[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.
Full-text · Article · Apr 2005 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Introduction: Doxorubicin (Dox), an anthracycline antibiotic, has a broad spectrum of antitumor activity and has been widely used in breast cancer treatment for many years. Pemetrexed (Alimta) is a novel antifolate that inhibits multiple enzymes, notably TS, DHFR and GARFT. Alimta has shown impressive activity in a range of tumors, including breast cancer refractory to both anthracyclines and taxanes. A Phase I clinical trial of the drug combination is being explored, in order to determine the maximum tolerated dose (MTD) and recommend a dose for Phase II studies. Methods: 14 patients (pts) (9m:5f) with various malignancies have been treated to date on 4 different dose levels. The starting dose (level 1) was Alimta 400mg/m2 and Dox 40mg/m2. Doses were escalated as follows: level 2 - Alimta 500mg/m2, Dox 40mg/m2; level 3 - Alimta 500mg/m2, Dox 50mg/m2; level 4 - Alimta 500mg/m2, Dox 60mg/m2. Alimta was administered by 10 minute i.v. infusion followed, 10 minutes later, by dox. Cycles were repeated every 21 days. Standard Phase I eligibility criteria applied. All pts received vitamin supplementation in order to reduce toxicities. Results: 3 pts were treated on dose levels 1 and 2 and no dose-limiting toxicities (DLTs) were observed. On dose level 3, the first of 3 pts treated had a DLT (neutropenic sepsis). Three more pts were enrolled with no further problems. Both pts on dose level 4 had a DLT (1 hematological and 1 gastrointestinal), rendering this dose the MTD. Dose level 3 will therefore be expanded to 9 pts. 57 courses of treatment have been administered to date. Although no objective responses have been observed, 7 pts achieved static disease after 6 courses (5 had malignant mesothelioma). Toxicities have been mild with the most common being leukopenia, neutropenia and nausea. Conclusion: This combination can be safely administered at therapeutic doses. The MTD is Alimta 500mg/m2, dox 60mg/m2. The likely recommended Phase II dose is Alimta 500mg/m2, dox 50mg/m2. Due to the documented activity of both drugs, this novel cytotoxic combination is worthy of further investigation in the treatment of breast cancer.
[Show abstract][Hide abstract] ABSTRACT: A clinical study of nolatrexed dihydrochloride (AG337, Thymitaq(TM)) 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 μM) and areas under the curve (392-565 vs 180-291 μM 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.
Full-text · Article · Jun 2000 · British Journal of Cancer
[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 H 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 H oral dose was 800 mg/m2/day. After a standard meal, the peak plasma nolatrexed concentration achieved was lower (median, 8.3 μg/ml versus 15.0 μg/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 μg/ml versus 2.1 μg/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 μg/ml, where C50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils (r2 = 0.63; C50 = 0.6 μg/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.
No preview · Article · Feb 1999 · Clinical Cancer Research