A phase 2 trial of LY231514 (thymidylate synthase inhibitor) administered intravenously every 21 days in patients with gastric cancer

Lo studio (Protocollo 95/16) aveva l’obiettivo di verificare la tollerabilità e l’efficacia in termini di risposte obiettive in pazienti affetti da carcinoma gastrico metastatico trattati con LY231514 (pemetrexed), nonchè di valutare l’influenza dei folati sulla tossicità mediante la misurazione delle vitamine a livello plasmatico.

Sono stati arruolati 36 pazienti.

Lo studio ha dimostrato una promettente attività del pemetrexed nei pazienti affetti da carcinoma gastrico avanzato, con discreta tollerabilità, quando associato all’acido folico.

Centri partecipanti :                     Istituto Nazionale Tumori, MILANO

Ospedale S. Raffaele, MILANO

Ospedale S. Luigi Gonzaga, ORBASSANO

Ospedale S. Chiara, PISA

Ospedale G. Rummo, BENEVENTO

Centro Oncologico G. Porfiri, LATINA

Ospedali Riuniti, BERGAMO


Riferimenti Bibliografici:

  • Pemetrexed in gastric cancer: clinical experience and future perspectives.
    (Celio L, Buzzoni R, Longarini R, Marchianò A, Bajetta E).
    Semin Oncol. 2002 Dec;29(6 Suppl 18):63-8.

    The development of more effective and convenient chemotherapy regimens for the treatment of gastric cancer that incorporate novel agents remains an exciting area of research. A phase II study was conducted to assess the response rate and toxicity profile of pemetrexed, a novel multitargeted antifolate, in previously untreated patients with measurable, advanced, or metastatic adenocarcinoma of the stomach or gastroesophageal junction. In this study, pemetrexed-induced toxicity at the starting dose of 500 mg/m(2) intravenously once every 21 days was considerable with each of the first six patients who experienced at least one episode of grade 3/4 toxicity. Two patients discontinued from study, and two patients died. All deaths were caused by drug-related toxicity. No responses were seen in this briefly treated group. These observations led to an amended study protocol designed to improve tolerability of pemetrexed with folic acid supplementation. Supplementation with folic acid 5 mg was given orally once daily for 2 days before pemetrexed on the day of treatment, and for 2 days following treatment. Tumor evaluation was performed after every two cycles of therapy. The trial was recently closed to accrual and preliminary clinical results are reported here. Thirty-two patients were enrolled and 30 patients were evaluable for efficacy. A total of 129 courses of pemetrexed were administered, and the median number of courses received per patient was four (range, one to eight courses). Two complete and five partial responses were observed, with four patients experiencing stable disease. In an intent-to-treat analysis, the overall response rate was 22%, and 23% for the evaluable patients. Median duration of response was 4.4 months (range, 3 to 11 months) and median time to treatment failure was 2.6 months (range, 0.5 to 12 months). Of the 32 patients treated, eight experienced grade 4 neutropenia and one had grade 4 thrombocytopenia. The most common nonhematologic toxicities were diarrhea, fatigue, mucositis, nausea and vomiting, skin rash, and reversible abnormalities in liver function. There was no case of nonhematologic grade 4 toxicity. Although the clinical experience with pemetrexed in advanced gastric cancer remains limited, the promising activity observed in this study indicates that combination studies are warranted. In addition, high-dose intermittent oral folic acid given in this study allowed administration of pemetrexed at the dose and schedule explored with a highly satisfactory safety profile and with no apparent compromise in efficacy. This article discusses how pemetrexed may be investigated in future clinical trials in gastric cancer.

    PMID: 12571814   [PubMed – indexed for MEDLINE]

  • Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer.
    (Bajetta E, Celio L, Buzzoni R, Ferrari L, Marchianò A, Martinetti A, Longarini R, Becerra C, Ilardi C, John W).
    Ann Oncol. 2003 Oct;14(10):1543-8.

    The aim of this study was to assess the activity of pemetrexed in patients with advanced gastric cancer.

    Thirty-eight eligible patients (median age 60 years) received pemetrexed 500 mg/m(2) every 3 weeks. Since toxicity was considerable in the first six patients, the protocol was amended to supplement subsequent patients with oral folic acid (5 mg/day on days -2 to +2 of every cycle).

    Among 36 stage IV patients evaluable for efficacy (six non-supplemented\30 supplemented), there were two complete and six partial responses. The response rate was 21% (95% confidence interval 8% to 32%) according to intention-to-treat analysis. All responding patients were in the supplemented group. The median duration of response was 4.6 months and the median survival was 7.8 months. Five of six non-supplemented patients (83%) developed grade 3/4 neutropenia; two (33%) unsupplemented patients discontinued; two (33%) patients died due to toxicity. In the supplemented group, 12 of 32 patients (37%) had grade 3/4 neutropenia. None of the supplemented patients discontinued treatment due to hematological toxicity. Severe non-hematological toxicities were infrequent.

    The activity of pemetrexed is promising in light of the tumor burden in these patients (all patients were stage IV and 39% had three or more organs involved). Toxicities were remarkably decreased with folic acid supplementation. Combination studies are warranted.

    PMID: 14504056   [PubMed – indexed for MEDLINE]

    Download articolo: Ann Oncol. 2003