Phase I clinical and pharmacokinetic study of E7070, a novel sulfonamide given as a 5-day continuous infusion repeated every 3 weeks in patients with solid tumours. A study by the EORTC Early Clinical Study Group (ECSG).

A single-agent dose-escalating phase I study on the novel sulfonamide E7070 was performed to determine the toxicity profile and the recommended dose for phase II studies. The pharmacokinetic profile of E7070 was also determined. E7070 was administered as a continuous infusion over 5 days repeated every 3 weeks. 27 patients were treated at doses ranging from 6 to 200 mg/m(2)/day. As with other administration schedules, the dose-limiting toxicities were dose-dependent, reversible neutropenia and thrombocytopenia. Although no objective responses were observed, seven patients had stable disease. E7070 displayed a non-linear pharmacokinetic profile, especially at dose-levels greater than 24 mg/m(2)/day, with a reduction in clearance and an increase in the half-life at the higher dose levels. The risk of myelosuppression became significant with an AUC greater than 4000 microg h/ml. The recommended dose of E7070 for further studies is 96 mg/m(2)/day when administered on a 5-day continuous infusion schedule every 3 weeks.

Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours.

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.

Phase I and pharmacokinetic study of E7070, a novel sulfonamide, given at a daily times five schedule in patients with solid tumors. A study by the EORTC-early clinical studies group (ECSG).

BACKGROUND: E7070 is a novel antitumor sulfonamide which blocks the cell in G1 phase. A phase I study was initiated to investigate the toxicity, maximum tolerated dose (MTD), and pharmacokinetics of this compound when administered intravenously at a daily times five schedule once every three weeks. PATIENTS AND METHODS: Patients with solid tumors not amenable to standard forms of therapy were eligible. E7070 was administered to cohorts of 3-6 patients per dose level, the starting dose was 10 mg/m2/day. Dose escalation was performed according to a Fibonacci-like scheme. RESULTS: Thirty-three patients entered the study. At E7070 doses of 200 and 160 mg/m2/day dose-limiting toxicities occurred, which consisted of febrile neutropenia, thrombocytopenia. diarrhea, skin folliculitis, asthenia, and stomatitis. The pharmacokinetic profile of E7070 at this schedule is non-linear with increasing dose. A partial response was observed in a patient with heavily pretreated breast cancer. Disease stabilizations and some minor responses were also documented. CONCLUSIONS: Myelosuppression is the predominant toxicity of E7070. Clinical efficacy with E7070 was observed. The recommended dose for further studies at this daily times five schedule is 130 mg/m2/day.

Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.

Scaling anticipatory postural adjustments dependent on confidence of load estimation in a bi-manual whole-body lifting task.

Anticipatory control of motor output enables fast and fluent execution of movement. This applies also to motor tasks in which the performance of movement brings about a disturbance to balance that is not completely predictable. For example, in bi-manual lifting the pick-up of a load causes a forward shift of the centre of mass with consequent disturbance of posture. Anticipatory postural adjustments are scaled to the expected magnitude of the perturbation and are initiated well before the availability of sensory information characterising the full nature of the postural disturbance. However, when the postural disturbance unexpectedly changes, the anticipatory adjustment of joint torques is not equilibrated and may result in a disturbance to balance. In a previous study, it was demonstrated that apart from anticipatory postural adjustments, corrective responses after load pick-up are used to further compensate the postural disturbance. In this study it was examined whether the central nervous system (CNS) assembles a strategy that incorporates both anticipatory control and corrective responses, in which the magnitude of the anticipatory postural adjustments depends on the perceived level of predictability of the postural disturbance. Subjects performed series of lifts in which the magnitude of the load was never revealed to the subject. Two boxes equal in size and colour, but different in mass (6 and 16 kg), were used. Differences in expectation were created by several lifts with the 16-kg load before the 6-kg box was presented. It was observed that the number of strong corrective responses (stepping) varied with the number of 16-kg trials that formed the prior experience when the final 6-kg trial was presented. The follow-up question was whether control relied more on anticipation in the stepping trials, compared with trials in which such gross signs of imbalance were absent. In this study it was shown that subjects when stepping (i) exhibited differential anticipatory postural adjustments in comparison with 6-kg trials in which expectation was not shaped by preceding 16-kg trials, and (ii) scaled the anticipatory postural adjustments similar to those preceding lift-off of the 16-kg trial preceding it. These findings emphasise the programmed nature of the anticipatory postural adjustments and the ability of the CNS to selectively tune the anticipatory postural adjustments to stored information gained during the previous lift(s).