Jan H M Schellens

Utrecht University, Utrecht, Utrecht, Netherlands

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Publications (873)3592.48 Total impact

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    ABSTRACT: 5-Fluorouracil (5-FU) and capecitabine (CAP) are among the most frequently prescribed anticancer drugs. They are inactivated in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or CAP. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care. Our goal was to present the available evidence in favour of prospective genotyping, including discussion of unjustified worries on cost-effectiveness, and potential underdosing. We conclude that there is convincing evidence to implement prospective DPYD genotyping with an upfront dose adjustment in DPD deficient patients. Immediate benefit in patient care can be expected through decreasing toxicity, while maintaining efficacy.
    Full-text · Article · Feb 2016 · European journal of cancer (Oxford, England: 1990)
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    ABSTRACT: Background: The objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care. Patients and methods: A total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early - i.e. cycle one or two - severe (grade ≥ 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis. Results: Among 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade ≥3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio [OR] 0.85 per 10 ml/min/1.73 m(2), p = 0.0007), body surface area (BSA) (OR 0.33 per m(2), p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade ≥3 toxicity was 0.704 (95% confidence interval 0.666-0.743, optimism-corrected AUC 0.690). Conclusion: Renal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care.
    Full-text · Article · Feb 2016 · European journal of cancer (Oxford, England: 1990)
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    ABSTRACT: The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A. The predictive value of MIR27A variants for early-onset grade ≥3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. 1592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95%CI 0.87-1.82, p=0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95%CI 1.24-19.7, p=0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, p=0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95%CI 1.27-4.37, p=0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.4, 95%CI 0.09-1.82, p=0.236). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95%CI 1.83-15.7, p=0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · International Journal of Cancer
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    ABSTRACT: A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for afatinib, an irreversible inhibitor of the ErbB (erythroblastic leukemia viral oncogene homolog)) tyrosine kinase family, was developed and validated. Plasma samples were pre-treated using salting-out assisted liquid-liquid extraction (SALLE) with acetonitrile, magnesium chloride and a stable isotopically labeled internal standard. After dilution, 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 were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer.
    No preview · Article · Jan 2016 · Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
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    ABSTRACT: Background Integrin signaling is an attractive target for anti-cancer treatment. GLPG0187 is a broad spectrum integrin receptor antagonist (IRA). GLPG0187 inhibited tumor growth and metastasis in mouse models. Methods We aimed to determine the Recommended Phase II Dose (RP2D) and to assess safety and tolerability of continuous i.v. infusion in patients with advanced malignant solid tumors. Anticipated dose levels were 20, 40, 80, 160, 320, and 400 mg/day in a modified 3 + 3 design. Plasma concentrations of GLPG0187 were assessed to characterize the pharmacokinetics (PK). C-terminal telopeptide of type I collagen (CTX) was used as pharmacodynamics marker. Results Twenty patients received GLPG0187. No dose limiting toxicities (DLTs) were observed. The highest possible and tested dose was 400 mg/day. Fatigue was the most frequently reported side effect (25 %). Recurrent Port-A-Cath-related infections and skin toxicity suggest cutaneous integrin inhibition. No dose-dependent toxicity could be established. PK analysis showed a short average distribution (0.16 h) and elimination (3.8 h) half-life. Continuous infusion resulted in dose proportional PK profiles. We observed decreases in serum CTX levels independent of the dose given, suggesting target engagement at the lowest dose level tested. Single agent treatment did not result in tumor responses. Conclusions GLPG0187 was well tolerated with a dose-proportional PK profile upon continuous infusion. No formal maximal tolerated dose could be established. GLPG0187 showed signs of target engagement with a favourable toxicity profile. However, continuous infusion of GLPG0187 failed to show signs of monotherapy efficacy.
    Full-text · Article · Jan 2016 · Investigational New Drugs
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    ABSTRACT: To facilitate future pharmacokinetic studies of combination treatments against leishmaniasis in remote endemic regions, a simple and cheap sampling methodology was required for miltefosine quantification. The aim of this study was to validate a liquid chromatography-tandem mass spectrometry method to quantify miltefosine in dried blood spots (DBS) and to validate its use in Ethiopian visceral leishmaniasis (VL) patients. Since hematocrit (Ht) values are typically severely decreased in VL patients, regressing to normal during treatment, the method was evaluated over a range of clinically relevant Ht values. Miltefosine was extracted from DBS using a simple pre-treatment method with methanol, resulting in >97% recovery. The method was validated over a calibration range of 10-2,000 ng/mL and accuracy and precision were within ±11.2% and ≤7.0% (≤19.1% at LLOQ), respectively. The method was accurate and precise for blood spot volumes between 10-30 μL and for an Ht of 20-35%, though a linear effect of Ht on miltefosine quantification was observed in the bioanalytical validation. DBS samples were stable for at least 162 days at 37°C. Clinical validation of the method using paired DBS and plasma samples from 16 VL patients showed a median observed DBS:plasma miltefosine concentration ratio of 0.99, with good correlation (Pearson's r=0.946). Correcting for patient-specific Ht did not further improve the concordance between the sampling methods. This successfully validated method to quantify miltefosine in DBS was demonstrated to be a valid and practical alternative to venous blood sampling which can be applied in future miltefosine pharmacokinetic studies in leishmaniasis patients, without Ht-correction.
    Preview · Article · Jan 2016 · Antimicrobial Agents and Chemotherapy
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    ABSTRACT: Background: Elderly patients receiving anticancer drugs may have an increased risk to develop treatment-related toxicities compared to their younger peers. However, a potential pharmacokinetic (PK) basis for this increased risk has not consistently been established yet. Therefore, the objective of this study was to systematically review the influence of age on the PK of anticancer agents frequently administered to elderly breast cancer patients. Methods: A literature search was performed using the PubMed electronic database, Summary of Product Characteristics (SmPC) and available drug approval reviews, as published by EMA and FDA. Publications that describe age-related PK profiles of selected anticancer drugs against breast cancer, excluding endocrine compounds, were selected and included. Results: This review presents an overview of the available data that describe the influence of increasing age on the PK of selected anticancer drugs used for the treatment of breast cancer. Conclusions: Selected published data revealed differences in the effect and magnitude of increasing age on the PK of several anticancer drugs. There may be clinically-relevant, age-related PK differences for anthracyclines and platina agents. In the majority of cases, age is not a good surrogate marker for anticancer drug PK, and the physiological state of the individual patient may better be approached by looking at organ function, Charlson Comorbidity Score or geriatric functional assessment.
    Preview · Article · Jan 2016 · Cancers
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    ABSTRACT: Aim: Three intracellularly formed metabolites are responsible for the antineoplastic effect of capecitabine: 5-fluorouridine 5'-triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP), and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). The objective of this study was to explore the pharmacokinetics of these intracellular metabolites during capecitabine treatment. Methods: Serial plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 13 patients treated with capecitabine 1000 mg QD (group A) and 8 patients receiving capecitabine 850 mg/m(2) BID for fourteen days, every three weeks (group B). Samples were collected on day 1 and, for 4 patients of group B, also on day 14. The capecitabine and 5-fluorouracil (5-FU) plasma concentrations and intracellular metabolite concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using non-compartmental analysis. Results: Only FUTP could be measured in the PBMC samples. The FdUTP and FdUMP concentrations were below the detection limits (LOD). No significant correlation was found between the plasma 5-FU and intracellular FUTP exposure. The FUTP concentration-time profiles demonstrated considerable inter-individual variation and accumulation of the metabolite in PBMCs. FUTP levels ranged between <LOD and 1.0 μM on day 1, and from 0.64 to 14 μM on day 14. The area under the FUTP concentration-time curve was significantly increased on day 14 of the treatment compared to day 1 (mean ±SD: 28 ±19 μM*h vs. 2.0 ±1.9 μM*h). Conclusions: To our knowledge, this is the first time that intracellular FUTP concentrations were measured in patients treated with capecitabine. During 14 days of treatment with capecitabine twice daily, intracellular accumulation of FUTP occurs.
    No preview · Article · Dec 2015 · British Journal of Clinical Pharmacology
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    ABSTRACT: Objective To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Methods In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5 mg/kg (day 1), docetaxel 50 mg/m(2) (day 1), oxaliplatin 100 mg/m(2) (day 1), capecitabine 850 mg/m(2) b.i.d. (days 1-14), and trastuzumab 6 mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6 months (observed in the ToGA trial) determined according to the lower limit of the 95 % confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS). Results Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17 months, median PFS was 10.8 months (95%CI: 9.0-NA), OS was 17.9 months (95%CI: 12.4-NA). One-year PFS and OS were 52 % and 79 %, respectively. The ORR was 74 % (95%CI: 52-90 %). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related grade ≥ 3 adverse events were: neutropenia (16 %), diarrhoea (16 %), and hypertension (16 %). Conclusions B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC.
    No preview · Article · Dec 2015 · Investigational New Drugs
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    ABSTRACT: Breast cancer is the most common type of cancer among women worldwide. In low and middle-income countries (LMICs), appropriate selection of medicines on national essential medicines lists (NEMLs) is a first step towards adequate access to treatment. We studied selection of systemic treatments for breast cancer on NEMLs and assessed its alignment with treatment guidelines for different types of early and advanced breast cancer. Furthermore, influence of country characteristics on the selection was investigated. NEMLs from 75 LMICs were studied for inclusion of all components of therapy in each stage of breast cancer according to international consensus guidelines. The results were then grouped by income level, WHO region and the NEMLs' release date. Non parametric tests were used for statistical analysis. Unlike HER2-targeted therapies (<10 %), aromatase inhibitors (12 %) and taxanes (28 %); tamoxifen and first generation chemotherapeutic regimens (e.g., anthracycline-based regimens) were frequently found in the NEMLs (71-78 %). Consequently, all components of treatment for "Luminal A" early breast cancer and non HER2 overexpressed advanced breast cancer were found on the NEMLs of over 70 % of countries. However, 40 % of the low income countries did not have all the components of therapy for any type of early breast cancer in their NEMLs, and adequate treatment of HER2 overexpressed breast cancer was hardly possible with the current selections. Recent NEMLs were more aligned with the guidelines (p < 0.05). Eastern Mediterranean and African regions less frequently incorporated all components of breast cancer treatment in their NEMLs. Alignment of selection with guidelines' recommendations was inconsistent for different types of early and advanced breast cancer in NEMLs. Regular updates and more attention to clinical guidelines is therefore recommended.
    Full-text · Article · Dec 2015 · BMC Cancer
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    ABSTRACT: Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.
    No preview · Article · Dec 2015
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    ABSTRACT: In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK)-pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock-out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti-tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti-tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti-tumour effect of ritonavir.
    No preview · Article · Nov 2015 · The AAPS Journal
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    ABSTRACT: Purpose: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, δ), with pre-clinical studies demonstrating broad anti-tumor activity. We performed a first-in-human phase 1 study in patients with advanced solid tumors. Experimental design: Patients received oral GSK458 once or twice daily in a dose escalation design to define the maximally tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics (PD), pharmacokinetics (PK), and clinical activity in histologically- and molecularly-defined cohorts. Results: 170 patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (DLTs) (grade 3 diarrhea, n=4; fatigue and rash, n=1) occurred in 5 patients (n=3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). PK analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (OR) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated with PIK3CA mutations (OR rate: 5% wild-type versus 6% mutant). Conclusions: Although the MTD of GSK458 was 2.5 mg once daily, twice daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as PD markers of drug exposure. Select patients achieved durable responses however PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.
    No preview · Article · Nov 2015 · Clinical Cancer Research
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    ABSTRACT: Purpose: Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing. Patients and methods: Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses. Results: A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs. Conclusion: DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.
    No preview · Article · Nov 2015 · Journal of Clinical Oncology
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    ABSTRACT: Background Moderate diagnostic accuracy of MRI and initial cerebrospinal fluid (CSF) cytology analysis results in at least 10%–15% false negative diagnoses of leptomeningeal metastases (LM) of solid tumors, thus postponing start of therapy. The aim of this prospective clinical study was to determine the diagnostic value of epithelial cell adhesion molecule (EpCAM)–based flow cytometry versus cytology in CSF for the diagnosis of LM in patients with epithelial tumors.
    No preview · Article · Nov 2015 · Neuro-Oncology
  • Linda M Henricks · Jan H.M. Schellens · Alwin D.R. Huitema · Jos H Beijnen
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    ABSTRACT: Treatment with monoclonal antibodies is becoming increasingly important in clinical oncology. These antibodies specifically inhibit signaling pathways in tumor growth and/or induce immunological responses against tumor cells. By combining monoclonal antibodies several pathways may be targeted simultaneously, potentially leading to additive or synergistic effects. Theoretically, antibodies are very suitable for use in combination therapy, because of limited overlapping toxicity and lack of pharmacokinetic interactions. In this article an overview is given of preclinical and clinical data on twenty-five different combinations of antibodies in oncology. Some of these combinations have proven clinical benefit, for example the combination of trastuzumab and pertuzumab in HER2-positive breast cancer, which exemplifies an additive or synergistic effect on antitumor activity in clinical studies and the combination of nivolumab and ipilimumab, which results in significant increases in progression-free and overall survival in patients with advanced melanoma. However, other combinations may lead to unfavorable results, such as bevacizumab with cetuximab or panitumumab in advanced colorectal cancer. These combinations result in shorter progression-free survival and increased toxicity compared to therapy with a single antibody. In summary, the different published studies showed widely varying results, depending on the combination of antibodies, indication and patient population. More preclinical and clinical studies are necessary to unravel the mechanisms behind synergistic or antagonistic effects of combining monoclonal antibodies. Most research on combination therapies is still in an early stage, but it is expected that for several tumor types the use of combination therapy of antibodies will become standard of care in the near future.
    No preview · Article · Nov 2015 · Cancer Treatment Reviews

  • No preview · Article · Nov 2015 · Value in Health
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    ABSTRACT: Purpose: The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses. Methods: Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1-14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome. Results: A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m(2), oxaliplatin 100 mg/m(2) plus capecitabine 850 mg/m(2) b.i.d. The median number of treatment cycles was 6 (range 2-8). Grade ≥ 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4-7.6) and 11.0 months (95 % CI 7.9-14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival. Conclusion: Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome.
    No preview · Article · Oct 2015 · Cancer Chemotherapy and Pharmacology
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    ABSTRACT: The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood-brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies.
    No preview · Article · Oct 2015 · Journal of Neurology
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    ABSTRACT: Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in advanced cancer patients. Experimental design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1600 and 2000 mg) q2w in 3+3 dose escalation phase. Additionally, 22 patients were enrolled into an extension cohort at 2000 mg q2w. Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients [46.8%]), fatigue (21 patients [44.7%]), decreased appetite (15 patients [31.9%]), infusion-related reactions (13 patients [27.7%]) and constipation (10 patients [21.3%]). The peak concentration (Cmax) and area under the concentration - time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥400 mg q2w indicating target-mediated drug disposition saturation. Down-regulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex-vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared to a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range: 80 to 225 days). Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.
    Full-text · Article · Oct 2015 · Clinical Cancer Research

Publication Stats

23k Citations
3,592.48 Total Impact Points


  • 1999-2016
    • Utrecht University
      • • Department of Pharmaceutical Sciences
      • • Faculty of Science
      • • Division of Biomedical Analysis
      • • Division of Toxicology
      Utrecht, Utrecht, Netherlands
    • Medisch Spectrum Twente
      Enschede, Overijssel, Netherlands
  • 1995-2015
    • Netherlands Cancer Institute
      • • Department of Medical Oncology
      • • Department of Clinical Pharmacology
      • • Division of Experimental Therapy
      • • Division of Surgical Oncology
      Amsterdamo, North Holland, Netherlands
  • 1996-2014
    • Erasmus MC
      • Department of Medical Oncology
      Rotterdam, South Holland, Netherlands
  • 2012
    • Queen's University Belfast
      • Centre for Cancer Research and Cell Biology
      Béal Feirste, Northern Ireland, United Kingdom
  • 2011
    • University Medical Center Hamburg - Eppendorf
      • Department of Internal Medicine II. (Oncology/Haematologie with Sections Bone Marrow Transplantation and Pneumologie)
      Hamburg, Hamburg, Germany
  • 1994-2011
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 2009
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2007
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2006-2007
    • University of Florence
      Florens, Tuscany, Italy
  • 2005
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2004
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2003
    • Nevada cancer institute
      Las Vegas, Nevada, United States
  • 1999-2003
    • Centro de Investigación del Cáncer
      Helmantica, Castille and León, Spain
  • 2002
    • Pfizer Inc.
      New York, New York, United States
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 2001
    • Institut Bergonié
      Burdeos, Aquitaine, France
  • 1996-1998
    • Erasmus Universiteit Rotterdam
      • Department of Medical Oncology
      Rotterdam, South Holland, Netherlands