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Biomedical subjects

J Verweij

Publications and source records attributed to J Verweij.

At least 37 records · Page 2Linked to original sources
PubMed2004

Real-time pharmacokinetics guiding clinical decisions; phase I study of a weekly schedule of liposome encapsulated paclitaxel in patients with solid tumours.

The purpose of this weekly schedule phase I study of liposome encapsulated paclitaxel (LEP) was to define the maximum-tolerated dose (MTD), the recommended dose (RD), the dose-limiting toxicities (DLTs), the pharmacokinetic profiles, and to evaluate preliminarily antitumour effects in patients with refractory solid malignancies. LEP was administered as an intravenous (i.v.) infusion over 45 min once every week for 6 out of 8 weeks. Fourteen patients were treated at doses ranging from 90 to 150 mg/m(2)/week. In one patient, DLT was observed at the dose level of 150 mg/m(2)/week, who received less than 70% of the intended cumulative dose. No cumulative toxicities were observed. Stabilisation of disease for 8 weeks was documented in two patients. The whole blood clearance of total paclitaxel was similar for LEP (15.3+/-8.98 l/h/m(2)) and Taxol (17.5+/-3.43 l/h/m(2)), and the extraliposomal to total drug ratio increased rapidly to unity at later sampling time points. The trial was discontinued upon completion of enrolment of the 150 mg/m(2)/week cohort because an assessment of the pharmacokinetics and clinical data suggested that LEP was unlikely to have any advantages over Taxol. It is concluded that this formulation of LEP is unlikely to provide improvements over the taxanes currently in clinical use.

Adult↗
PubMed2004

Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy.

Current dosing strategies for anticancer drugs result in wide interindividual pharmacokinetic variability. Here, we explored the influence of age, body size, concomitant drugs, dose, infusion duration, and sex on the clearance for doxorubicin and docetaxel in 243 individual patients. Patients received doxorubicin (n=110) or docetaxel (n=152) as monotherapy or in combination chemotherapy regimens. The mean (+/-S.D.) clearance was 63.6+/-22.7 L/h for doxorubicin and 42.8+/-14.9 L/h for docetaxel. Normalisation for body surface area (BSA) reduced the interindividual variability by only <1.7%. Doxorubicin clearance was significantly reduced when administered at doses >50 mg/m(2) or in combination with cyclophosphamide. Upper extremes of body size were associated with increased clearance for both drugs, whereas no consistent effect of age on clearance was discerned. Overall, these findings suggest that incorporation of variables in addition to BSA should be considered in routine dosing strategies for doxorubicin and docetaxel.

Adult↗
PubMed2004

A phase II study of ET-743/trabectedin ('Yondelis') for patients with advanced gastrointestinal stromal tumours.

Primary or secondary resistance to imatinib may occur in patients with gastrointestinal stromal tumours (GISTs) while these tumours have repeatedly been shown to be highly resistant to conventional doxorubicin- and ifosfamide-containing regimens. The investigation of new drugs is therefore warranted in GIST. A phase II study was conducted between May 1999 and November 2000 in eight centres of the EORTC STBSG group to establish the efficacy and safety of ET743 ('Yondelis') in GIST previously untreated with cytotoxic chemotherapy before the imatinib era. ET-743 was given was given at 1.5 mg/m(2) per course as a 24-h continuous intravenous infusion every 3 weeks. Twenty-eight patients were included, 16 males and 12 females. Median age was 54 years (range 25-73 years). Median performance status was 0 (range 0-1). 17 (63%), 4 (12%) and 7 (25%) patients, received 0-2, 3-5, and > or = 6 courses of ET-743, respectively. The best response was stable disease in 9 (33%) patients, and disease progression in 18 patients (67%), with a median time to disease progression and overall survival of 51 days and 589 days, respectively. The treatment was well tolerated: there were grades 3-4 neutropenia, thrombocytopenia, and transaminase increases in 13 (48%), 1 (4%) and 16 (59%) patients, respectively. There were no toxic deaths. ET-743 at this dose and schedule is not an effective treatment for advanced GIST.

Adult↗
PubMed2004

Limited potential of hepatic arterial infusion of irinotecan.

Intravenously administered irinotecan has gained an important place in the struggle against metastatic and/or irresectable colorectal cancer. In patients with irresectable metastases confined to the liver, hepatic arterial infusion (HAI) of this anti-cancer agent has considered to be an option. Partly based on conducted phase I- and II-studies, here we conclude that irinotecan as single agent HAI therapy has limited potential compared to intravenous administration. From a pharmacokinetic-pharmacodynamic point of view, in particular the long half-life of the active metabolite, SN-38, its use is limited as well. In our view, future clinical implementation of irinotecan as HAI chemotherapy is unrealistic.

Antineoplastic Agents, Phytogenic↗
PubMed2003

[Several patients with a metastasised gastrointestinal stroma-cell tumor for whom the tide turned by the introduction of imatinib].

The introduction of imatinib for gastrointestinal stroma-cell tumours (GISTs) reversed the chances of 3 cancer patients who had given up hope. One 40-year-old man with multiple chemotherapy-resistant GIST responded well to imatinib treatment in a phase-I setting. Another patient, a woman aged 77 years, was initially considered too old for chemotherapy, but was later accepted for treatment in an imatinib phase-III trial due to the positive results in other patients. The last patient, a woman aged 48 years, also responded to treatment with imatinib despite a massive tumour load and a WHO performance status of 3. She was almost free of complaints within a period of just a few weeks. Until recently, the prognosis for metastatic or irresectable GIST was almost certain death within 1 year after diagnosis. The recent registration of imatinib has dramatically changed the prognosis of this disease. These case reports also demonstrate that some patients in phase-I studies can actually benefit from participation in such trials. Furthermore, treating GIST patients in a poor condition with imatinib is justified by the high response rates and mild toxicity.

Adult↗
PubMed2003

[Imatinib, a specific tyrosine-kinase inhibitor, for the treatment of patients with a gastrointestinal stroma cell tumor].

The c-kit oncogene, encoding for a transmembrane growth-factor receptor with tyrosine-kinase activity (KIT), plays an important role in the tumourigenesis of gastrointestinal stroma-cell tumours (GISTs). GISTs are a heterogeneous group of mesenchymal tumours, mainly localised in the abdomen. Immunohistochemical staining using antibodies directed towards the c-kit protein on the cell surface, is a useful tool in the often difficult differential diagnosis of GISTs from other mesenchymal tumours. The correct diagnosis of GISTs is crucial for the new treatment option with imatinib, the tyrosine-kinase inhibitor specifically targeted against KIT. The clinical development of imatinib for patients with GISTs has been extraordinarily rapid. As a result of the short period of time between the drug's experimental introduction and actual registration, many unanswered questions about its use for the treatment of GISTs remain. These can only be answered in well-designed clinical trials. It is therefore recommended that patients with these rare tumours are referred to a centre with experience in the diagnosis and treatment of these soft-tissue sarcomas.

Antineoplastic Agents↗
PubMed2003

Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients.

In the present study we describe the toxicity of weekly high-dose (70-85 mg x m(-2)) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990-2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250 ml NaCl 3% over 3 h, for six intended administrations. The mean number of administrations was 5.3 (range, 1-6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patient's request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade 1 (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen.

Adult↗
PubMed2003

Adaptive intrapatient dose escalation of cisplatin in combination with low-dose vp16 in patients with nonsmall cell lung cancer.

The objective of this phase II and pharmacologic study was to explore the feasibility, toxicity and activity of adaptive intrapatient dose escalation of cisplatin in a dose-intensive weekly schedule using predefined levels of exposure, with the ultimate aim to improve the antitumour activity of the therapy in patients with nonsmall cell lung cancer (NSCLC). Platinum DNA-adduct levels in peripheral white blood cells during treatment were used as the primary parameter for adaptive dosing. If DNA-adduct levels were not available, the area under the concentration-time curve (AUC) of unbound platinum in plasma was used for dose adaptation. Target levels for DNA-adducts and AUC have been defined in a previously performed pharmacologic study. The feasibility of adaptive dosing was tested in 76 patients with stage IIIB and IV NSCLC, who were planned to receive 6 weekly courses of cisplatin at a starting dose of 70 mg m(-2), together with daily low oral dose of 50 mg VP16. In total, 37 patients (49%) who were given more than one course received a dose increase varying from 10 to 55%. The majority of patients reached the defined target levels by a dose increase during course two. Relevant grade 2 neurotoxicity was observed in eight (10%) patients and reversible ototoxicity grade 2 in 14 (18%) patients. The strategy of adaptive intrapatient dose adjustment of cisplatin is practically feasible in a research setting even when results for dose adaptation have to be reported within a short time-period of 1 week. The toxicity appeared to be manageable in this cohort of patients. In some patients, exposure after the standard dose was substantially lower than the defined target level and significant dose escalations of more than 50% had to be applied. The response rate (RR) was relatively high: overall 40% (29 out of 72 patients) partial remission (PR), in patients with stage IIIB the RR was 60% (15 out of 25 patients) and with stage IV 30% (14 out of 47 patients). Randomised studies are needed to determine whether the adaptive dosing strategy results in better efficacy than standard dosing.

Administration, Oral↗
PubMed2003

Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy.

Adult patients with metastatic or locally advanced irresectable soft-tissue sarcoma (ASTS) are generally considered as incurable. Whether some of these patients achieve long-term survival after first-line treatment with chemotherapy is not known. Patients with ASTS still alive 5 years after initial treatment with a doxorubicin-containing regimen, i.e. long-term survivors, were analysed among the 2187 patients included in first-line chemotherapy protocols between 1976 and 1990 in seven trials of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG) group. 1888 patients were followed for at least 5 years. The initial clinical characteristics and the outcome of the long-term survivors were investigated. 66 of the 1888 patients were alive at 5 years and the projected 5-year survival was 8% in this series. Age or histological subtypes were similar in the long-term survivors compared with the other patients. The percentages of females (69%), of grade 1 tumours (35%), of patients with an initial performance status (PS) of 0 (63%) were significantly higher in the long-term survivors while liver metastasis (6% versus 21%) were significantly less frequent. Long-term survivors were observed in all subgroups of patients. 31, 31, 31 and 6% of the long-term survivors were in complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, after the first-line regimen. A CR to a doxorubicin-containing regimen was the major parameter correlated to 5-year survival. In multivariate analysis using a logistic model, independent parameters correlated to 5-year survival were PS, female gender, grade I tumours, and the achievement of a CR after first-line treatment, which was retained as the most powerful predictor for 5-year survival. 10 of the 66 patients died after 5 years in this series, including 8 patients in PD or SD after first-line treatment versus 2 patients in PR or CR (P=0.01). 8% of patients with ASTS are alive 5 years after first-line chemotherapy with a doxorubicin-containing regimen. Long-term survivors are observed in all prognostic subgroups of patients, in particular those achieving a CR to first-line chemotherapy.

Adult↗
PubMed2003

Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer.

The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (>or=70 years) with metastatic breast cancer (median age (range), 77 years (70-84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22-69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m(2) (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration-time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124+/-35.0 (elderly) versus 247+/-55.4 l/h/m(2) (<70 years) (P=0.002), and was inversely related to the patient's age (R(2)=0.857; P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150+/-60.7 (elderly) versus 115+/-39.2 ml/h/m(2) (<70 years) (P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.

Adult↗
PubMed2003

Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens.

Previous studies have shown that STI571, a selective tyrosine kinase inhibitor of c-KIT, is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumours (GIST), especially those that have activating mutations in the c-kit exon 11 that encodes the juxtamembrane (JM) domain of the c-KIT oncoprotein. We examined the prevalence of activating exon 11 c-kit mutations in 26 small-cell lung cancer (SCLC) cases in order to explore whether this disease is also a potential target for treatment with STI571. Expression of c-KIT, estimated by immunohistochemistry, was demonstrated in 14 out of 22 SCLC samples (64%); nine samples showed moderate to strong staining (41%), five samples were weakly positive (23%), whereas eight samples (36%) were negative for CD117. Next, we examined the mutational status of exon 11 of the c-kit gene, by single-stranded conformational polymorphism (SSCP) and sequencing in all of the cKIT/CD117-positive tumours. However, no activating mutations in the c-kit exon 11 were found by either technique. Apparently, c-KIT oncoprotein expression in SCLC was not correlated with activating mutations in c-kit exon 11. In analogy to GISTs, our results could imply that SCLC patients would not benefit from treatment with STI571.

Carcinoma, Small Cell↗
PubMed2003

Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours.

A single-agent dose escalating phase I and pharmacokinetic study with Cilengitide, an inhibitor of the integrins alphavbeta3 and alphavbeta5, was performed to determine its safety and toxicity. Cilengitide was administered as a one-hour infusion twice weekly without interruption to patients with histologically- or cytologically-confirmed metastatic solid tumours. Plasma pharmacokinetics were determined at days 1 and 15. 37 patients were enrolled into the study. Dose levels studied were 30, 60, 120, 180, 240, 400, 600, 850, 1200, and 1600 mg/m(2)/infusion. There was no dose-limiting toxicity (DLT). Pharmacokinetics were dose-independent and time-invariant. Apparent terminal half-life ranged from 3 to 5 h. At 120 mg/m(2)/infusion, peak plasma concentrations were attained that optimally inhibited tumour growth in preclinical models. Cilengitide can be safely administered using a continuous twice-weekly infusion regimen. As DLT was not reached, future trials should explore Cilengitide at different doses.

Adult↗
PubMed2003

Influence of the cisplatin hydration schedule on topotecan pharmacokinetics.

The study described here was designed to investigate the influence of the hydration schedule of cisplatin on the pharmacokinetics of topotecan. To test this hypothesis, 13 adult cancer patients were treated with intravenous (i.v.) cisplatin followed by i.v. topotecan for 5 days every 3 weeks using a short hydration schedule (SHS) for cisplatin in the first course and a hyper-hydration schedule (HHS) in the second course or vice versa. Topotecan pharmacokinetic analysis was performed in plasma, whole blood and red blood cells in both courses on days 1, 2 and 5. 11 patients received both courses and were pharmacokinetically evaluable. No significant differences between the two studied schedules were noted in the clearances of topotecan on day 1 in the different matrices. However, in both hydration schedules, on average, slightly lower topotecan clearances were observed on both days 2 and 5 compared with day 1 in all of the matrices, while no differences were noted between days 2 and 5. This alteration was independent of the schedule used and was less pronounced than that which has been initially reported for SHS and, overall, will not have clinical consequences.

Adult↗
PubMed2003

Cancer drug development in Europe: a selection of new agents under development at the European Drug Development Network.

From may 99, three european leaders in anti-cancer drug development (EORTC, Cancer Research UK, SENDO) have got together to form a network of collaborating groups: the European Drug Development Network. The member organisations have all agreed to join their efforts in developing new drugs. They have acquired a great and efficient expertise in anticancer drug development covering all aspects from drug screening to refinement of trial methodology and translational research. In this paper, the most interesting drugs under development in each of the three organisations are being described and discussed.

Angiogenesis Inhibitors↗
PubMed2003

Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.

The aim of this study was to assess the antitumour response and time to progression (TTP) of patients treated with imatinib mesylate (Glivec, Gleevec, formerly STI-571) who had advanced and/or metastatic gastrointestinal stroma tumours (GIST) or other soft tissue sarcomas (STS). Patients with measurable lesions and adequate organ function were entered. They were treated with imatinib mesylate at the dose of 400 mg twice daily (bid). All tumours were subject to a stringent pathological review by an expert panel. Immunohistochemical expression of KIT expression was evaluated. A total of 51 patients (27 GIST, 24 other STS), median age 53 years, median World Health Organization (WHO) performance score 1, were entered. 71% of the patients had received prior chemotherapy. The most frequent side-effects were anaemia (92%), periorbital oedema (84%), skin rash (69%), fatigue (76%), nausea (57%), granulocytopenia (47%) and diarrhoea (47%). Most of these side-effects were mild to moderate and no patient was taken off study due to side-effects. Skin rash and periorbital oedema frequently seem to be self limiting, despite continued treatment. In GIST patients, the current response rates (RRs) are 4% complete remission (CR), 67% partial remission (PR), 18% stable disease (SD) and 11% progression (PD). 73% of GIST patients are free from progression at 1 year. In the other STS group, there were no objective responses. The median time to progression in this subgroup was only 58 days. Imatinib mesylate is well tolerated at a dose of 400 mg bid. This dose is active in patients with KIT-positive GIST, but patients with other STS subtypes unselected for a molecular target are unlikely to benefit.

Adult↗
PubMed2002

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38.

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.

Adult↗
PubMed2002

Phase II study of bi-weekly administration of paclitaxel and cisplatin in patients with advanced oesophageal cancer.

In a phase I study we demonstrated the feasibility of a bi-weekly combination of paclitaxel 180 mg x m(-2) with cisplatin 60 mg x m(-2). In this study we further assessed toxicity and efficacy of this schedule in the treatment of advanced cancer of the oesophagus or the gastro-oesophageal junction. Patients received paclitaxel 180 mg x m(-2) administered over 3 h followed by a 3-h infusion of cisplatin 60 mg x m(-2). Patients were retreated every 2 weeks unless granulocytes were <0.75x10(9) or platelets <75x10(9). Patients were evaluated after three and six cycles and responding patients received a maximum of eight cycles. Fifty-one patients were enrolled into the study. The median age was 56 years (range 32-78). WHO performance status were: 0 (19 patients); 1 (29 patients); 2 (three patients). All patients received at least three cycles of chemotherapy and all were evaluable for toxicity and response. Haematological toxicity consisted of uncomplicated neutropenia grade 3 in 39% and grade 4 in 31% of patients. Five patients (10%) were hospitalised, three patients because of treatment related complications and two patients because of infections without neutropenia. Sensory neurotoxicity was the predominant non-haematological toxicity; grade 1 and 2 neurotoxicity was observed in 43 and 20% of patients, respectively. Response evaluation in 51 patients with measurable disease: complete response 4%, partial response 39%, stable disease 43% and progressive disease in 14% of the patients. The median duration of response was 8 months. The median survival for all patients was 9 (range 2-29+) months and the one-year survival rate was 43%. Four patients who received additional local treatment (two patients surgery and two patients radiotherapy) are still disease free after a follow-up of 20-29 months. This bi-weekly treatment of paclitaxel and cisplatin is well tolerated by patients with advanced oesophageal cancer. The toxicity profile of this regimen compares favourable to that of previously used cisplatin- and paclitaxel-based regimens. Trials are underway evaluating this bi-weekly regimen in a neo-adjuvant setting.

Adenocarcinoma↗