{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:40:28Z","timestamp":1791193228353,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[1995,1]]},"abstract":"PURPOSE<\/jats:title> A phase I study was undertaken to determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacokinetics of the novel topoisomerase I inhibitor irinotecan (CPT-11). <\/jats:p><\/jats:sec>PATIENTS AND METHODS<\/jats:title> Sixty-four patients meeting standard phase I eligibility criteria were included (24 women, 40 men; median age, 51 years; primary sites: colon, head and neck, lung, pleura; 60 of 64 had been previously treated). Pharmacokinetics was determined by high-performance liquid chromatography (HPLC). <\/jats:p><\/jats:sec>RESULTS<\/jats:title> One hundred ninety CPT-11 courses were administered as a 30-minute intravenous (IV) infusion every 3 weeks (100 to 750 mg\/m2). Grade 3 to 4 nonhematologic toxicities included diarrhea (16%; three hospitalizations), nausea and vomiting (9%), asthenia (14%), alopecia (53%), elevation of hepatic transaminases (8%), and one case of skin toxicity. An acute cholinergic syndrome was observed during CPT-11 administration. Diarrhea appeared dose-limiting at 350 mg\/m2, but this was circumvented by using a high-dose loperamide protocol that allowed dose escalation. Dose-dependent, reversible, noncumulative granulocytopenia was the dose-limiting toxicity (nadir, days 6 to 9; median recovery time, 5 days). Grade 3 to 4 anemia was observed in 9% of patients. One patient died during the study, 8 days after CPT-11 treatment. Two complete responses (cervix, 450 mg\/m2; head and neck, 750 mg\/m2) and six partial responses in fluorouracil (5-FU)-refractory colon cancer were observed (260 to 600 mg\/m2). Pharmacokinetics of CPT-11 and active metabolite SN-38 were performed in 60 patients (94 courses). CPT-11 plasma disposition was bi- or triphasic, with a mean terminal half-life of 14.2 +\/- 0.9 hours (mean +\/- SEM). The mean volume of distribution (Vdss) was 157 +\/- 8 L\/m2, and total-body clearance was 15 +\/- 1 L\/m2\/h. The CPT-11 area under the plasma concentration versus time curves (AUC) and SN-38 AUC increased linearly with dose. SN-38 plasma decay had an apparent half-life of 13.8 +\/- 1.4 hours. Both CPT-11 and SN-38 AUCs correlated with nadir leukopenia and granulocytopenia, with grade 2 diarrhea, and with nausea and vomiting. <\/jats:p><\/jats:sec>CONCLUSION<\/jats:title> The MTD of CPT-11 administered as a 30-minute IV infusion every 3 weeks is 600 mg\/m2, with granulocytopenia being dose-limiting. At 350 mg\/m2, diarrhea appeared dose-limiting, but high-dose loperamide reduced this toxicity and allowed dose escalation. For safety reasons, the recommended dose is presently 350 mg\/m2 every 3 weeks; more experience must be gained to establish the feasibility of a higher dose in large multicentric phase II studies. However, when careful monitoring of gastrointestinal toxicities is possible, a higher dose of 500 mg\/m2 could be recommended in good-risk patients. The activity of this agent in 5-FU-refractory colorectal carcinoma makes it unique and mandates expedited phase II testing. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.1995.13.1.210","type":"journal-article","created":{"date-parts":[[2017,2,23]],"date-time":"2017-02-23T13:24:36Z","timestamp":1487856276000},"page":"210-221","source":"Crossref","is-referenced-by-count":227,"title":["Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients."],"prefix":"10.1200","volume":"13","author":[{"given":"D","family":"Abigerges","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G G","family":"Chabot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J P","family":"Armand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"H\u00e9rait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Gouyette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Gandia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.1995.13.1.210","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T19:57:36Z","timestamp":1653508656000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.1995.13.1.210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,1]]},"references-count":0,"journal-issue":{"issue":"1","published-print":{"date-parts":[[1995,1]]}},"alternative-id":["10.1200\/JCO.1995.13.1.210"],"URL":"https:\/\/doi.org\/10.1200\/jco.1995.13.1.210","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,1]]}}}