Phase I study of irinotecan and raltitrexed in patients with advanced gastrointestinal tract adenocarcinoma

Abstract

To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175-350 mg m-2 followed by raltitrexed 2.6 mg m-2. Level VI was irinotecan 350 mg m-2 plus raltitrexed 3.0 mg m-2, level VII was irinotecan 400 mg m-2 plus raltitrexed 2.6 mg m-2; 261 courses were administered. Only one patient at dose levels I-V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m-2 and raltitrexed 3.0 mg m-2. (C) 2000 Cancer Research Campaign.