Phase I trial of 6-hour infusion of glufosfamide, a new alkylating agent with potentially enhanced selectivity for tumors that overexpress transmembrane glucose transporters: a study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group.

PURPOSE: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. PATIENTS AND METHODS: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m(2). Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. RESULTS: The MTD was 6,000 mg/m(2). At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time-versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. CONCLUSION: The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommended phase II dose is 4, 500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.

Phase I clinical and pharmacokinetic study of carzelesin (U-80244) given daily for five consecutive days.

Carzelesin (U-80244), one of the synthetic DNA minor groove binding cyclopropylpyrroloindole analogues, was selected for clinical development because of its high potency, promising antitumor activity in murine solid tumors and leukemia, and significant therapeutic efficacy against colon and rhabdomyosarcoma xenografts. In this Phase I study, carzelesin was given daily for 5 consecutive days to (a) determine the maximum tolerable dose (MTD) and the pattern of toxicity of this schedule; (b) define the pharmacokinetic profile of the parent, as was done for the intermediate compound U-76073 and the DNA-reactive agent U-76074; and (c) document any antitumor activity observed. Carzelesin was given as a 10-min infusion with a constant-rate infusion pump. Treatment was repeated every 4 weeks or when blood counts had recovered to normal values. The starting dose of 12 microgram/m2/day was escalated by 20-30% increments until the MTD (defined as the dose leading to grade 4 hematological or grade 3 nonhematological toxicity in at least two of six patients) was reached. Pharmacokinetic studies were planned on days 1 and 5 of the first cycle in at least two patients per dose level. Plasma levels of carzelesin, U-76073, and U-76074 were determined by high-performance liquid chromatography with UV detection and a detection limit of 0.5 ng/ml. Twenty-five patients were entered in the study, and 56 cycles were evaluable for hematological toxicity. Subsequent dose levels evaluated were 24, 30, 35, and 40 microgram/m2. Both neutropenia and thrombocytopenia were dose limiting and cumulative, with a high interpatient variability. Neutropenia occurred earlier (median time to neutrophil nadir and recovery, 15 and 29 days, respectively) than thrombocytopenia (median time to platelet nadir and recovery, 25 and >/=26 days, respectively); there were delays of treatment because of persisting thrombocytopenia in all patients treated at the MTD. At the MTD, the peak plasma concentrations of carzelesin were achieved at the end of the infusion and were higher than those found cytotoxic in vitro against tumor cell lines. Carzelesin was detectable up to a maximum of 1 h after the infusion. Smaller amounts of U-76073 were detectable for a maximum of 30 min only at the MTD, whereas U-76074 was never found. An 8-month partial remission was reported in one previously untreated patient with hepatocellular carcinoma at 40 microgram/m2. The MTD was fixed at 40 microgram/m2 daily; 35 and 30 microgram/m2 are the daily doses recommended for Phase II studies in good- and poor-risk patients. The daily regimen for 5 days seems to offer no advantage over the single intermittent schedule that has been selected for the Phase II program in Europe.

Phase I pharmacokinetics and limited sampling strategies for the bioreductive alkylating drug EO9. EORTC Early Clinical Trials Group.

EO9 is a synthetic indoloquinone which was designed to undergo redox cycling and formation of alkylating intermediates under bioreductive conditions. As part of a phase I clinical trial, EO9 plasma disposition was evaluated in 20 patients receiving 2.7-15 mg/m2i.v. weekly for 3 weeks. Pharmacokinetic studies were performed with the first and third dose of therapy and nine blood samples were obtained over 30 min postinfusion. Plasma EO9 was detected using HPLC UV and the disposition described by a two-compartment model. Wide variability in EO9 pharmacokinetics was observed. EO9 was rapidly eliminated from plasma with a median systemic clearance of 3.5 l/min/m2 (range 1.2-9.8), apparent volume of distribution of 6.2 l/m2 (1.0-34.9) and t 1/2 beta of 10.1 min (2.2-63.0). Substantial intrapatient variability was observed for all pharmacokinetic parameters. Linear regression and Bayesian methods were developed and validated for estimation of EO9 plasma AUC using up to three samples postinfusion. The use of two or three plasma samples provided precise estimation with acceptable prediction bias. In addition, a Bayesian algorithm offered more robust estimation of AUC and is preferable to linear regression models for future EO9 population pharmacokinetic analysis.

A clinical pharmacokinetics study of carzelesin given by short-term intravenous infusion in a phase I study.

We investigated the pharmacokinetic behavior of carzelesin in 31 patients receiving this drug by 10-min intravenous infusion in a Phase I clinical trial, which was conducted at institutions in Nijmegen (institution 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 microg/m2. Carzelesin is a cyclopropylpyrroloindole prodrug that requires metabolic activation via U-76,073 to U-76,074. The lower limit of quantitation (LLQ) of the high-performance liquid chromatography (HPLC) method used in this study was 1 ng/ml for the parent drug and its metabolic products. Carzelesin was rapidly eliminated from plasma (elimination half-life 23 +/- 9 min; mean value +/- SD). At all dose levels, U-76,073 was found as early as in the first samples taken after the start of the infusion. However, the concentration of U-76,074 exceeded the LLQ for only short periods and only at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC50 values obtained by in vitro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance observed between patients from institution 1 (7.9 +/- 2.1 l h[-1] m[-2]) and those from institution 2 (18.4 +/- 13.6 l h[-1] m[-2]; P = 0.038), probably reflecting problems with drug administration in the latter institution. The results recorded for patients in institution 1 indicated that the AUC increased proportionately with increasing doses. There was a good correlation between the maximal plasma concentration and the AUC, enabling future monitoring of drug exposure from one timed blood sample. Urinary excretion of carzelesin was below 1% of the delivered dose.

Ethical and practical considerations concerning perimortem sperm procurement in a severe neurologically damaged patient and the apparent discrepancy in validation of proxy consent in various postmortem procedures.

INTRODUCTION: Although sperm procurement and preservation has been become commonplace in situations in which infertility can be easily foreseen, peri- or postmortem sperm procurement for reproductive use in unexpected coma or death is not generally accepted. There are no laws and regulations for this kind of intervention in all countries and they may also differ from country to country. Intensive care specialists can be confronted with a request for peri- or postmortem sperm procurement, while not being aware of the country-specific provisions. CASE DESCRIPTION: A young male patient who suffered 17 L blood loss and half an hour of cardiopulmonary resuscitation was admitted to a university hospital for an ill-understood unstoppable abdominal bleed. After rapid deterioration of the neurological situation, due to severe post-anoxic damage, the decision was made to withdraw life-sustaining treatment. At that moment the partner of the patient asked for perimortem sperm procurement, which was denied, on the basis of the ethical reasoning that consent of the man involved was lacking. Retrospectively the decision was right according to Dutch regulations; however, with more time for elaborate ethical reasoning, the decision outcome, without the awareness of an existing prohibition, also could have been different. CONCLUSIONS: Guidelines and laws for peri- or postmortem sperm procurement differ from country to country, so any intensive care specialist should have knowledge from the latest legislation for this specific subject in his/her country. An overview is provided. A decision based on ethical reasoning may appear satisfying, but can unfortunately be in full contrast with the existing laws.

Cerebral blood flow velocity wave form as an indicator of neonatal left ventricular heart function.

OBJECTIVE: To investigate the relationship between cerebral blood flow velocity wave form (CBFV-WF) parameters and myocardial contractility indices in healthy and sick preterm and term newborns. METHODS: Total group of 82 babies was divided into four subgroups: prematures with gestational age <34 weeks with (n=20) and without (n=14) respiratory distress syndrome (RDS) and infants with gestational age of >33 weeks with (n=18) and without (n=30) asphyxia. On day 1, 2, 3, 6 and 14, the acceleration time, Q(ECG)-peak(flow) time and preejection period of CBFV-WF (internal carotid artery) were measured through the anterior fontanel by Doppler ultrasonography. Simultaneously cardiac output, fractional shortening, systolic time intervals and their ratio were determined echocardiographically. RESULTS: RDS-babies had higher cardiac output and better myocardial performance then non-RDS-babies. Asphyxiated babies had lower cardiac output as compared to healthy babies, improving over time. Correlations were found between CBFV-WF parameters and several myocardial function indicators, but preejection period of cerebral blood flow velocity correlated closest with the same period measured echocardiographically (r=0.67, P<0.0001). Multiple linear regression revealed no influence of gestational age or clinical condition on this relationship. Assessment of agreement indicated that only substantial changes in myocardial performance could be monitored using preejection period of CBFV. CONCLUSION: Although a relationship was detected between the preejection period of CBFV and left ventricular systolic time interval (used as indicator of changes in left ventricular function), only rather large changes in left ventricular performance can be reliably detected using the preejection period of CBFV.

Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide.

We performed a phase I and pharmacological study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of the novel topoisomerase I inhibitor topotecan in combination with the topoisomerase II inhibitor etoposide, and to investigate the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5 followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day-1)/(mg bid). After encountering DLT, additional patients were treated at 3-week intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and etoposide administration prolonged from 7 to 10 days to allow further dose intensification. Of 30 patients entered, 29 were assessable for toxicity in the first course and 24 for response. The DLT was neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia grade IV that lasted more than 7 days. Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose intensification, as a time delay to retreatment owing to unrecovered bone marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion. Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concentration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stable disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide 40 mg bid on days 6-12 every 4 weeks.

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule.

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min i.v. infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 microg m(-2). According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 microg m(-2), the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 microg m(-2). From the dose level 170 microg m(-2), the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 microg m(-2). The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml(-1)) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values.