Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid tumors.

Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administered once daily for 14 days every 3 weeks in patients with solid tumors. In the pilot food effect part, patients received a single dose of 20 mg indibulin on day-8 and -4, fasted or fed, in a randomized crossover design. In the dose-escalation part, patients received a single dose of indibulin on day-4. Three dose levels were evaluated: 20, 40 and 80 mg. After a washout period, patients received indibulin once daily for 14 days every 3 weeks (multiple dose part). Blood samples were collected in the pilot food effect- and in the dose escalation study. A total of 14 patients entered, of which 6 completed the food effect study. The ratio of indibulin (fed/fasted) in the food effect study for AUC(0-72) was estimated as 1.24 (P=0.082, 95%CI 0.96-1.41) and C(max) ratio was 0.89 (P=0.54, 95%CI 0.55-1.44). Interpatient variability was high. Higher peak plasma concentrations were reached under fasting conditions which was undesired regarding tolerability. Therefore the dose escalation study was continued under fed conditions. Dose limiting toxicities, nausea and vomiting, appeared to be related to the increased volume of the solvent lactic acid. This study is continued, evaluating indibulin administered as capsules on the recommended dose level of 60 mg daily for 14 days.

Phase I study of an oral formulation of irinotecan administered daily for 14 days every 3 weeks in patients with advanced solid tumours.

A phase I study was conducted with oral irinotecan given daily for 14 days every 3 weeks in 45 patients with solid tumours to establish the maximum tolerated dose (MTD), toxicity, preliminary antitumour response and pharmacokinetics. Irinotecan was administered orally as a powder-filled capsule at doses ranging from 7.5 to 40 mg/m2 per day. Tumours were predominantly colorectal (30) together with 10 other gastrointestinal, 2 breast, 2 small cell lung and 1 ovarian. All but three patients had received prior chemotherapy. The median number of administered cycles was 3 (range 1-19). Gastrointestinal toxicities (grade 3 nausea, grade 3/4 vomiting and diarrhoea) and one incidence of grade 3 asthenia were dose limiting. There were no grade 3/4 haematological toxicities. The MTD was 30 mg/m2 per day. There were two documented partial responses, one in a patient with cancer of the small intestine and the other in a patient with colon cancer. Stable disease was seen in 16 patients (35.5%). Peak concentrations of irinotecan and metabolite SN-38 were reached within 2.0-2.4 h. The metabolic ratio of SN-38 AUC to irinotecan AUC was 0.17+/-0.10 (mean+/-SD). The dose recommended for phase II studies is 30 mg/m2 per day administered daily for 14 days every 3 weeks.

Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093).

OBJECTIVE: Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated. PATIENTS AND METHODS: A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated. RESULTS: The apparent relative oral bioavailability of docetaxel was 26+/-8%. Orally administered docetaxel combined with oral OC144-093 resulted in a Cmax of 415+/-255 ng ml(-1), an AUC0-infinity of 844+/-753 ng h ml(-1) and kel of 0.810+/-0.296 h(-1). These values differed significantly from those following i.v. administration of docetaxel, with a Cmax of 2124+/-1054 ng ml(-1), an AUC0-infinity of 2571+/-1598 ng h ml(-1) and a kel of 1.318+/-0.785 h(-1) (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21. CONCLUSION: The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.

Quantitative analysis of docetaxel in human plasma using liquid chromatography coupled with tandem mass spectrometry.

An assay for the quantitative determination of docetaxel in human plasma is described. Docetaxel was extracted from the matrix using liquid-liquid extraction with ter-butylmethylether, followed by high-performance liquid chromatographic analysis using an alkaline eluent. Paclitaxel was used as internal standard. Positive ionization electrospray tandem mass spectrometry was performed for selective and sensitive detection. The method was validated according to the FDA guidelines on bioanalytical method validation. The validated range for docetaxel was from 0.25--1000 ng/mL using 200 microL plasma aliquots. The method requires only a limited volume (200 microL) of human plasma and the method can be applied in studies requiring a low lower limit of quantitation of 0.25 ng/mL. The assay was applied successfully in several clinical and pharmacological studies with docetaxel.

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer.

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.