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G A Taylor - One of the best experts on this subject based on the ideXlab platform.

  • 2-[11C]Thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337
    Journal of the National Cancer Institute, 2003
    Co-Authors: Paula Wells, Alan V Boddy, G A Taylor, Eric O. Aboagye, Roger N. Gunn, Safiye Osman, Imran Rafi, Andrew N. Hughes, A. Hilary Calvert, Patricia Price
    Abstract:

    Background: 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-[ 1 1 C]thymidine positron emission tomography (PET) to measure thymidine salvage kinetics in vivo in humans. Methods: Five patients with advanced gastrointestinal cancer were PET scanned both before and I 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-[ 1 1 C]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. Results: 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-[ 1 1 C]thymidine FRT and plasma deoxyuridine levels was statistically significantly correlated with AG337 exposure (r = 1.00, P = .01 for both). Conclusions: AG337 administration was associated with increased tumor tracer retention that was consistent with tumor cell uptake of exogenous 2-[ 1 1 C]thymidine as a result of TS inhibition. 2-[ 1 1 C]Thymidine PET can be used to measure thymidine salvage kinetics directly in the tissue of interest.

  • A phase I study of Nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation
    British Journal of Cancer, 2001
    Co-Authors: E J Estlin, D R Newell, A V Boddy, C R Pinkerton, I J Lewis, L Lashford, H Mcdowell, B Morland, J Kohler, G A Taylor
    Abstract:

    A phase I study of Nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m^2 24 h^−1. 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m^2 24 h^−1, dose-limiting oral mucositis and myelosuppression were observed. Plasma Nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg^−1 ml^−1 min^−1, 50 mg ml^−1 min^−1 and 80 mg ml^−1 min^−1 at the 3 dose levels studied. Whereas no toxicity was encountered if the Nolatrexed AUC was 60 mg ml^−1 min^−1. Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of Nolatrexed in children at the maximum tolerated dose of 640 mg/m^2 24 h^−1are warranted. © 2001 Cancer Research Campaign

  • a phase i study of Nolatrexed dihydrochloride in children with advanced cancer a united kingdom children s cancer study group investigation
    British Journal of Cancer, 2001
    Co-Authors: E J Estlin, Alan V Boddy, C R Pinkerton, I J Lewis, L Lashford, H Mcdowell, B Morland, J Kohler, David R Newell, G A Taylor
    Abstract:

    A phase I study of Nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m2 24 h−1. 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m2 24 h−1, dose-limiting oral mucositis and myelosuppression were observed. Plasma Nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg−1 ml−1 min−1, 50 mg ml−1 min−1 and 80 mg ml−1 min−1at the 3 dose levels studied. Whereas no toxicity was encountered if the Nolatrexed AUC was 60 mg ml−1 min−1. Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of Nolatrexed in children at the maximum tolerated dose of 640 mg/m2 24 h−1are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.com

  • A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (Nolatrexed dihydrochloride) given by 10-day oral administration
    British Journal of Cancer, 1999
    Co-Authors: D I Jodrell, I Rafi, A Johnston, G A Taylor, A Bowman, B Byrne, A Boddy, N J Clendeninn
    Abstract:

    2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (Nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered Nolatrexed is active clinically. As oral bioavailability is high (70–100%), Nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m^–2day^–1in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses ≥ 318 mg m^–2day^–1and neutropenia (grade 2) at 429 and 572 mg m^–2day^–1. An erythematous maculopapular rash occurred at dosages ≥ 318 mg m^–2day^–1(7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m^–2day^–1. Nolatrexed plasma concentrations 1 h after dosing were 6–16 μg ml^–1, and trough 3–8 μg ml^–1, at 572 mg m^–2day^–1. Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral Nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m^–2day^–1. Nine patients were treated at 429 mg m^–2day^–1; three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.

  • a phase i study of the lipophilic thymidylate synthase inhibitor thymitaq Nolatrexed dihydrochloride given by 10 day oral administration
    British Journal of Cancer, 1999
    Co-Authors: D I Jodrell, I Rafi, A Johnston, Alan V Boddy, G A Taylor, A Bowman, B Byrne, N Clendeninn
    Abstract:

    A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (Nolatrexed dihydrochloride) given by 10-day oral administration

D R Newell - One of the best experts on this subject based on the ideXlab platform.

  • A phase I study of Nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation
    British Journal of Cancer, 2001
    Co-Authors: E J Estlin, D R Newell, A V Boddy, C R Pinkerton, I J Lewis, L Lashford, H Mcdowell, B Morland, J Kohler, G A Taylor
    Abstract:

    A phase I study of Nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m^2 24 h^−1. 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m^2 24 h^−1, dose-limiting oral mucositis and myelosuppression were observed. Plasma Nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg^−1 ml^−1 min^−1, 50 mg ml^−1 min^−1 and 80 mg ml^−1 min^−1 at the 3 dose levels studied. Whereas no toxicity was encountered if the Nolatrexed AUC was 60 mg ml^−1 min^−1. Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of Nolatrexed in children at the maximum tolerated dose of 640 mg/m^2 24 h^−1are warranted. © 2001 Cancer Research Campaign

  • Clinical pharmacokinetic and in vitro combination studies of Nolatrexed dihydrochloride (AG337, Thymitaq™) and paclitaxel
    British Journal of Cancer, 2000
    Co-Authors: A N Hughes, M J Griffin, A H Calvert, A Johnston, D R Newell, B Kerr, B Liang, A V Boddy
    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^–2over 3 h and Nolatrexed at a dose of 500 mg m^–2day^–1as 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^–1m^–2) than those on schedule 2 (165–238 ml min^–1m^–2). Peak plasma concentrations (1.66–1.93 vs 0.86–1.32 μ M ) 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. © 2000 Cancer Research Campaign

  • Potentiation of the cytotoxicity of thymidylate synthase (TS) inhibitors by dipyridamole analogues with reduced α _1-acid glycoprotein binding
    British Journal of Cancer, 1999
    Co-Authors: N J Curtin, A H Calvert, K J Bowman, R N Turner, B Huang, P J Loughlin, B T Golding, R J Griffin, D R Newell
    Abstract:

    Dipyridamole has been shown to enhance the in vitro activity of antimetabolite anticancer drugs through the inhibition of nucleoside transport. However, the clinical potential of dipyridamole has not been realized because of the avid binding of the drug to the plasma protein α_1-acid glycoprotein (AGP). Dipyridamole analogues that retain potent nucleoside transport inhibitory activity in the presence of AGP are described and their ability to enhance the growth inhibitory and cytotoxic effects of thymidylate synthase (TS) inhibitors has been evaluated. Three dipyridamole analogues (NU3026, NU3059 and NU3060) were shown to enhance the growth inhibitory activity of the TS inhibitor CB3717 and block thymidine rescue in L1210 cells. The extent of potentiation at a fixed analogue concentration (10 μ M ) was related to the potency of inhibition of thymidine uptake. A further analogue, NU3076, was identified, which was more potent than dipyridamole with a K _i value for inhibition of thymidine uptake of 0.1 μ M compared to 0.28 μ M for dipyridamole. In marked contrast to dipyridamole, inhibition of thymidine uptake by NU3076 was not significantly affected by the presence of AGP (5 mg ml^–1). NU3076 and dipyridamole produced equivalent potentiation of the cytotoxicity of the non-classical antifolate TS inhibitor, Nolatrexed, in L1210 cells with both compounds significantly reducing the LC_90 by > threefold in the absence of salvageable thymidine. Thymidine rescue of L1210 cells from Nolatrexed cytotoxicity was partially blocked by both 1 μ M NU3076 and 1 μ M dipyridamole. NU3076 also caused a significant potentiation of FU cytotoxicity in L1210 cells. These studies demonstrate that nucleoside transport inhibition can be maintained in the absence of AGP binding with the dipyridamole pharmacophore and that such analogues can enhance the cytotoxicity of TS inhibitors.

  • Clinical pharmacokinetics of antitumor antifolates.
    Seminars in oncology, 1999
    Co-Authors: D R Newell
    Abstract:

    Antifolate drugs, as a class, have broad-spectrum activity against both hematologic and solid human malignancies. The pharmacokinetics of the classical antifolate methotrexate have been well-defined and pharmacokinetic data can be exploited to reduce the toxicity and enhance the activity of the drug. Methotrexate remains the only anticancer drug for which plasma drug level monitoring is used in routine clinical practice. Recently, novel classical and nonclassical antifolates have been developed that target either specific folate-dependent enzymes (e.g., thymidylate synthase [CB3717, raltitrexed, ZD9331, 1843U89, Nolatrexed, AG331], glycinamide ribonucleotide transformylase [lometrexol, LY309887, AG2034] or multiple folate-dependent enzymes (e.g., MTA/LY231514). In the early clinical trials of these agents, a number of pharmacokinetic-pharmacodynamic relationships were identified and it is highly likely that the full therapeutic potential of these new drugs will also require the exploitation of pharmacokinetic data.

  • preclinical and phase i clinical studies with the nonclassical antifolate thymidylate synthase inhibitor Nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors
    Journal of Clinical Oncology, 1998
    Co-Authors: I Rafi, J A Calvete, Alan V Boddy, D R Newell, G A Taylor, N P Bailey, M J Lind, M Green, J Hines, A Johnstone
    Abstract:

    PURPOSEA phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (Nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects.METHODSIn vitro and in vivo preclinical studies demonstrated increased activity with prolonged Nolatrexed exposure. In 32 patients, Nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition.RESULTSThe MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatr...

Alan V Boddy - One of the best experts on this subject based on the ideXlab platform.

  • 2-[11C]Thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337
    Journal of the National Cancer Institute, 2003
    Co-Authors: Paula Wells, Alan V Boddy, G A Taylor, Eric O. Aboagye, Roger N. Gunn, Safiye Osman, Imran Rafi, Andrew N. Hughes, A. Hilary Calvert, Patricia Price
    Abstract:

    Background: 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-[ 1 1 C]thymidine positron emission tomography (PET) to measure thymidine salvage kinetics in vivo in humans. Methods: Five patients with advanced gastrointestinal cancer were PET scanned both before and I 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-[ 1 1 C]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. Results: 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-[ 1 1 C]thymidine FRT and plasma deoxyuridine levels was statistically significantly correlated with AG337 exposure (r = 1.00, P = .01 for both). Conclusions: AG337 administration was associated with increased tumor tracer retention that was consistent with tumor cell uptake of exogenous 2-[ 1 1 C]thymidine as a result of TS inhibition. 2-[ 1 1 C]Thymidine PET can be used to measure thymidine salvage kinetics directly in the tissue of interest.

  • a phase i study of Nolatrexed dihydrochloride in children with advanced cancer a united kingdom children s cancer study group investigation
    British Journal of Cancer, 2001
    Co-Authors: E J Estlin, Alan V Boddy, C R Pinkerton, I J Lewis, L Lashford, H Mcdowell, B Morland, J Kohler, David R Newell, G A Taylor
    Abstract:

    A phase I study of Nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m2 24 h−1. 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m2 24 h−1, dose-limiting oral mucositis and myelosuppression were observed. Plasma Nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg−1 ml−1 min−1, 50 mg ml−1 min−1 and 80 mg ml−1 min−1at the 3 dose levels studied. Whereas no toxicity was encountered if the Nolatrexed AUC was 60 mg ml−1 min−1. Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of Nolatrexed in children at the maximum tolerated dose of 640 mg/m2 24 h−1are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.com

  • a phase i study of the lipophilic thymidylate synthase inhibitor thymitaq Nolatrexed dihydrochloride given by 10 day oral administration
    British Journal of Cancer, 1999
    Co-Authors: D I Jodrell, I Rafi, A Johnston, Alan V Boddy, G A Taylor, A Bowman, B Byrne, N Clendeninn
    Abstract:

    A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (Nolatrexed dihydrochloride) given by 10-day oral administration

  • phase i studies with the nonclassical antifolate Nolatrexed dihydrochloride ag337 thymitaq administered orally for 5 days
    Clinical Cancer Research, 1999
    Co-Authors: A N Hughes, I Rafi, M J Griffin, A H Calvert, David Richard Newell, J A Calvete, A Johnston, N Clendeninn, Alan V Boddy
    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/m 2 /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/m 2 /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/m 2 /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 ( r 2 = 0.58; C 50 = 6.0 μg/ml, where C 50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils ( r 2 = 0.63; C 50 = 0.6 μg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m 2 /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.

  • preclinical and phase i clinical studies with the nonclassical antifolate thymidylate synthase inhibitor Nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors
    Journal of Clinical Oncology, 1998
    Co-Authors: I Rafi, J A Calvete, Alan V Boddy, D R Newell, G A Taylor, N P Bailey, M J Lind, M Green, J Hines, A Johnstone
    Abstract:

    PURPOSEA phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (Nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects.METHODSIn vitro and in vivo preclinical studies demonstrated increased activity with prolonged Nolatrexed exposure. In 32 patients, Nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition.RESULTSThe MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatr...

N Clendeninn - One of the best experts on this subject based on the ideXlab platform.

  • result of two randomized trials comparing Nolatrexed thymitaq versus methotrexate in patients with recurrent head and neck cancer
    Annals of Oncology, 2001
    Co-Authors: X Pivot, S Wadler, C Kelly, R Ruxer, Jacques Tortochaux, J Stern, D Belpomme, Y Humblet, C Domenge, N Clendeninn
    Abstract:

    We report on two randomized trials performed in the USA and Europe, which compared methotrexate and Nolatrexed as treatment for patients with recurrent head and neck cancer. Eligibility criteria included: histologically confirmed squamous-cell carcinoma, measurable disease, adequate hematological, renal and hepatic functions, failure of a first-line chemotherapy, and informed consent. Methotrexate 40 mg/m(2) was weekly given by short infusion, and Nolatrexed 725 mg/m(2) per day was administered as a five-day continuous infusion, every three weeks. A total of 139 patients (63 in the USA, 76 in Europe) were randomized based on a ratio of 2/1: 93 and 46 received Nolatrexed and methotrexate, respectively. Patient characteristics included 115 males and 24 females; median age 60 years. In the Nolatrexed arm, the following grade 3-4 toxicities occurred: neutropenia (29.9%) with 3.1% of febrile neutropenia, mucositis (33.3%), and vomiting (10.3%). In the MTX arm, the grade 3-4 toxicities were neutropenia (7.1%) and mucositis (6.9%). There was no difference in activity between the Nolatrexed and the methotrexate treatment: 3.3% and 10.8% of objective responses, 1.9 versus 1.5 months of disease-free progression and 3.5 versus 3.7 months of overall survival, respectively. Nolatrexed has demonstrated a similar activity to methotrexate.

  • a phase i study of the lipophilic thymidylate synthase inhibitor thymitaq Nolatrexed dihydrochloride given by 10 day oral administration
    British Journal of Cancer, 1999
    Co-Authors: D I Jodrell, I Rafi, A Johnston, Alan V Boddy, G A Taylor, A Bowman, B Byrne, N Clendeninn
    Abstract:

    A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (Nolatrexed dihydrochloride) given by 10-day oral administration

  • phase i studies with the nonclassical antifolate Nolatrexed dihydrochloride ag337 thymitaq administered orally for 5 days
    Clinical Cancer Research, 1999
    Co-Authors: A N Hughes, I Rafi, M J Griffin, A H Calvert, David Richard Newell, J A Calvete, A Johnston, N Clendeninn, Alan V Boddy
    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/m 2 /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/m 2 /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/m 2 /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 ( r 2 = 0.58; C 50 = 6.0 μg/ml, where C 50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils ( r 2 = 0.63; C 50 = 0.6 μg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m 2 /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.

I Rafi - One of the best experts on this subject based on the ideXlab platform.

  • A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (Nolatrexed dihydrochloride) given by 10-day oral administration
    British Journal of Cancer, 1999
    Co-Authors: D I Jodrell, I Rafi, A Johnston, G A Taylor, A Bowman, B Byrne, A Boddy, N J Clendeninn
    Abstract:

    2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (Nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered Nolatrexed is active clinically. As oral bioavailability is high (70–100%), Nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m^–2day^–1in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses ≥ 318 mg m^–2day^–1and neutropenia (grade 2) at 429 and 572 mg m^–2day^–1. An erythematous maculopapular rash occurred at dosages ≥ 318 mg m^–2day^–1(7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m^–2day^–1. Nolatrexed plasma concentrations 1 h after dosing were 6–16 μg ml^–1, and trough 3–8 μg ml^–1, at 572 mg m^–2day^–1. Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral Nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m^–2day^–1. Nine patients were treated at 429 mg m^–2day^–1; three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.

  • a phase i study of the lipophilic thymidylate synthase inhibitor thymitaq Nolatrexed dihydrochloride given by 10 day oral administration
    British Journal of Cancer, 1999
    Co-Authors: D I Jodrell, I Rafi, A Johnston, Alan V Boddy, G A Taylor, A Bowman, B Byrne, N Clendeninn
    Abstract:

    A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (Nolatrexed dihydrochloride) given by 10-day oral administration

  • phase i studies with the nonclassical antifolate Nolatrexed dihydrochloride ag337 thymitaq administered orally for 5 days
    Clinical Cancer Research, 1999
    Co-Authors: A N Hughes, I Rafi, M J Griffin, A H Calvert, David Richard Newell, J A Calvete, A Johnston, N Clendeninn, Alan V Boddy
    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/m 2 /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/m 2 /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/m 2 /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 ( r 2 = 0.58; C 50 = 6.0 μg/ml, where C 50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils ( r 2 = 0.63; C 50 = 0.6 μg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m 2 /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.

  • preclinical and phase i clinical studies with the nonclassical antifolate thymidylate synthase inhibitor Nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors
    Journal of Clinical Oncology, 1998
    Co-Authors: I Rafi, J A Calvete, Alan V Boddy, D R Newell, G A Taylor, N P Bailey, M J Lind, M Green, J Hines, A Johnstone
    Abstract:

    PURPOSEA phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (Nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects.METHODSIn vitro and in vivo preclinical studies demonstrated increased activity with prolonged Nolatrexed exposure. In 32 patients, Nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition.RESULTSThe MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatr...