertuzumab group. Toxicity was similar between groups except for higher incidence of diarrhea, rash, mucosal inflammation, dry skin, and neutropenia for pertuzumab compared with placebo. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).
    The Oncologist 06/2014; · 4.10 Impact Factor
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    ABSTRACT: The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-endoxifen, and a minimum therapeutic threshold for (Z)-endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and (Z)-endoxifen to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analyzed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula calculated serum concentration = DBS concentration/([1-haematocrit (Hct)] + blood cell-to-serum ratio × Hct). The blood cell-to-serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes. The average Hct for female adults was imputed as a fixed value. Calculated and analyzed serum concentrations were compared using weighted Deming regression. Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tamoxifen] serum, calculated = [Tamoxifen] DBS /0.779 and [(Z)-Endoxifen] serum, calculated = [(Z)-Endoxifen] DBS /0.663. Calculated serum concentrations were within 20 % of analyzed serum concentrations in 84 and 100 % of patient samples for tamoxifen and (Z)-endoxifen, respectively. In conclusion, DBS concentrations of tamoxifen and (Z)-endoxifen were equal to serum concentrations after correction for Hct and blood cell-to-serum ratio. DBS sampling can be used in clinical practice.
    Breast Cancer Research and Treatment 05/2014; · 4.47 Impact Factor
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    ABSTRACT: Purpose Renal impairment (RI) studies are conducted to estimate the impact of RI on pharmacokinetics (PK). In some disease areas, these studies can be difficult to conduct, for instance due to the limited number of eligible patients. The objective of this analysis was to evaluate bias and precision of population PK parameters, and the dose adjustment error (DAE) for RI studies i) with different levels of study design imbalance in the stratification of subjects across RI categories, and ii) that include additional patients in the control arm of RI studies, that may be available from previously conducted PK studies. Methods Study designs were simulated and re-estimated using a hypothetical 2-compartmental PK model with varying magnitude of the fraction of renal elimination (FR) and magnitude of between-subject variability (BSV). The DAE was computed based on the difference between the theoretical necessary dose adjustment versus the empirical estimated dose adjustment to reach a similar exposure as controls. Results Although some design imbalance may still lead to DAEs of acceptable magnitude (DAE < -11.05-14.44 inter-quartile range, IQR), at least some patients are necessary in the more severe RI groups. When 100 additional patients with normal renal function were included in a sub-informative design, the DAE changed from < -7.63-16.64 IQR to < -8.89-8.69 IQR. Conclusions We quantified the impact of study design imbalance on bias and precision of PK parameters and DAE, as may occur for RI studies in some indications. Adding additional data from earlier studies to the analysis dataset improves the bias and precision of PK parameters.
    Investigational New Drugs 05/2014; · 3.50 Impact Factor
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    ABSTRACT: Objectives The aim of this study is to establish the inhibitory effects of 14 commonly used complementary and alternative medicines (CAM) on the metabolism of cytochrome P450 2C9 (CYP2C9) substrates 7-methoxy-4-trifluoromethyl coumarine (MFC) and tolbutamide. CYP2C9 is important for the metabolism of numerous drugs and inhibition of this enzyme by CAM could result in elevated plasma levels of drugs that are CYP2C9 substrates. Especially for anticancer drugs, which have a narrow therapeutic window, small changes in their plasma levels could easily result in clinically relevant toxicities.Methods The effects of CAM on CYP2C9-mediated metabolism of MFC were assessed in Supersomes, using the fluorometric CYP2C9 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP2C9-mediated metabolism of tolbutamide was determined, using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).Key findingsThe results indicated milk thistle as the most potent CYP2C9 inhibitor. For milk thistle, silybin (main constituent of milk thistle) was mainly responsible for the inhibition of CY2C9.Conclusions Milk thistle and green tea were confirmed as potent inhibitors of CYP2C9-mediated metabolism of multiple substrates in vitro. Clinical studies with milk thistle are recommended to establish the clinical relevance of the demonstrated CYP2C9 inhibition.
    Journal of Pharmacy and Pharmacology. 05/2014;
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    ABSTRACT: Background:The intestinal uptake of the taxanes paclitaxel and docetaxel is seriously hampered by drug efflux through P-glycoprotein (P-gp) and drug metabolism via cytochrome P450 (CYP) 3A. The resulting low oral bioavailability can be boosted by co-administration of P-gp or CYP3A4 inhibitors.Methods:Paclitaxel or docetaxel (10 mg/kg) was administered to CYP3A4-humanised mice after administration of the P-gp inhibitor elacridar (25 mg kg(-1)) and the CYP3A inhibitor ritonavir (12.5 mg kg(-1)). Plasma and brain concentrations of the taxanes were measured.Results:Oral co-administration of the taxanes with elacridar increased plasma concentrations of paclitaxel (10.7-fold, P<0.001) and docetaxel (four-fold, P<0.001). Co-administration with ritonavir resulted in 2.5-fold (paclitaxel, P<0.001) and 7.3-fold (docetaxel, P<0.001) increases in plasma concentrations. Co-administration with both inhibitors simultaneously resulted in further increased plasma concentrations of paclitaxel (31.9-fold, P<0.001) and docetaxel (37.4-fold, P<0.001). Although boosting of orally applied taxanes with elacridar and ritonavir potentially increases brain accumulation of taxanes, we found that only brain concentrations, but not brain-to-plasma ratios, were increased after co-administration with both inhibitors.Conclusions:The oral availability of taxanes can be enhanced by co-administration with oral elacridar and ritonavir, without increasing the brain penetration of the taxanes.British Journal of Cancer advance online publication, 29 April 2014; doi:10.1038/bjc.2014.222 www.bjcancer.com.
    British Journal of Cancer 04/2014; · 5.08 Impact Factor
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    ABSTRACT: Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade 3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg.Results:Twenty-nine out of 43 patients were evaluable for PK assessments. Grade 3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.Conclusions:In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.British Journal of Cancer advance online publication, 15 April 2014; doi:10.1038/bjc.2014.194 www.bjcancer.com.
    British Journal of Cancer 04/2014; · 5.08 Impact Factor
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    ABSTRACT: Pregnant patients with cancer are increasingly treated with anti-cancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anti-cancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anti-cancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments. A pooled analysis of PK data was performed for pregnant (Pr) and non-pregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently we derived optimized dose regimens aiming to match to the area-under-the-concentration-time-curve (AUC) in non-pregnant patients. The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21 respectively, with adequate precision (relative standard error [RSE] <37%). For doxorubicin, no gestational effect could be estimated on clearance. For epirubicin, docetaxel and paclitaxel a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were respectively estimated on clearance. Calculated dose adjustment-requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%). Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy.
    Annals of Oncology 04/2014; · 7.38 Impact Factor
  • Annals of Oncology 03/2014; · 7.38 Impact Factor
  • Vincent A de Weger, Jos H Beijnen, Jan H M Schellens
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    ABSTRACT: Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The taxanes are administered as intravenous solutions in a short administration schedule. Distribution of both taxanes is rapid, with large volumes of distribution and significant binding to plasma proteins. The metabolism of paclitaxel is mediated primarily by the P450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after intravenous administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use.
    Anti-cancer drugs 03/2014; · 2.23 Impact Factor
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    ABSTRACT: Regorafenib has recently been approved for the treatment of colorectal cancer. A bioanalytical liquid chromatography-tandem mass spectrometric assay for this multikinase inhibitor was developed and validated in plasma. The concentration range of the assay was 25-25,000 ng/mL. Protein precipitation with acetonitrile was used as sample pre-treatment with sorafenib as internal standard. The extract was diluted with methanol (25%, v/v) and then injected onto the sub-2 µm particle, bridged ethylsilicia hybrid trifunctional bonded C18 column. Isocratic elution using 0.02% (v/v) formic acid in a methanol-water mixture was used. Compounds were monitored by a triple quadrupole mass spectrometer in the selected reaction monitoring mode after positive electrospray ionization. Double logarithmic calibration was used; within-day precisions, between-day precisions, and accuracies were 3.2-9.2, 4.1-12.3 and 94.8-103.0%, respectively. High drug stability was observed under all relevant storage conditions. The assay was used to measure drug concentrations in a pharmacokinetic study in wild-type FVB mice. Copyright © 2014 John Wiley & Sons, Ltd.
    Biomedical Chromatography 03/2014; · 1.95 Impact Factor
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    ABSTRACT: Although sarcomas account for only 1% of all solid tumors, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials. We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007. 178 patients diagnosed with advanced sarcoma or other mesenchymal tumors were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable to that previously published for patients receiving standard treatments beyond first-line. Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option.
    Annals of Oncology 03/2014; · 7.38 Impact Factor
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    ABSTRACT: There is accumulating evidence for potential benefits of therapeutic drug monitoring (TDM) in the treatment of cancer with tyrosine kinase inhibitors (TKIs). Relationships between exposure and response (efficacy/toxicity) have been established for several TKIs. For example, the pharmacokinetic targets for efficacy of imatinib, sunitinib and pazopanib have been defined as trough plasma concentrations (C trough) of >1,000, >50 and >20,000 ng/mL for selected indications, respectively. Dose adjustment based on pharmacokinetic targets could therefore increase response rates and duration. Furthermore, with appropriate target concentrations defined, excessive side effects in patients using the current fixed dosing strategy may be prevented. This review provides a practical guideline for TDM for the currently approved TKIs at 28 February 2013. The focus of this article is on the elaboration of exposure and response relationships of TKIs with proposed pharmacokinetic targets, mainly C trough, and further on the interpretation of the pharmacokinetic targets with recommendations for dose titrations.
    Clinical Pharmacokinetics 02/2014; · 5.49 Impact Factor
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    ABSTRACT: Genetics has importantly added to our understanding of variability in drug response, especially in cancer treatment. Pharmacogenetics, aimed at predicting a patients' chance for effective and safe drug treatment by interrogating germline genetic variants, has moved from a monogenetic candidate gene to complex phenotype based genome-wide approaches. With the rapidly advancing sequencing technologies, decline in costs and swift turnaround times, large scale genomic information will become available in the clinical setting, facilitating implementation of pharmacogenetics.Clinical Pharmacology & Therapeutics (2014); accepted article preview online 21 January 2014 doi:10.1038/clpt.2014.13.
    Clinical Pharmacology &#38 Therapeutics 01/2014; · 6.85 Impact Factor
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    ABSTRACT: A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for sepantronium bromide (YM155), an inhibitor of survivin, was developed and validated. Under reduced light exposure, plasma samples were pre-treated using protein precipitation with acetonitrile containing AT7519 as internal standard. After dilution with water, the extract was directly injected into the reversed-phase liquid chromatographic system. The eluate was transferred into the electrospray interface with positive ionization and compounds detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 0.5-100ng/ml calibration range with r(2)=0.9981±0.0007 using double logarithmic calibration (n=5). Within day precisions (n=6) were 3.6-8.8% and between day (3 days; n=18) precisions 6.5-11.1%. Accuracies were between 92 and 111% for the whole calibration range. The light sensitive drug sepantronium was sufficiently stable under all relevant analytical conditions. Finally, the assay was successfully used to determine plasma drug levels in mice after administration of sepantronium bromide by continuous infusion from subcutaneously implanted osmotic pumps.
    Journal of pharmaceutical and biomedical analysis 01/2014; 92C:144-148. · 2.45 Impact Factor

Publication Stats

13k Citations
2,873.78 Total Impact Points


  • 1995–2014
    • Utrecht University
      • • Department of Pharmaceutical Sciences
      • • Division of Biomedical Analysis
      • • Division of Toxicology
      • • Division of Veterinary Pharmaceuticals, Pharmacology and Toxicology
      Utrecht, Utrecht, Netherlands
  • 1993–2014
    • Netherlands Cancer Institute
      • • Department of Clinical Pharmacology
      • • Division of Molecular Pathology
      • • Department of Medical Oncology
      • • Division of Experimental Therapy
      • • Division of Molecular Biology
      • • Department of Neuro-oncology
      Amsterdamo, North Holland, Netherlands
  • 2013
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
    • Rijnstate Hospital
      Arnheim, Gelderland, Netherlands
  • 2011–2013
    • European Medicines Agency
      Londinium, England, United Kingdom
    • Cantonal Hospital of Schwyz
      Schwyz, Schwyz, Switzerland
    • Dana-Farber Cancer Institute
      • Carole M. and Philip L. Lowe Center for Thoracic Oncology
      Boston, MA, United States
  • 1994–2013
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2012
    • Queen's University Belfast
      • Centre for Cancer Research and Cell Biology
      Béal Feirste, N Ireland, United Kingdom
    • Nederlands Jeugd Instituut
      Utrecht, Utrecht, Netherlands
  • 2010–2012
    • The Royal Marsden NHS Foundation Trust
      Londinium, England, United Kingdom
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2009–2012
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2001–2012
    • Uppsala University
      • Department of Pharmacy
      Uppsala, Uppsala, Sweden
  • 2007–2011
    • Kantonsspital St. Gallen
      San Gallo, Saint Gallen, Switzerland
    • Leiden University Medical Centre
      • Department of Clinical Pharmacy and Toxicology
      Leyden, South Holland, Netherlands
    • Insitute de Cancérologie de l'Ouest - Centre René Gauducheau
      Naoned, Pays de la Loire, France
  • 2002–2010
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Medical Oncology
      Amsterdam, North Holland, Netherlands
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 2008–2009
    • Atrium Medisch Centrum Parkstad
      Heerlen, Limburg, Netherlands
    • Astellas Pharmaceutical
      Northbrook, Illinois, Japan
  • 2004
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2002–2004
    • Wyeth
      New Johnsonville, Tennessee, United States
  • 2003
    • Centre Jean Perrin
      Clermont, Auvergne, France
    • University of Antwerp
      Antwerpen, Flanders, Belgium
  • 1999–2001
    • Institut Bergonié
      Burdeos, Aquitaine, France
  • 1996–1999
    • Erasmus MC
      • Department of Internal Oncology
      Rotterdam, South Holland, Netherlands
  • 1998
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1991
    • Leiden University
      Leyden, South Holland, Netherlands