A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB12) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0–2, and adequate organ function. Pemetrexed from 300 to 1200 mg m−2 was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB12. Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m−2, and infection and skin rash at 1200 mg m−2. The MTD/RD were determined to be 1200/1000 mg m−2, respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1200/1000 mg m−2, respectively, that is, a higher RD than without FA/VB12 (500 mg m−2). Pemetrexed with FA/VB12 showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study

Laboratory and clinical studies with the novel antipurine antifolate lometrexol

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN008730 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Clinical pharmacokinetics of the antipurine antifolate (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) administered with an oral folic acid supplement

(6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) is an antipurine antifolate which selectively inhibits glycinamide ribonucleotide formyltransferase. Lometrexol pharmacokinetics were evaluated in 17 patients (32 courses) as part of a Phase I study in which folic acid supplementation was used to improve tolerance to the drug, its clinical utility being previously limited by severe cumulative toxicity, Lometrexol was administered as an i.v. bolus every 4 weeks at a starting dose of 12 mg/m(2), with subsequent interpatient dose escalation to 16, 30, and 45 mg/m(2), p.o. folic acid (5 mg/day) was given for 7 days before and 7 days after lometrexol administration, The disposition of total lometrexol in plasma was best described by a biexponential model for data acquired up to 12 h after drug administration, although triexponential plasma pharmacokinetics were often found to give a more adequate description when data were available at later time intervals (24 h and greater), Mean plasma half-lives (+/- SD) for model-dependent analysis were t(1/2)alpha 19 +/- 7 min, t(1/2)beta 256 +/- 96 min, and t(1/2)gamma (where measurable) 1170 +/- 435 min, Lometrexol area under plasma concentration versus time curve was proportional to the dose administered, Moderate plasma protein binding of lometrexol was evident (78 +/- 3%) with an inverse linear relationship between fraction of unbound lometrexol and the concentration of serum albumin, The volume of distribution of lometrexol at steady state was between 4.7 and 15.8 l/m(2), Renal elimination of lometrexol, studied in 19 patients (21 courses), was considerable, accounting for 56 +/- 17% of the total dose administered within 6 h of treatment, and 85 +/- 16% within 24 h of treatment, These recoveries of unchanged lometrexol indicate that the drug does not appear 60 undergo appreciable systemic metabolism at the range of concentrations studied

Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II study of combination chemotherapy against inoperable non-small-cell lung cancer previously untreated

[[abstract]]Background: Paclitaxel (Taxol) Plus carboplatin (PC) has shown activity in the treatment of advanced non-small-cell lung cancer (NSCLC). Non-platinum-containing combination chemotherapy, such as paclitaxel plus gemcitabine (PG), has also demonstrated reasonable efficacy. Our aim here was to evaluate the clinical efficacy and cost-effectiveness of PC versus PG in chemo-naive, advanced NSCLC patients. Patients and methods: Ninety (68 male, 22 female) patients were enrolled from August 1999 to August 2000. The performance status was one in 29 patients and two in 16 patients of the PC group, and one in 24 patients and two in 21 patient,., of the PG group. Seventeen patients had stage IIIb disease and 28 patients stage IV disease in the PC groups 18 patients had stage IIIb disease and 27 patients stage IV disease in the PG group (Now International Staging System), Treatment consisted of P 175 mg/m(2) and C at AUC = 7 (predicted using measured clearances and the Calvert formula) intravenous infusion (i.v.) on day 1, or P 175 mg/m(2) i.v. on day 1 and G 1000 mg/m(2) i.v. on days I and 8, every 3 weeks. Results: In all, 175 cycles of PC and 184 cycles of PG were given in the PC and PG groups, respectively. The median treatment cycle was four cycles in both groups. All the patients were assessable for toxicity and response measurement. There were three complete responses and 15 partial responses (overall 40%) in the PC group. and no complete response, but 18 partial responses (overall 40%) in the PG group. WHO grades 3/4 leukopenia, anemia and thrombocytopenia occurred in six (13.3%), seven (15.5%) and five patients (11.1%) in the PC group; and in four (8.9%), six ( 13.3%) and 0 patients in the PG group, respectively. Two patients in each group suffered from grade 3 peripheral neuropathy. Other non-hematological toxicities were mild and few. Median survival time was 14.1 months in the PC group and 12.6 month,, in the PG group. One-year survival was 50.7% in the PC group and 53.3% in the PG group. The PG group had a higher total expense and expended more days undergoing treatment than the PC group (P = 0.034 and 0.069, respectively). Conclusions: Both PC and PG combination chemotherapy produce a similar efficacy in the treatment of NSCLC. However, PC is more cost-effective than PG