A Phase I/II Study of Trimetrexate and Capecitabine in Patients With Advanced Refractory Colorectal Cancer

Abstract

The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting.

Molecular basis of antifolate resistance

“…Rationally-designed, novel generation antifolates also include potent TS inhibitors such as raltitrexed (Tomudex; ZD1694) [5] that have been approved for the treatment of advanced colorectal cancer [6] as well as pemetrexed (Alimta; MTA, LY231514) [7] that was registered in both the USA and Europe for the treatment of malignant pleural mesothelioma [8] and non-small cell lung cancer [9]. Additionally, other hydrophilic and lipophilic antifolates have been synthesized that are currently undergoing clinical evaluation as antitumor agents including the lipid-soluble antifolates nolatrexed (Thymitaq; AG337) [26], neutrexin (trimetrexate) [27] and piritrexim (BW301U [28], the polyglutamatable hydrophilic TS inhibitor OSI-7904(L) (GW1843U89) [29] as well as the non-polyglutamatable TS inhibitor plevitrexed (BGC9331; ZD9331) [30]. Antifolates including raltitrexed, pemetrexed, OSI-7904(L) and plevitrexed were rationally designed to be efficiently taken up by the reduced folate carrier (RFC), the primary transport system of both THF cofactors and antifolates (Fig 3; see the next section).…”

A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

“…Combination with MMC resulted in a response rate of 15% in irinotecan-resistant cancer, but its efficacy fell to 5% when the cancer was resistant to both irinotecan and oxaliplatin. Other combinations with trimetrexate or irinotecan did not show any additional benefit either (Chong et al, 2005;Gubanski et al, 2005;Matin et al, 2005).…”

“…Currently, chemotherapeutic option for these patients is quite limited. Cetuximab is regarded to be a promising option in this setting, and capecitabine is under study of alternative dosing method for use in combination regimens, and investigational agents such as bevacizumab have been tried restrictively for selected patients (Cunningham et al, 2004;Saltz et al, 2004;Gubanski et al, 2005;Matin et al, 2005).…”

What’s the news about antimetabolites in oncology?

“…1), cinq essais cliniques sont enregistré s aux É tats-Unis et en Amé rique du Sud, dans le traitement de l'osté osarcome, du cancer du cô lon, du cancer du pancré as et dans les leucé mies, mais plus aucune inclusion n'est ré alisé e. D'autres associations seraient plus efficaces, en deuxiè me ou troisiè me ligne, que l'association trimé trexate-capé citabine dans le traitement du cancer colorectal [14]. La double modulation du 5-FU par trimé trexate et LV n'entraîne qu'une modeste activité antitumorale [12].…”