Martha Swart

Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer

PURPOSE To determine the maximum-tolerated dose, toxicities, and pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered continuously via the oral route. PATIENTS AND METHODS Patients with advanced solid malignancies were treated with R115777 using an interpatient dose escalation scheme starting at 50 mg bid. Pharmacokinetics were assessed on days 1, 28, and 56. RESULTS Twenty-eight patients were entered onto the study and the median duration of treatment was 55 days. The dose-limiting toxicities were myelosuppression and neurotoxicity. At a dose of 400 mg bid, grade 4 leukocytopenia and neutropenia were seen in two of four patients. Neurotoxicity grade 3 developed in one of five patients at 500 mg bid and in one of 13 at 300 mg bid after 8 weeks of treatment. Common nonhematologic toxicities were nausea, vomiting, and fatigue. The recommended dose for phase II/III testing in this scheme is 300 mg bid. The pharmacokinetic studies indicated dose proportionality. Little accumulation occurred and steady-state levels were reached within 2 to 3 days. Analyses of historic tumor material showed that five of 15 of patients had a K-ras mutation in codon 12. Three patients with pancreatic, colon, and cervix carcinomas had stable disease and one patient with a colon carcinoma had a minor response accompanied by a more than 50% decrease in carcinoembryonic antigen tumor marker. A fifth patient, with platinum-refractory non-small-cell lung cancer, showed a partial response that lasted for 5 months. CONCLUSION Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.

A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin

Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m−2 day−1. Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m−2 day−1 and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1–3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4–5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.

Phase I and Pharmacokinetic Study of Oral Paclitaxel

PURPOSE To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). PATIENTS AND METHODS A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m(2) as a 3-hour infusion. RESULTS The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m(2). Dose escalation of oral paclitaxel from 60 to 300 mg/m(2) resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values +/- SD after 60, 180, and 300 mg/m(2) of oral paclitaxel were 1.65 +/- 0.93, 3.33 +/- 2.39, and 3.46 +/- 1.37 micromol/L.h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 +/- 3.26 micromol/L.h. CONCLUSION The MTD of oral paclitaxel was 300 mg/m(2). However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m(2), the oral paclitaxel dose of 180 mg/m(2) in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.

Phase I and Pharmacokinetic Study of Irinotecan Administered as a Low-Dose, Continuous Intravenous Infusion Over 14 Days in Patients With Malignant Solid Tumors

PURPOSE To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m(2)/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m(2)/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m(2)/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% +/- 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION The recommended dosage is 10 mg/m(2)/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel.

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m2 oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 μM (T>0.1 μM) of oral paclitaxel. The mean (±SD) AUC and T>0.1 μM values of oral paclitaxel with CsA 10 mg/kg were 4.29±0.88 μM·h and 12.0±2.1 h, respectively. With CsA 5 mg/kg these values were 2.75±0.63 μM·h and 7.0±2.1 h, respectively (p = 0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 μM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 μM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.

Metabolism and excretion of paclitaxel after oral administration in combination with cyclosporin A and after i.v. administration.

The objective of this study was to compare the quantitative excretion of paclitaxel and metabolites after i.v. and oral drug administration. Four patients received 300 mg/m2 paclitaxel orally 30 min after 15 mg/kg oral cyclosporin A, co-administered to enhance the uptake of paclitaxel. Three weeks later these and three other patients received 175 mg/m2 paclitaxel by i.v. infusion. Blood samples, urine and feces were collected up to 48-96 h after administration, and analyzed for paclitaxel and metabolites. The area under the plasma concentration-time curve of paclitaxel after i.v. administration (175 mg/m2) was 16.2±1.7 μM·h and after oral administration (300 mg/m2) 3.8±1.5 μM·h. Following i.v. infusion of paclitaxel, total fecal excretion was 56±25%, with the metabolite 6α-hydroxypaclitaxel being the main excretory product (37±18%). After oral administration of paclitaxel, total fecal excretion was 76±21%, of which paclitaxel accounted for 61±14%. In conclusion, after i.v. administration of paclitaxel, excretion occurs mainly in the feces with the metabolites as the major excretory products. Orally administered paclitaxel is also mainly excreted in feces but with the parent drug in highest amounts. We assume that this high amount of parent drug is due to incomplete absorption of orally administered paclitaxel from the gastrointestinal tract.

Successful treatment with paclitaxel of a patient with metastatic extra-adrenal pheochromocytoma (paraganglioma)

Abstract This case report describes the history of a patient with an aggressive course of a metastatic extra-adrenal pheochromocytoma (paraganglioma) who received different combination chemotherapy regimens with no or short-lasting clinical benefit. However, during treatment with single-agent paclitaxel, there was a significant clinical improvement, a partial biochemical response and a minor roentgenologic response, which was sustained for 1 year. In this report we present this case and also review the literature on the chemotherapy used for this rare disease over the past 15 years. To enable the activity of paclitaxel against this neoplasm to be determined, more patients need to be treated.

Evaluation of the bioequivalence of tablets and capsules containing the novel anticancer agent R115777 (Zarnestra) in patients with advanced solid tumors

SummaryR 115777 (Zarnestra) is a novel anticancer agent, currently undergoing phase III clinical testing. An open, cross-over trial was performed in 24 patients with solid tumors to compare the bioavailability of a new tablet formulation with the standard capsule formulation. Both dosage forms were administered once daily in doses of 300 or 400 mg. Patients received R 115777 as a capsule on day 1 and as a tablet on day 2, or vice versa. Blood samples were drawn up to 24 hours after drug intake and R 115777 levels were measured using a validated high performance liquid chromatography, (HPLC) method. The following pharmacokinetic parameters were determined and compared for the two formulations: time to maximal plasma concentration (Tmax), half-life (t1/2), maximal plasma concentration (Cmax) and area under the curve at twenty-four hours (AUC24h). For the latter two parameters, 90% classical confidence intervals of the ratio tablet/capsule were calculated after a log-transformation, using an Analysis of Variance (ANOVA). For t1/2 and Tmax, no statistically significant differences were found between tablet and capsule. The point estimates of the ratio’s of the log-normalized Cmax and AUC24h were 0.94 and 0.92, respectively, and the 90% confidence intervals were 0.81–1.09 and 0.83–1.03, which is within the critical range for bioequivalence of 0.80–1.25. In conclusion, the established pharmacokinetic parameters demonstrate that the capsule and tablet formulations, of R 115777 are interchangeable.

Phase I and pharmacokinetic study of the combination of topotecan and ifosfamide administered intravenously every 3 weeks

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetics of topotecan administered as a 30-min intravenous (i.v.) infusion over 5 days in combination with a 1-h i.v. infusion of ifosfamide (IF) for 3 consecutive days every 3 weeks. Patients with advanced malignancies refractory to standard therapy were entered into the study. The starting dose of topotecan was 0.4 mg m−2 day−1 × 5 days. Ifosfamide was administered at a fixed dose of 1.2 g m−2 day−1 × 3 days. In all, 36 patients received 144 treatment courses. Owing to toxicities, the schedule of topotecan administration was reduced from 5 to 3 days. The MTD was reached at topotecan 1.2 mg m−2 day−1 × 3 days with IF 1.2 g m−2 day−1 × 3 days. Haematological toxicities were dose limiting. Neutropenia was the major toxicity. Thrombocytopenia and anaemia were rare. Nonhaematological toxicities were relatively mild. Partial responses were documented in three patients with ovarian cancer dosed below the MTD. Topotecan and IF did not appear to interact pharmacokinetically. The relationships between the exposure to topotecan lactone and total topotecan, and the decrease in absolute neutrophil count and the decrease in thrombocytes, were described with sigmoidal–Emax models. The combination of 1.0 mg m−2 day−1 topotecan administered as a 30-min i.v. infusion daily times three with 1.2 g m−2 day−1 IF administered as a 1-h i.v. infusion daily times three every 3 weeks was feasible. However, the combination schedule of topotecan and IF did result in considerable haematological toxicity and in conjunction with previously reported pronounced nonhaematological toxicities and treatment related deaths, it may be concluded that this is not a favourable combination.

Phase I and pharmacokInetic (PK) study of Irinotecan (CPT11) with a prolonged (14D) infusion schedule

CPT11 isa a topoisomerase I inhibitor with substantial anti tumor activity. Preclinical data suggest that prolonged exposure has better efficacy and possibly less toxicity. A dose-escalation phase I study of CPT11 continuous I.v (c.i.v.) over 14-days every 3 to 5 weeks was conducted in order to de• termine the maximal tolerated dose (MTD). Since March 1996, 15 patients (pt) have been enrolled with the following characteristics: median age: 57 (range 29-70): median PS 1 (range 0-2): sex: 12 FI3 M, primary sites: col• oractal cancer 8, unknown primary 1, other 6; all heavily pre-treated. Only 10 patients evaluable for toxicity and PK. Already at the first dose of 12.5 mglm/d dose limiting toxicity was encountered consisting of cumulative gr 3-4 diarrhea 3/5 pt and gr 3-4 neutropenia 2/5 pt. At a dose of 10 mg/m2/d 1/4 pt had gr 4 diarrhea (despite high dose of loperamide) and myelosup• pression was not dose limiting. Other side effects were moderate: fatigue 2 pt, thrombocy1openia 1 pt; alopecia was minimal. One response (not yet confirmed) in colorectal cancer was observed. Substantial Interpatlent and intrapatient variability in systemic exposure was observed. The mean total AUC of CPT11 was 8.9 ± 5.4 and 8.0 ±0.2 h./lg/ml at 12.5 and 10 mg/m2/d respectively. For SN38 AUC values were 0.93 ± 0.47 and 0.59 ± 0.06 h./lg/ml. The active lactone torms of CPT11 and SN38 accounted for by 36 ± 9% and 64 ± 6% respectively, of total drug exposure. At 12.5 mg/m2/d, plasma levels were higher during the second course. This increase was not due to changes in the fraction of CPT11 metabolized to SN38 which was stable over both courses (mean values: 10.3 ± 5.1 and 8.0 ± 1.7% at 12.5 and 10 mg/m2 /d respectively). The MTD of this schedule (175 mg/m2) is much lower than that with short infusion (350 mg/m2). AUC metabolic ratio SN38ICPT11 is higher and a cumulative effect was observed. The dose of 140 mg/m2/d leads to a SN38 AUC close to that of 350 mg/m2 short infusion (0.59 vs 0.45 /lg/ml) and is probably the recommended dose. The dose of 10 mg/m2 over a 17-21-days c.i.v. is under evaluation.