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J Verweij

Publications and source records attributed to J Verweij.

At least 289 records · Page 16Linked to original sources
PubMed1994

Phase II study of liposomal muramyl tripeptide phosphatidylethanolamine (MTP/PE) in advanced soft tissue sarcomas of the adult. An EORTC Soft Tissue and Bone Sarcoma Group study.

The EORTC Soft Tissue and Bone Sarcoma Group conducted a phase II study with intravenous muramyl tripeptide phosphatidylethanolamine (MTP/PE) at a dose of 4 mg once weekly in 20 patients with metastatic soft tissue sarcomas. Responses were not seen in 19 evaluable patients. Toxicity consisted mainly of a mild flu-like syndrome after 62% of drug administrations. It is concluded that MTP/PE at this dose and schedule has no activity in metastatic soft tissue sarcoma.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1994

Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group.

The antitumour activity of docetaxel was investigated in patients with advanced malignant melanoma. Docetaxel, 100 mg/m2, intravenous, over 60 min, was administered every 3 weeks. Response evaluation was performed after two cycles. No prophylactic treatment with steroids or antihistamines was given. 38 patients were included, 36 were eligible and evaluable for toxicity and 30 patients were evaluable for response. The main haematological toxicity was neutropenia [17 patients with common toxicity criteria (CTC) grade 4 and 11 CTC grade 3] with nadir after 5-8 days and rapid recovery. The most frequent non-haematological toxicity was generalised alopecia (83% of the patients). Asthenia, malaise and fatigue were also seen in 58%. Skin toxicity was also frequent. Hypersensitivity reactions (erythematous rash, urticaria, blood pressure changes and tachycardia), seen in 42% of the patients, were mild to moderate. Oedema was registered in one fifth of the patients and developed after four or more treatment cycles. The overall response rate in the evaluable patients was 17% (five partial responders). We conclude that docetaxel has activity in advanced malignant melanoma.

Adult↗
PubMed1994

Paclitaxel (Taxol) induces cumulative mild neurotoxicity.

Paclitaxel (Taxol), a new antineoplastic drug, has been reported to be neurotoxic at doses above 200 mg/m2 per course. It is uncertain whether neurotoxicity is related to cumulative amounts of paclitaxel. Neuropathy was prospectively assessed in 18 patients with breast cancer, receiving between two and eight courses of 135 or 175 mg/m2 of paclitaxel. Vibratory perception thresholds (VPT) and tendon reflex scores were proportionally related to the corresponding cumulative amounts of paclitaxel (P = 0.002; P = 0.0003). The amounts of paclitaxel administered between the first and last assessments (175-1225 mg/m2) were related to concomitant changes in VPT (P = 0.034). Paclitaxel had no clear neurotoxic threshold; if present, it lies below 540 mg/m2. Rather, VPT appeared to increase 0.1 micron per 400 mg/m2 over the entire range of 175-1225 mg/m2 of paclitaxel. Clinical neuropathy prevailed in 0/8 patients at screening and in 5/10 patients at the final assessment (P = 0.029). Neuropathy never exceeded grade 1. Thus, although neurotoxicity of paclitaxel is frequent and cumulative, it remains mild or subclinical up to at least 1400 mg/m2 administered over eight cycles.

Adult↗
PubMed1994

Pharmacokinetic-dynamic relationship of cisplatin in vitro: simulation of an i.v. bolus and 3 h and 20 h infusion.

The profiles of an i.v. bolus and 3 h and 20 h infusion of cisplatin (CDDP) were simulated in vitro by using a culture of the IGROV1 human ovarian cancer cell line. Disappearance of pharmacologically active unbound CDDP was accomplished by adding human albumin to the medium. Total and unbound CDDP and CDDP-DNA adduct levels were quantitated by atomic absorption spectroscopy (AAS), and tumour cell survival was measured by the clonogenic assay. The design of the experiment resulted in non-significant differences in the magnitude of the area under the concentration-time curve (AUC) of unbound CDDP between the three dose-input functions (AUC i.v. bolus, 6.34 +/- 0.36; 3 h infusion, 6.35 +/- 0.59; and 20 h infusion, 6.76 +/- 0.40 micrograms h ml-1). Also, the differences between the area under the CDDP-DNA adduct-time curves (AUA) of the three dose-input functions were not significant. The initial rate of decline of the CDDP-DNA adduct-time curve was significantly higher for the i.v. bolus and 3 h infusion than for the 20 h infusion. There was a log-linear relationship between the AUC of unbound CDDP and cell survival. These relationships were not significantly different between the three dose-input functions. Variation in the rate of input of CDDP leads to differences in the shape of the AUC and AUA without significant effects on cell survival.

Adenocarcinoma↗
PubMed1994

Docetaxel (Taxotere) in advanced gastric cancer: results of a phase II clinical trial. EORTC Early Clinical Trials Group.

Thirty-seven eligible patients, median age 59 years (range 37-72) and median performance status 1 (0-2), with advanced, untreated, measurable gastric carcinoma were given docetaxel, 100 mg m-2 i.v. over 60 min without premedication, once every 3 weeks. Metastatic sites included the liver in 12 patients and retroperitoneal lymph nodes in 16. Eight of the 33 evaluable patients (24%) achieved a partial remission for a median of 7.5 months (3-11+). An additional 11 patients had stabilisation of disease. The patients received a median of four cycles of docetaxel (range 1-8) for a total of 156 courses. Dose reduction was necessary in 30 cycles; 14 cycles were delayed a mean of 3 days. Haematological toxicity consisted mainly of non-cumulative neutropenia, with a median nadir count of 0.35 x 10(9) l-1 (0.04-1.64) and eight episodes (5%) of leucopenic fever; non-haematological toxicities included alopecia, mild nausea and vomiting and allergic manifestations such as skin rash and pruritus. There were no drug-related deaths. Our data indicate that docetaxel is an active agent in advanced gastric cancer; further clinical investigations seem warranted.

Adult↗
PubMed1994

Limited sampling models for topotecan pharmacokinetics.

BACKGROUND: Limited sampling models for the estimation of the topotecan Area Under the concentration versus time Curve (AUC) and its lactone ring opened form (AUC Tm), from one or more plasma concentration determinations, are desired for further population-kinetic studies. PATIENTS AND METHODS: The models were developed and validated using 34 pharmacokinetic curves in 19 patients who participated in a phase I study. RESULTS: A single point model was selected as optimal: AUC (mumol/L.min) = 499 (min).C2h (mumol/L) +0.85 (m2/mg.mumol/L.min).dose(mg/m2), and for topotecan-metabolite (Tm), AUC Tm (mumol/L.min) = 55.1 (min).CTm2h (mumol/L) -0.011 (m2/mg.mg.mumol/L.min).dose (mg/m2), where C2h is the plasma concentration (mumol/L) of topotecan at 2 h after the end of a 30-min infusion, and CTm2h the concentration of the opened form at the same time point. The models are valid for dosages ranging from 0.5 to 1.5 mg/m2/day and proved to be unbiased (MPE% = -1.8% and -9.3%, respectively) and precise (RMSE% = 17.9% and 22.7%, respectively). From the predicted AUCs, the clearance (Cl = dose (mumol)/AUC(mumol/L.min)) could also reliably be predicted, as well as the total AUC (AUC+AUC Tm) RMSE% = 17.1% and MPE% = -0.02%). Half-life values could not be predicted with acceptable precision and accuracy. CONCLUSION: The limited sampling models presented may useful for future studies focused on pharmacokinetic/pharmacodynamic relationships of topotecan in large populations.

Adolescent↗
PubMed1994

Weekly high-dose cisplatin in malignant pleural mesothelioma.

BACKGROUND: Cisplatin at conventional doses has marginal activity in mesothelioma. A dose-response relation for cisplatin has been suggested in other tumor types. In a phase I study on weekly cisplatin administration, 3 of 5 patients with mesothelioma responded. Therefore, a phase II study with weekly cisplatin was started with the recommended dose of 80 mg/m2/week for six weeks. PATIENTS AND METHODS: Fourteen patients with mesothelioma stage II, with measurable lesions, were treated with cisplatin at a dose of 80 mg/m2 weekly for six weeks. Cisplatin was administered in 3% NaCl and combined with ondansetron as antiemetic. RESULTS: Five patients had partial responses (response rate 36%; 95% confidence interval 12%-65%) lasting 2-8 months. Seven patients had stable disease. Ototoxicity, grade 2 in 3 patients and grade 3 in 2, was the most troublesome side effect. CONCLUSIONS: Cisplatin given at a higher dose intensity than in conventional schedules is active in mesothelioma. The response duration is short, however, possibly due to lack of effective maintenance therapy.

Adult↗
PubMed1994

Phase II studies of Elsamitrucin in breast cancer, colorectal cancer, non-small cell lung cancer and ovarian cancer. EORTC Early Clinical Trials Group.

PURPOSE: To test the antitumor activity of Elsamitrucin in metastatic cancer of the breast, colon and rectum, non-small cell lung and ovary. PATIENTS AND METHODS: Eligibility required histologically proven cancer. Patients with colorectal or non-small cell lung cancer could not have received prior chemotherapy. Patients were entered if WHO PS was < or = 2 and organ functions were normal. Treatment consisted of Elsamitrucin 25 mg/m2/week given as a 5-10 min infusion for at least 3-6 weekly doses. RESULTS: One hundred and five patients entered the studies, 97 were eligible, 94 are evaluable for toxicity and 75 for response. Toxicity mainly consisted of mild nausea/vomiting, and less frequently reversible hepatotoxicity and malaise. No objective responses were seen. CONCLUSION: Elsamitrucin at this dose and schedule is not an active drug in metastatic breast cancer, colorectal cancer, non-small cell lung cancer or ovarian cancer.

Adolescent↗
PubMed1994

Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind.

Paclitaxel and docetaxel are the two presently clinically available representatives of the new class of taxane drugs. They share major parts of their structures and mechanisms of action, but differ in several other aspects. For instance, there is a difference in their tubulin polymer generation, and docetaxel appears twice as active in depolymerization inhibition. In vitro docetaxel also tends to be more potent in different cell lines and investigational models. While in vitro and in vivo studies suggest that prolonged exposure to paclitaxel is better than a brief exposure, no such tendency is seen for docetaxel, indicating it to be a schedule-independent drug. Clinical studies have not confirmed an advantage for prolonged exposure to paclitaxel; but do show differences in the toxicity profiles of the two drugs. These topics will be addressed in detail.

Animals↗
PubMed1994

Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group.

BACKGROUND: The EORTC Head and Neck Cancer Cooperative Group conducted a randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in chemotherapy naive patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The primary objectives of this study were to investigate whether the CF regimen was in anyway superior to the CABO regimen and to detect any superiority of these two combinations over cisplatin alone. PATIENTS AND METHODS: Three hundred eighty-two patients were randomized to one of three treatments: (1) methotrexate (40 mg/m2) days 1 and 15, bleomycin (10 mg) and vincristine (2 mg) days 1, 8 and 15, cisplatin (50 mg/m2) day 4, repeated every 21 days, (2) cisplatin (100 mg/m2) and 5-FU (1 g/m2 x 4), repeated every 21 days, and (3) cisplatin (50 mg/m2) days 1 and 8, repeated every 28 days. After 3 cycles, all responding and stable disease patients in the three arms of the study continued with cisplatin alone. RESULTS: The overall response rates to CABO (34%) and CF (31%) were superior to C (15%) (p < 0.001, p = 0.003, respectively). In addition, complete response rate to CABO (9.5%) was superior to that of C (2.5%) (p = 0.02), and also superior to that of CF (1.7%) (p = 0.01). Response was associated with performance status and prior treatment, but by multivariate analysis treatment type was the important determinant of response (p = 0.0006). Although CABO and CF were superior to C with respect to time to progression within the first 6 to 8 months after randomization, there was no overall difference in progression-free survival or survival between the three arms of the study. Both hematologic and non-hematologic toxicity were worse in the combination chemotherapy arms. CONCLUSION: We conclude that the CF regimen has no advantage over the CABO regimen, which in fact showed a higher complete response rate. Both combinations showed improved response rates but also more toxicity and no improvement in overall survival in comparison with cisplatin alone.

Adult↗
PubMed1994

Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group.

BACKGROUND: Docetaxel (Taxotere) is a new cytotoxic agent acting as a promoter of tubulin polymerisation with broad spectrum antitumor activity in preclinical testing. Phase I clinical trials have shown promising activity of docetaxel in patients with breast, ovarian and lung carcinomas. The objective of this open multicentre phase II study was to determine the efficacy and tolerability of this agent in patients with head and neck cancer. PATIENTS AND METHODS: Patients with proven advanced and/or recurrent squamous cell carcinoma of the head and neck without prior chemotherapy for advanced disease were eligible for this trial. Docetaxel was given at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks. Dose reductions were performed according to hematological and non-hematological toxicities. No pre-medication was given to prevent hypersensitivity reactions. RESULTS: Fourty-three patients entered this trial: 39 patients were evaluable for toxicity and 37 patients were evaluable for response. Sixty-five percent of the patients had locoregional disease, 28% had metastatic disease, and 7% had both. Twenty-five percent of the patients had previously received neo-adjuvant cisplatin-based chemotherapy. A total of 166 docetaxel courses were administered. The most frequent side-effects associated with docetaxel were alopecia (90% of the patients), asthenia (69% of the patients) and short lasting neutropenia (grade 3-4 neutropenia in 61% of the courses). Fifty-four percent of the patients experienced skin toxicity, 23% experienced hypersensitivity reaction, and 31% developed peripheral edema. Ten partial and 2 complete responses were observed, yielding a response rate of 32% (95% confidence interval 17%-47%). CONCLUSION: Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck.

Adult↗
PubMed1994

Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcomas of the adult. EORTC Soft Tissue and Bone Sarcoma Group.

BACKGROUND: Current regimens for treatment of distant metastases of soft tissues sarcomas result in response rates of about 25%. Therefore the search for active drugs remains a task for investigational groups. Taxoids offer a new class of cytostatic drugs. Docetaxel has been studied as a second line chemotherapy in advanced soft tissue sarcomas of the adult. PATIENTS AND METHODS: In a multi-center non-randomized phase II study docetaxel was administered at a dose of 100 mg/m2 in a 1-hour i.v. infusion q 3 weeks. RESULTS: Twenty-nine patients (pts), median age 52 yr, performance status WHO 0: 16 pts, WHO 1: 11 pts, WHO 2: 2 pts, were eligible. One patient had early death due to malignant disease, 1 patient died due to toxicity and progression, 1 pt refused after 1 course. Five partial responses (5/29 = 17%, C.I. 6%-36%) have been observed. Grade > or = 3 leucopenia occurred in 76% of patients and grade > or = 3 thrombopenia did not occur. Median nadir of neutrophils was 0.23 x 10(9)/l. Episodes of fever and documented infection have been observed in 10 and 5 pts respectively. Anaphylactoid type reactions occurred in 5 patients: ranging from flushing in 5 pts to cardiovascular symptoms in 1 pt. Sensory neurotoxicity was observed in 14 pts grade 1: 10 pts, grade 2: 3 pts, grade 3: 1 pt). Grade 1 motor neurotoxicity was experienced by 3 pts. Skin reactions (pruritus, erythema, urticaria, exfoliation grade 1: 11 pts, grade 2: 7 pts, grade 3: 1 pt, grade 4: 1 pt) in 20 pts, among them 9 patients with nail changes. Peripheral edema and fluid retention has been observed in 12 pts. CONCLUSION: Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy.

Adult↗
PubMed1994

A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group.

BACKGROUND: Gemcitabine is a new pyrimidine antimetabolite with novel metabolic properties and mechanism of action. Phase I clinical trials have demonstrated acceptable toxicity and promising antitumor activity. The objectives of this open multicenter phase II trial were to determine the efficacy and toxicity of this agent in patients with advanced head and neck cancer. PATIENTS AND METHODS: Sixty-one patients with advanced and/or recurrent squamous cell carcinoma of the head and neck were treated with Gemcitabine as a weekly 30 minutes i.v. administration for 3 consecutive weeks followed by one week rest. The Gemcitabine starting dose was 800 mg/m2/week in 47 patients (a majority being pre-treated with chemotherapy) and was later increased to 1250 mg/m2 in 14 chemotherapy-naive patients. Dose adjustments were based on hematologic and non-hematologic toxicities. RESULTS: Seven partial responses were observed among 54 evaluable patients, yielding a response rate of 13% (95% confidence interval: 4%-22%). The incidence of hematologic toxicity was low, with grade 3-4 neutropenia in less than 10% of the courses. Fifty-three percent of the patients experienced an increased in liver enzymes, mainly grade 1 or 2. Fatigue was reported by 39% of the patients, frequently associated with flu-like symptoms. CONCLUSION: Gemcitabine is a drug with documented anti-tumor activity in patients with advanced squamous cell carcinoma of the head and neck.

Adult↗
PubMed1994

Phase II study of prolonged oral etoposide in patients with ovarian cancer refractory to or relapsing within 12 months after platinum-containing chemotherapy.

PATIENTS AND METHODS: Twenty-eight patients with ovarian cancer refractory to or relapsing within 12 months after cisplatin-containing chemotherapy were treated with etoposide 50 mg/m2 daily for 21 days, followed by a 7-day break. RESULTS: Of 25 evaluable patients, 4 achieved partial responses (16%, 95% confidence interval 5%-36%) of 4, 4, 7, and 10 months' duration. The platinum treatment-free intervals for these patients were 2, 9, 7, and 10 months, respectively. Etoposide in this schedule was generally well tolerated, with myelosuppression as the major toxicity, resulting in a median dose intensity over all cycles of 83% (range 47%-100%). CONCLUSIONS: Prolonged oral etoposide is moderately active both in relapsed and platinum-refractory ovarian cancer, and a schedule of 50 mg/m2 days 1-21, every 4 weeks is fairly well tolerated in this usually heavily pretreated and elderly patient population.

Administration, Oral↗
PubMed1994

Clinical studies with EO9, a new indoloquinone bioreductive alkylating cytotoxic agent. EORTC Early Clinical Trials Group.

EO9 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)-prop-be ta- en-alpha-ol] is a new bioreductive alkylating indoloquinone with a distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, and lack of bone marrow toxicity in preclinical models. Clinical phase I studies were performed to determine the toxicities, maximally tolerated dose, and pharmacology of EO9. The drug was administered as a 5-min IV infusion at intervals of 3 weeks or weekly to 59 patients with solid tumors. The starting dose of 2.7 mg/m2 was one-tenth of the mouse-equivalent dose lethal to 10% of mice. Doses were escalated according to a Fibonacci-like schedule. The pharmacokinetics of EO9 and its aziridine ring-opened metabolite EO5A were determined using a new high performance liquid chromatography method and noncompartmental calculation of kinetic parameters. The sigmoid maximal effects (Emax) model was used to fit pharmacokinetic parameters to toxicities. The 59 patients received in total 150 evaluable courses of EO9. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. With the 3-weekly schedule, all symptoms were reversible on day 15 except in 2 patients, who developed acute renal failure. The renal function and proteinuria were quantitated and further evaluated by determining renal clearance ratios of immunoglobulin G/albumin and pancreatic/salivary amylase. The immunogobuline G/albumin and pancreatic/salivary amylase ratios pointed to a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The maximum tolerated dose was 27 mg/m2, the recommended dose 22 mg/m2. The pharmacokinetics showed rapid elimination from the central compartment and wide interpatient variation in disposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer. A study of the EORTC Early Clinical Trials Group.

BACKGROUND: Docetaxel, a semisynthetic analog of paclitaxel, made for the needles of the European yew, Taxus baccata, is a potentially important chemotherapeutic agent for the treatment of cancer. PATIENTS AND METHODS: In a phase II study patients with advanced and/or metastatic breast cancer and bidimensionally measurable disease, were treated with docetaxel 100 mg/m2 every 3 weeks as a 1 hour infusion without any premedication. Treatment was evaluated after 2 courses and every 2 subsequent courses. RESULTS: Thirty-nine patients were entered, 32 were eligible. The eligible patients had a median age of 51 years (range 30-73) and a performance status WHO 1 median, (range 0-2). Twenty-eight patients had been treated with surgery, 24 with radiation. Hormonal treatment was previously given in 23, chemotherapy in 32. Of 24 patients treated as second line strategy, 13 achieved a partial remission, 1 a complete remission (overall response rate 58% (95% CI 37%-78%)). Eight patients treated as first line: 2 PR's, 1 CR. The median overall response duration was 38 weeks. The main toxicity consisted of transient grade 4 neutropenia in 149 of 167 evaluable courses (89%). However, the related infection rate was low. Re-treatment at 3 weeks, as scheduled, was nearly always possible. Other toxicities consisted of skin reactions (81%) and nail changes (41%), neurosensory toxicity (59%) and occasionally hypersensitivity reactions (16%). Fluid retention was a toxicity of major concern, observed in 59% of patients. CONCLUSION: Docetaxel is a very active drug against breast cancer. Further studies are required to alleviate the non-hematological toxicities.

Adult↗
PubMed1993

Sensitive isocratic high-performance liquid chromatographic determination of a novel indoloquinone cytotoxic drug (EO9) in human plasma and urine.

A reversed-phase isocratic high-performance liquid chromatographic method is described for the simultaneous determination of EO9, 3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-beta- en-alpha-ol (I), and its ring-opened aziridine analogue EO5A (II), employing ultraviolet detection. Solid-phase sample extraction was used without addition of an internal standard. Plots of peak heights and areas of I and II were linear in the range 5-10,000 ng/ml. The lower limit of detection of both I and II in plasma was 2 ng/ml. The between-day variation of I was 13.9% at 5 ng/ml and lower than 6.2% for concentrations > or = 10 ng/ml. The between-day variation of II at 5 ng/ml was 13.8% and lower than 4.5% for concentrations > or = 10 ng/ml. The assay was developed to enable pharmacological guiding of a phase I study of I in solid tumour cancer patients.

Antineoplastic Agents↗