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J H Schellens

Publications and source records attributed to J H Schellens.

At least 109 records · Page 6Linked to original sources
PubMed1997

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.

PURPOSE: This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS: Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS: Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION: The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.

Adult↗
PubMed1997

Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. RESULTS: Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function. CONCLUSION: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Administration, Oral↗
PubMed1997

Optimal sampling strategies for bayesian estimation of docetaxel (Taxotere) clearance.

Docetaxel activity has been documented in many solid tumors, including metastatic breast cancer and non-small cell lung cancer. However, as clinical studies in other tumor types are now being conducted, the validation of an optimal sampling strategy would allow the performance of pharmacokinetics/pharmacodynamics studies with minimum inconvenience for the patient. Six optimal sampling strategies with one to six sampling times were computed, based on the D-optimality theory, using population pharmacokinetic parameters estimated from a large pharmacokinetic database of 547 patients treated in previous Phase II studies. Validation of these sampling strategies was performed on a set of 35 patients, from two Phase I studies, who received docetaxel as a 1-h infusion at doses ranging from 50 to 100 mg/m2. Validation consisted of comparing clearance assessed by maximum likelihood estimation obtained using complete plasma concentration-time data (considered as the reference) and clearance determined by Bayesian estimation with an optimal design. For all of the optimal sampling strategies tested, clearance was found to be well estimated when at least two samples were taken. Bayesian estimation with two measured levels (at the end of infusion and at 6 h after the start of infusion) can be selected, because it allows adequate estimation of clearance with a nonsignificant bias of +1.37% and a precision of 12.3%.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Sensitive high-performance liquid chromatographic fluorescence assay for the quantitation of topotecan (SKF 104864-A) and its lactone ring-opened product (hydroxy acid) in human plasma and urine.

A sensitive reversed-phase high-performance liquid chromatographic fluorescence method is described for the simultaneous determination of topotecan (I) and the hydrolysed lactone ring-opened product hydroxy acid (II) in plasma and for the determination of I in urine. To 250 microliters of plasma, a 750-microliters volume of cold methanol was added to stabilize the pH-dependent conversion of I into II. In plasma, the lower limit of quantitation (LLQ) for both compounds was 0.10 ng/ml. The between-day variation for I at the LLQ was 7.1% and for II was 5.5%. Prior to injection, urine samples were acidified with orthophosphoric acid and diluted with phosphate-buffered saline (PBS). In urine, the calibration curve for I was linear in the range of 10 to 250 ng/ml and the LLQ was 10 ng/ml. The assay was developed to enable pharmacological analysis of I, in on-going phase I and II studies, in patients with solid tumors.

Camptothecin↗
PubMed1996

Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model.

The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (+/- 19 SD) ng/ml in plasma and 925 (+/- 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (+/- 6 SD) ng/ml and 289 (+/- 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.

Adenocarcinoma↗
PubMed1996

Docetaxel and paclitaxel inhibit DNA-adduct formation and intracellular accumulation of cisplatin in human leukocytes.

The purpose of this study was to determine the mechanism of the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin. Cisplatin-induced DNA-adducts and cisplatin accumulation were quantitated in peripheral blood leukocytes (WBC). The WBC were obtained from patients treated with docetaxel or paclitaxel in phase I/II studies and were incubated in vitro with cisplatin. In addition, blank whole-blood samples were obtained from patients and healthy subjects and incubated in intro with cisplatin or docetaxel/paclitaxel and cisplatin. The cisplatin-induced DNA-adduct levels measured in WBC after treatment with docetaxel or paclitaxel were significantly lower than those determined in non-pretreated WBC. Docetaxel and paclitaxel reduced the intracellular accumulation of cisplatin in WBC by 46-47%. If the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin also occurs in other normal tissues such as bone marrow, it may well contribute to the sequence dependent toxicity that has been observed in clinical studies.

Antineoplastic Agents↗
PubMed1996

Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.

Aged↗
PubMed1996

Comparison of ethanol plasma-protein precipitation with plasma ultrafiltration and trichloroacetic acid protein precipitation for the measurement of unbound platinum concentrations.

Sample preparation for the measurement of non-protein-bound platinum was evaluated by precipitation of plasma proteins with cold ethanol. The method was compared with the routinely used plasma ultrafiltration and with trichloroacetic acid (TCA) protein precipitation. After incubation of human plasma samples with cisplatin or carboplatin, unbound platinum concentrations were determined applying Amicon Diaflo ultrafiltration membranes and Millipore ultrafree-MC filters. For protein precipitation, 1 ml of cold (-20 degrees C) pure ethanol was added to 0.5 ml of human plasma and the supernatant was collected after 2 h, or 0.5 ml of cold 20% TCA was added to 0.5 ml of plasma. Platinum was analyzed by atomic absorption spectrophotometry (AAS). There was no significant difference between the ethanol and ultrafiltration methods in the unbound platinum concentration. The protein content in the supernatant (1.00 +/- 0.20%) was slightly higher than that in the Amicon (0.58 +/- 0.05%) and Millipore (0.55 +/- 0.04%) ultrafiltrates. On average, the TCA and ethanol method seemed to be equally appropriate. The ethanol precipitation method is concluded to be simple, convenient, and reproducible and has negligible costs.

Blood Proteins↗
PubMed1996

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic malignant melanoma.

The results of cytostatic therapy in metastatic melanoma are very disappointing. In phase II studies with high-dose cisplatin regimens, a remarkably high response rate was observed. In a phase I study with a short course of weekly cisplatin, combined with oral etoposide, we were able to reach, in most patients, a cisplatin dose intensity of 60 mg/m2/week. We performed a phase II study with this schedule in metastatic malignant melanoma. 15 consecutive patients were entered in the study. Treatment consisted of cisplatin 70 mg/m2 on days 1, 8, 15 and days 29, 36, 43 combined with oral etoposide 50 mg daily, days 1-15 and days 29-43. Patients with a response or stable disease continued treatment with oral etoposide 50 mg/m2 daily, days 1-21 every 4 weeks. All patients were evaluable for response and toxicity. The majority of the patients received six cycles of cisplatin with the planned cisplatin dose intensity of 60 mg/m2/week. A partial response was observed in 2 patients (13%; 95% confidence interval (CI) 2-44%) of, respectively, 22 and 12 weeks; stable disease was observed in 6 patients. Toxicity consisted mainly of alopecia and bone marrow suppression. 4 patients had tinnitus, one patient had neurotoxicity grade 1. The regimen studied has only limited activity in metastatic melanoma in spite of the high-dose intensity of cisplatin reached with this schedule.

Administration, Oral↗
PubMed1996

Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x 5 intravenous administration.

Topoisomerase I inhibitors are interesting anti-cancer agents with a novel mechanism of action. We performed a phase I study with intravenous GI147211, a new semisynthetic camptothecin analogue, using a daily x 5 schedule administered every 3 weeks, to evaluate the side-effects and pharmacokinetics of the agent. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard froms of therapy were eligible for the study. GI147211 was given as a 30 min intravenous infusion daily for 5 consecutive days, repeated every 3 weeks. In subsequent patient cohorts the dose was escalated from 0.3 to 1.5 mg m-2 day-1. Pharmacokinetics analysis was performed on days 1 and 4 of the first course using a validated high-performance liquid chromatographic assay and non-compartmental methods. A total of 19 patients were entered into the study, one patient was not evaluable for toxicity because only one drug administration was given. Eighteen patients received a total of 67 courses through four dose levels. The dose-limiting toxicities were neutropenia and thrombocytopenia at the dose of 1.5 mg m-2 day-1. Nadirs occurred on day 15 and day 15 respectively. Other toxicities were mild and infrequent and included nausea/vomiting, headache and alopecia. The maximal tolerated dose was 1.2 mg m-2 day-1. One partial response was observed in a patient with colorectal cancer. The total plasma clearance was 999+/-184 ml min-1 (range 640-1329). The volume of distribution was 190+/-461 m-2 and the terminal half-life was 3.7+/-1.2 h. The AUC increased linearly with the administered dose. A steep and significant sigmoid relationship was established between the AUC and the percent decrease of ANC. GI147211 is a new topoisomerase I inhibitor that induced dose-limiting neutropenia and thrombocytopenia in this phase I study. The recommended dose for phase II studies with this schedule is 1.2 mg m-2 x 5 every 3 weeks.

Adult↗
PubMed1996

Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor.

The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan (SKF 104864-A) when administered as a chronic treatment. We determined the apparent bioavailability and pharmacokinetics of topotecan administered orally to 12 patients with solid tumours in a two-part crossover study. The oral dose of 1.5 mg m-2 was administered as a drinking solution of 200 ml on day 1. The i.v. dose of 1.5 mg m-2 was administered as a 30 min continuous infusion on day 2. The bioavailability was calculated as the ratio of the oral to i.v. area under the curve (AUC) calculated up to the last measured time point. The oral drinking solution was well tolerated. The bioavailability revealed moderate inter-patient variation and was 30% +/- 7.7% (range 21-45%). The time to maximum plasma concentration after oral administration (Tmax) was 0.78 h (median; range 0.33-2.5). Total i.v. plasma clearance of topotecan was 824 +/- 154 ml min-1 (range 535-1068 ml min(-1)). The AUC ratio of topotecan and the lactone ring-opened hydrolysis product (hydroxy acid) was of the same order after oral (0.34-1.13) and i.v. (0.47-0.98) administration. The bioavailability of topotecan after oral administration illustrates significant systemic exposure to the drug which may enable chronic oral treatment.

Administration, Oral↗
PubMed1996

Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours.

The study was designed to investigate possible relationships between tumour response and exposure to cisplatin (area under the curve of unbound cisplatin in plasma, AUC) and DNA-adduct formation in leucocytes (WBC) in patients with solid tumours. Patients were treated with six weekly courses of cisplatin at a dose of 70 or 80 mg m-2. The AUC was determined during the first course and DNA-adduct levels in WBC during all courses at baseline, 1 h (A(max)) and 15 h after a 3 h infusion of cisplatin. The area under the DNA-adduct-time curve (AUA) was calculated. The tumour response was determined after six courses. Forty-five evaluable patients received 237 courses of cisplatin. Sixteen patients with head and neck cancer received a dose of 80 mg m-2 and 29 with various other tumour types received 70 mg m-2 plus daily 50 mg oral etoposide. There were 20 responders (partial and complete) and 25 non-responders (stable and progressive disease). The AUC was highly variable (mean +/- s.d. = 2.48 +/- 0.51 micrograms h-1 ml-1; range 1.10-3.82) and was closely correlated with the AUA (r = 0.78, P < 0.0001) and A(max) (r = 0.73, P < 0.0001). The AUC, AUA and A(max) were significantly higher in responders than in non-responders in the total population (P < 0.0001) and in the two subgroups treated at 70 or 80 mg m-2. In logistic regression analysis AUC, AUA and A(max) were important predictors of response. The magnitude of exposure to cisplatin is, through DNA-adduct formation, the major determinant of the response rate in this population. Hence, individualised dosing of cisplatin using AUC or DNA-adducts should lead to increased response rates.

Adult↗
PubMed1996

Pharmacokinetic profile and clinical efficacy of a once-daily ondansetron suppository in cyclophosphamide-induced emesis: a double blind comparative study with ondansetron tablets.

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available oral formulation.

Administration, Oral↗
PubMed1996

Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Preclinical data have indicated that topoisomerase I inhibitors demonstrate more efficacy and have a greater therapeutic index with prolonged continuous exposure. The feasibility of this concept in humans using a 21-day continuous infusion of topotecan has been reported. We conducted a phase II study of this 21-day continuous topotecan administration schedule in patients with locally advanced, unresectable or metastatic colorectal cancer. PATIENTS AND METHODS: Topotecan, initially applied at a dose of 0.6 mg/m2/d, was administered as a continuous infusion via an ambulatory pump for 21 days repeated every 4 weeks. The starting dose was reduced to 0.5 mg/m2/d, because in five of the first 11 patients, the second course had to be delayed due to prolonged myelosuppression. Forty-two patients entered the study; one patient was ineligible and was excluded from further analyses. RESULTS: The overall response rate was 10%, with one complete and three partial responses. The median response duration was 7 months (range, 4 to 11). With this schedule, the major toxicity was prolonged cumulative myelosuppression, including a marked inhibition of erythropoiesis. A total transfusion of 250 U of erythrocytes was needed to maintain a hemoglobin level greater than 6.0 mmol/L. Other side effects were mild, and included alopecia (47%), periodic nausea (40%)/vomiting (22%), and fatigue (16%). Pharmacokinetic evaluation showed a mean steady-state plasma concentration (Css) of topotecan of 0.62 ng/mL (range, 0.33 to 1.1), with a significant relationship between the Css of topotecan and common cytotoxicity criteria (CTC) grade of leukocytopenia. CONCLUSION: Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.

Adult↗
PubMed1996

Emerging drug treatments for solid tumours.

A number of novel anticancer agents have emerged during the past few decades, which show high activity in preclinical tumour models and promising activity in early trials in patients with solid tumours. Most of the agents have novel and unique mechanisms of action, and show activity against a variety of malignancies, including tumours which are notoriously resistant to systemic treatment. Recently, our understanding of the molecular basis of cancer has increased considerably. This is reflected in the development of agents that are directed at well defined molecular targets, such as the mitotic tubulin/microtubuli system (taxoids), nuclear enzymes (topoisomerase I inhibitors) and cell signal transduction pathways (protein kinase C inhibitors). In addition, significant advances have been made in our understanding of mechanisms of toxicity, especially of cisplatin. This has resulted in the development of agents modulating cisplatin toxicity, among which amifostine (WR-2721) is one of the most promising. The outlined emerging drug therapies with novel anticancer agents and treatment modalities will, it is hoped, result in increased response rates of advanced tumours, longer disease-free and total survival and better palliative care.

Amifostine↗
PubMed1996

Bleomycin.

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Antimetabolites, Antineoplastic↗
PubMed1995

Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(alpha) and t1/2(beta) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6-99.5) min and t1/2 (elimination of 123.2 (range 32-265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m-2 day-1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models.

Adult↗