[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1-5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m(-2) day(-1) temozolomide and 225 mg m(-2) day(-1) paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.
British Journal of Cancer 04/2005; 92(6):1006-12. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Some anticancer drugs inhibit thymidylate synthase (TS), a key enzyme for thymidine nucleotide biosynthesis. Cells can compensate for depleted thymidine levels by taking up extracellular thymidine via a salvage pathway. We investigated the use of 2-[11C]thymidine positron emission tomography (PET) to measure thymidine salvage kinetics in vivo in humans.
Five patients with advanced gastrointestinal cancer were PET scanned both before and 1 hour after oral administration of the TS inhibitor AG337 (THYMITAQ [nolatrexed]); seven control patients were scanned twice but not treated with AG337. Thymidine salvage kinetics were measured in vivo using 2-[11C]thymidine PET and spectral analysis to obtain the standardized uptake values (SUV), the area under the time-activity curve (AUC), and the fractional retention of thymidine (FRT). Changes in PET parameters between scans in the AG337-treated and control groups were compared using the Mann-Whitney U test. The relationship between AG337 exposure and AG337-induced changes in tumor FRT and in plasma deoxyuridine levels (a conventional pharmacodynamic systemic measure of TS inhibition) was examined using Spearman's regression analysis. Statistical tests were two-sided.
The between-scan change in FRT in patients treated with AG337 (38% increase, 95% confidence interval [CI] = 8% to 68%) was higher than that in control patients (3% increase, 95% CI = -11% to 17%) (P =.028). The level of AG337-induced increase in both 2-[11C]thymidine FRT and plasma deoxyuridine levels was statistically significantly correlated with AG337 exposure (r = 1.00, P =.01 for both).
AG337 administration was associated with increased tumor tracer retention that was consistent with tumor cell uptake of exogenous 2-[11C]thymidine as a result of TS inhibition. 2-[11C]Thymidine PET can be used to measure thymidine salvage kinetics directly in the tissue of interest.
[Show abstract][Hide abstract] ABSTRACT: A clinical study of nolatrexed dihydrochloride (AG337, Thymitaq) in combination with paclitaxel was performed. The aims were to optimize the schedule of administration and determine any pharmacokinetic (PK) interactions between the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three different schedules of administration of the two drugs: (1) paclitaxel 0-3 h, nolatrexed 24-144 h; (2) nolatrexed 0-120 h, paclitaxel 48-51 h; (3) nolatrexed 0-120 h, paclitaxel 126-129 h. Paclitaxel was administered at a dose of 80 mg m(-2) over 3 h and nolatrexed at a dose of 500 mg m(-2) day(-1) as a 120-h continuous intravenous infusion. Plasma concentrations of both drugs were determined by high performance liquid chromatography. In vitro growth inhibition studies using corresponding schedules were performed using two head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, synergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, patients on schedules 1 and 3 had a higher clearance of paclitaxel (322-520 ml min(-1) m(-2)) than those on schedule 2 (165-238 ml min(-1) m(-2)). Peak plasma concentrations (1.66-1.93 vs. 0.86-1.32 microM) and areas under the curve (392-565 vs. 180-291 microM min(-1)) of paclitaxel were correspondingly higher on schedule 2. The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatrexed and paclitaxel may be safely given together when administered sequentially at the doses used in this study. Studies in vitro suggest some synergy, however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during nolatrexed infusion.
British Journal of Cancer 06/2000; 82(9):1519-27. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THYMITAQ), a nonclassical thymidylate synthase inhibitor, were performed to establish the maximum tolerated dose and a recommended dose for Phase II studies. The bioavailability and pharmacokinetic and pharmacodynamic properties of oral nolatrexed were also studied. Forty-five patients were treated with oral nolatrexed every 6 h for 5 days at doses of 288-1000 mg/m2/day. The bioavailability of the oral preparation was determined, and the effect of a standard meal on nolatrexed absorption was investigated at a dose of 800 mg/m2/day. Nolatrexed plasma concentrations were analyzed by high-performance liquid chromatography. Nolatrexed was rapidly absorbed with a median bioavailability of 89% (range 33-116%), with 88% of patients above 70%. The dose-limiting toxicities were gastrointestinal, and the recommended Phase II oral dose was 800 mg/m2/day. After a standard meal, the peak plasma nolatrexed concentration achieved was lower (median, 8.3 microg/ml versus 15.0 microg/ml; P = 0.001), and the time taken to reach the peak was longer (median, 180 min versus 45 min; P = 0.00003), but the trough concentration was higher (median, 3.6 microg/ml versus 2.1 microg/ml; P = 0.004) when compared with the fasted state. The area under the nolatrexed plasma concentration versus time curve was not affected by food. Average trough nolatrexed concentration, but not dose, was significantly related to the % decrease in both thrombocytes (r2 = 0.58; C50 = 6.0 microg/ml, where C50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils (r2 = 0.63; C50 = 0.6 microg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m2/day for 5 days. Bioavailability was close to 100% and, because inhibition of thymidylate synthase by nolatrexed is rapidly reversible, the slower absorption after a standard meal may result in a shorter duration of noninhibitory concentrations between doses.
Clinical Cancer Research 02/1999; 5(1):111-8. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Data from various phase I/II studies of carboplatin in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have suggested that the degree of thrombocytopenia seen is less than that expected when carboplatin is given alone. However, some studies also have suggested that the area under the plasma concentration-time curve (AUC) of carboplatin is lower than that expected, raising the possibility of a pharmacokinetic interaction. Patients with advanced epithelial ovarian cancer were treated with first-line carboplatin (AUC = 7, using the 51Cr EDTA [edetic acid] clearance method) and escalating doses of paclitaxel. Thrombocytopenia was mild and was significantly less when the paclitaxel dose was 175 mg/m2 versus 150 mg/m2. Paclitaxel kinetics were nonlinear, as previously reported. The achieved carboplatin AUC was 7 +/- 1 mg/mL.min, indicating that the pharmacokinetics of carboplatin are not affected by paclitaxel. Glomerular filtration rates measured in 184 patients using the 51Cr EDTA clearance method were compared with rates estimated from the plasma creatinine level using the Cockcroft-Gault or Jeliffe formulas and showed a significant bias of these two formulas. Clearances above 50 mL/min were underestimated by an amount that became greater as the clearance increased and was approximately 25% to 35% for patients with clearances in the normal range. Since creatinine-based methods have been used in many previous studies, care is needed in interpreting the predicted AUC values from these studies. Carboplatin and paclitaxel may be given safely in combination at full doses, and the thrombocytopenia seen is significantly less than that observed with single-agent carboplatin. No evidence exists of a pharmacokinetic interaction, and the observation in some studies that the carboplatin AUC was lower than expected was probably due to the methodology used to estimate the glomerular filtration rate.