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

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). © 2000 Cancer Research Campaign