Petronella O Witteveen

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (60)318.12 Total impact

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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.
    Clinical Cancer Research 11/2015; DOI:10.1158/1078-0432.CCR-15-1665 · 8.72 Impact Factor
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    ABSTRACT: Background: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. Methods: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. Results: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. Conclusions: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; number, NCT00330447.).
    New England Journal of Medicine 09/2015; 373(19). DOI:10.1056/NEJMoa1508913 · 55.87 Impact Factor
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    ABSTRACT: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours. Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in a 21-day cycle, both in combination with daily pazopanib, were explored. In total, 67 patients were enroled. Pazopanib co-administration caused a substantial increase in exposure to total topotecan (1.7-fold) compared with topotecan alone, which is considered clinically relevant. Topotecan had no effect on pazopanib concentrations. Safety findings were consistent with the known profile of both agents. There were three drug-related deaths, liver failure, tumour haemorrhage and myelosuppression. Two patients experienced dose-limiting toxicities (DLTs; hand-foot syndrome, myelosuppression and diarrhoea) on the weekly topotecan schedule and four patients experienced DLTs (myelosuppression) on the daily-times-five topotecan schedule. When combined with pazopanib, 800 mg daily, the recommended doses for oral topotecan are: 8 mg weekly and 2.5 mg daily-times-five. Seven of eight patients with partial response had platinum-resistant ovarian cancer. In addition, 54% of patients had stable disease with 22% stable for 6 months. Total topotecan exposure is 1.7-fold higher when co-administered with pazopanib. Both schedules of administration were tolerated and would permit further evaluation, especially the weekly schedule.British Journal of Cancer advance online publication, 20 August 2015; doi:10.1038/bjc.2015.257
    British Journal of Cancer 08/2015; 113(5). DOI:10.1038/bjc.2015.257 · 4.84 Impact Factor
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    ABSTRACT: To determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicities and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB)-chemotherapy. A multi-center phase I toxicity and pharmacokinetic study of oral topotecan in patients with advanced solid tumors. Patients were grouped by normal renal function with limited- or prior PB-chemotherapy or impaired renal function (mild [creatinine clearance (Clcr) = 50-79 mL/min], moderate [Clcr = 30-49 mL/min], severe [Clcr <30 mL/min]). Fifty-nine patients were evaluable. Topotecan lactone and total topotecan 'area under the concentration-time curve' (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly hematological. The maximum-tolerated dose (MTD) was 2.3 mg/m(2) /day, given on days 1 to 5 in a 21-day cycle, for patients with prior PB-chemotherapy or mild renal impairment, and 1.2 mg/m(2) /day for patients with moderate renal impairment (suggested dose 1.9 mg/m(2) /day for non-Asians). Due to incomplete enrollment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg/m(2) /day in this cohort. Oral topotecan dose adjustments are not required in patients with prior PB-chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 02/2015; 80(2). DOI:10.1111/bcp.12606 · 3.88 Impact Factor
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    ABSTRACT: Purpose This study assessed the pharmacokinetics and safety of oral panobinostat and its metabolite BJB432 in patients with advanced solid tumors and normal to severely impaired renal function. Methods Patients with varying degrees of renal impairment, defined by their 24-h baseline urine creatinine clearance (as normal, mild, moderate or severe), received a single oral dose of 30 mg panobinostat. Serial plasma samples were collected pre-dose and up to 96-h post-dose. Serial urine samples were collected for 24-h post-dose. Following the serial PK sampling, patients received 30 mg oral panobinostat thrice weekly for as long as the patient had benefit. Pharmacokinetic parameters were derived using non-compartmental analysis. Results Thirty-seven patients were enrolled, and median age was 64 (range 40–81) years. Eleven patients had normal renal function; 10, 10, and 6 patients had mild, moderate, and severe renal impairment, respectively. Geometric means of AUC0–∞ in the normal, mild, moderate, and severe groups were 224.5, 144.3, 223.1, and 131.7 ng h/mL, respectively. Geometric mean ratio of BJB432 to parent drug plasma AUC0–∞ was 0.64 in the normal group and increased to 0.81, 1.13, and 1.20 in the mild, moderate, and severe groups, respectively. The fraction excreted as unchanged panobinostat was small (
    Cancer Chemotherapy and Pharmacology 11/2014; 75(1). DOI:10.1007/s00280-014-2612-8 · 2.77 Impact Factor

  • European Journal of Cancer 11/2014; 50:185. DOI:10.1016/S0959-8049(14)70698-7 · 5.42 Impact Factor
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    ABSTRACT: Optimal long-lasting treatment with sunitinib and sorafenib is limited by dose modifications (DMs) due to adverse events (AEs). These AEs may be underrecognized and their influence on health-related quality of life (HRQL) underestimated. Improved insight into the relationship between AEs and therapy decisions is needed. To improve decision making around managing symptoms and reduce DMs, this study was set up to explore the influence of patient-reported symptoms on therapy decisions. In this multicenter cohort study, patient characteristics, reasons for and different forms of used dose modifications, and AEs were prospectively obtained from cancer patients on sunitinib/sorafenib treatment. Used instruments to get insight into AEs were the patient-scored Utrecht Symptom Diary (USD) and the professional-scored Common Terminology Criteria for AEs version 3.0. Median total treatment duration in 42 patients was 16 weeks. Median time till dose modification was 10 weeks. DMs occurred mostly due to multiple mild AEs. By using the USD, a higher prevalence of most AEs was found compared to the literature. Sixty percent of the patients experienced a decreased HRQL due to multiple AEs. Because severe AEs due to sunitinib/sorafenib treatment seldom occur, it is more important to focus on treating and preventing multiple mild AEs with higher impact on HRQL, when trying to avoid dose modifications. Using patient self-reported measurement methods helps to early recognize symptoms and to differentiate among symptom intensities. This systematic approach might help to achieve the optimal dosing, which might improve PFS and OS.
    Supportive Care in Cancer 04/2014; 22(9). DOI:10.1007/s00520-014-2223-2 · 2.36 Impact Factor
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    ABSTRACT: Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the ovaries. Several cancer genes such as NF1, CDKN2A and FANCD2 were affected by lesion-specific breakpoints. Furthermore, the intra-tumor variability involved different mutational hallmarks including lesion-specific kataegis (local mutation shower coinciding with genomic breakpoints), rearrangement classes and coding mutations. In one extreme case, we identified two independent TP53 mutations in ovary tumors and omentum/peritoneum metastases, respectively. Examination of gene expression dynamics revealed upregulation of key cancer pathways including WNT, integrin, chemokine and hedgehog signalling in only subsets of tumor samples from the same patient. Finally, we took advantage of the multi-level tumor analysis to understand the effects of genomic breakpoints on qualitative and quantitative gene expression changes. We show that intra-tumor gene expression differences are caused by site-specific genomic alterations, including formation of in frame fusion genes. These data highlight the plasticity of ovarian cancer genomes, which may contribute to their strong capacity to adapt to changing environmental conditions and give rise to the high rate of recurrent disease following standard treatment regimes.
    Genome Research 11/2013; 24(2). DOI:10.1101/gr.161026.113 · 14.63 Impact Factor
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    M Y V Homs · H W R Schreuder · G N Jonges · P O Witteveen ·
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    ABSTRACT: Malignant ovarian germ cell tumor is a rare disease, but with current treatment strategies including surgery and platinum based chemotherapy survival is excellent. After treatment, intensive followup is indicated to encounter tumor relapse at an early stage. This case describes a 22-year-old female with a history of common variable immune deficiency (CVID) who underwent a resection of a large ovarian germ cell tumor followed by 4 cycles of cisplatin and etoposide resulting in clinical complete remission. During followup, she developed a mass at the umbilicus and ascites. Initially, the cytology of the ascites was interpreted as tumor positive, suspicious of relapse of the disease, but tumor markers remained negative. However, during laparoscopy it turned out to be a mature teratoma, which can develop after chemotherapy, the so called growing teratoma syndrome. In retrospect, the ascites was false positive. This case shows that current diagnostic tools are not sufficient to distinguish between vital tumor and mature teratoma and can be misleading. Tumor biopsy and/or laparoscopic inspection are therefore indicated.
    10/2013; 2013:984524. DOI:10.1155/2013/984524
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    ABSTRACT: Purpose: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. Method: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose-volume parameters D90 HR-CTV (high-risk clinical target volume) and D(2cc) OARs (organs at risk) were determined and converted into biologically equivalent doses in 2 Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. Results: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm(3) at time of first brachytherapy (BT). Median follow-up was 41 (range, 4-67) months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p=0.013), OS 77 versus 50% (p=0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p=0.002), OS 83 versus 46% (p=0.007), respectively). Late grade 3-4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D(2cc) OAR values. Conclusion: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity.
    Radiotherapy and Oncology 04/2013; 107(1). DOI:10.1016/j.radonc.2013.04.006 · 4.36 Impact Factor
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    ABSTRACT: PURPOSEWe aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP). PATIENTS AND METHODS In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy.ResultsThe registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%. CONCLUSION The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy.
    Journal of Clinical Oncology 04/2013; 31(20). DOI:10.1200/JCO.2012.45.6335 · 18.43 Impact Factor
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    ABSTRACT: CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.
    Investigational New Drugs 01/2013; 31(4). DOI:10.1007/s10637-013-9925-z · 2.92 Impact Factor

  • Cancer Research 12/2012; 72(24 Supplement):P6-07-05-P6-07-05. DOI:10.1158/0008-5472.SABCS12-P6-07-05 · 9.33 Impact Factor
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    ABSTRACT: Purpose: The aim of this study was to determine the plasma pharmacokinetics of eribulin mesylate in patients with solid tumors with mild and moderate hepatic impairment. Patients and methods: A phase I, pharmacokinetic study was performed in patients with advanced solid tumors and normal hepatic function or Child-Pugh A (mild) or Child-Pugh B (moderate) hepatic impairment. Treatments were given on day 1 and 8 of a 21-day cycle and consisted of 1.4, 1.1 and 0.7 mg/m(2) eribulin mesylate, for normal hepatic function, Child-Pugh A and B hepatic impairment, respectively. Also safety and anti-tumor activity were determined. Results: Hepatic impairment increased exposure to eribulin. In patients with Child-Pugh A (N = 7) and Child-Pugh B (N = 5), mean dose-normalized AUC(0-∞) was 1.75-fold (90 % confidence intervals (CI): 1.16-2.65) and 2.48-fold (90 % CI: 1.57-3.92) increased, respectively, compared with patients who have normal function (N = 6). The most frequently reported treatment-related events were alopecia (12/18) and fatigue (7/18) and these were observed across all groups. Nine patients (50 %) had stable disease as best response. Conclusions: A reduced dose of 1.1 and 0.7 mg/m(2) of eribulin mesylate is recommended for patients with Child-Pugh A or B hepatic impairment, respectively.
    Cancer Chemotherapy and Pharmacology 09/2012; 70(6). DOI:10.1007/s00280-012-1976-x · 2.77 Impact Factor
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    ABSTRACT: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours. An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m−2 eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and Cmax for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m−2 eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed. Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and Cmax = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%). These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.
    British Journal of Clinical Pharmacology 07/2012; 75(2). DOI:10.1111/j.1365-2125.2012.04381.x · 3.88 Impact Factor
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    ABSTRACT: This study evaluates intra- and interobserver variability of automatic diameter and volume measurements of colorectal liver metastases (CRLM) before and after chemotherapy and its influence on response classification. Pre-and post-chemotherapy CT-scans of 33 patients with 138 CRLM were evaluated. Two observers measured all metastases three times on pre-and post-chemotherapy CT-scans, using three different techniques: manual diameter (MD), automatic diameter (AD) and automatic volume (AV). RECIST 1.0 criteria were used to define response classification. For each technique, we assessed intra- and interobserver reliability by determining the intraclass correlation coefficient (α-level 0.05). Intra-observer agreement was estimated by the variance coefficient (%). For inter-observer agreement the relative measurement error (%) was calculated using Bland-Altman analysis. In addition, we compared agreement in response classification by calculating kappa-scores (κ) and estimating proportions of discordance between methods (%). Intra-observer variability was 6.05%, 4.28% and 12.72% for MD, AD and AV, respectively. Inter-observer variability was 4.23%, 2.02% and 14.86% for MD, AD and AV, respectively. Chemotherapy marginally affected these estimates. Agreement in response classification did not improve using AD or AV (MD κ=0.653, AD κ=0.548, AV κ=0.548) and substantial discordance between observers was observed with all three methods (MD 17.8%, AD 22.2%, AV 22.2%). Semi-automatic software allows repeatable and reproducible measurement of both diameter and volume measurements of CRLM, but does not reduce variability in response classification.
    European journal of radiology 01/2012; 81(10):2543-9. DOI:10.1016/j.ejrad.2011.12.026 · 2.37 Impact Factor

  • European Journal of Cancer 09/2011; 47. DOI:10.1016/S0959-8049(11)70855-3 · 5.42 Impact Factor
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    ABSTRACT: LY2334737 is an orally available prodrug of gemcitabine. The objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of daily administration of LY2334737 with or without erlotinib. Patients with advanced or metastatic cancer were treated with escalating doses of LY2334737 monotherapy or in combination with continuous daily administration of 100 mg erlotinib. LY2334737 was given once daily for 14 days of a 21-day cycle. The study was extended with a bioequivalence trial to investigate a novel LY2334737 drug formulation. A total of 65 patients were treated in this study. The MTD was 40 mg LY2334737. Fatigue was the most frequent DLT for LY2334737 monotherapy (4 patients) followed by elevated transaminase levels (2 patients), both observed at the 40- to 50-mg dose levels. Among the 10 patients in the combination arm, 2 had DLTs at the 40-mg dose level. These were fatigue and elevated liver enzyme levels. The most common adverse events were fatigue (n = 38), nausea (n = 27), vomiting (n = 24), diarrhea (n = 23), anorexia (n = 20), pyrexia (n = 18), and elevated transaminase levels (n = 14). The pharmacokinetics showed dose proportional increase in LY2334737 and gemcitabine exposure. The metabolite 2',2'-difluorodeoxyuridine accumulated with an accumulation index of 4.3 (coefficient of variation: 20%). In one patient, complete response in prostate-specific antigen was observed for 4 cycles, and stable disease was achieved in 22 patients overall. Pharmacokinetic analysis showed that the 2 investigated LY2334737 drug formulations were bioequivalent. LY2334737 displays linear pharmacokinetics and the MTD is 40 mg with or without daily administration of 100 mg erlotinib. Signs of antitumor activity warrant further development.
    Clinical Cancer Research 07/2011; 17(18):6071-82. DOI:10.1158/1078-0432.CCR-11-0353 · 8.72 Impact Factor
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    ABSTRACT: Blocking both receptor and ligand of the vascular endothelial growth factor (receptor) VEGF(R) pathway might be feasible and increase antitumor activity. This phase I study investigated telatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, combined with bevacizumab, in adults with solid tumors. Twenty-six patients were treated in successive cohorts with telatinib (twice-daily continuously, 450-900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed. Most frequent adverse events were pain, nausea, voice changes and fatigue. Five dose-limiting toxicities (DLTs) occurred: hypertension (cohort I and II), bowel perforation, lipase increase and atrial flutter (cohort III). Cumulative toxicity resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. Twelve patients had stable disease (clinical benefit 46%). EPC and SDF-1α levels increased during monotherapy telatinib. Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.
    Annals of Oncology 03/2011; 22(11):2508-15. DOI:10.1093/annonc/mdq767 · 7.04 Impact Factor
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    ABSTRACT: Anti-VEGF (vascular endothelial growth factor) therapy with the monoclonal antibody bevacizumab can cause gastrointestinal (GI) perforations. In recent years it became apparent that GI perforations also occur during treatment with antiangiogenic tyrosine kinase inhibitors (TKIs). It is of clinical importance to consider (vague) abdominal complaints during antiangiogenic treatment as a sign of a GI perforation. To illustrate this serious complication, we report four cases of antiangiogenic treatment related GI perforations. In three cases this was due to antiangiogenic TKI treatment. Reported risk factors of GI perforations due to bevacizumab include the presence of a primary tumor in situ and recent history of endoscopy or abdominal radiotherapy. Pathology assessments of surgical removal of the perforated intestinal part reveal that perforations are predominantly seen at the tumor or anastomotic site, in case of carcinomatosis or diverticulitis or when GI obstruction or an intra-abdominal abscess is present. Whether the same risk factors may be involved in antiangiogenic TKI related GI perforations is unknown. The underlying mechanisms responsible for GI perforation during antiangiogenic treatment is unknown, but disturbance of host cell homeostasis of immune cells as well as platelet-endothelial cell interactions may play an important role. In conclusion, while clinical awareness that antiangiogenic treatment can cause GI perforations is critical for current medical practice, it is also very important to get more insight in its underlying mechanisms so that this life-threatening complication may be prevented in the near future.
    Angiogenesis 12/2010; 14(2):135-41. DOI:10.1007/s10456-010-9197-6 · 4.88 Impact Factor

Publication Stats

700 Citations
318.12 Total Impact Points


  • 1995-2015
    • University Medical Center Utrecht
      • • Julius Center for Health Sciences and Primary Care
      • • Division Internal Medicine and Dermatology
      Utrecht, Utrecht, Netherlands
  • 2010
    • St. Antonius Ziekenhuis
      Nieuwegen, Utrecht, Netherlands