Phase I Study of Weekly Intravenous Infusions of CPT-11, a New Derivative of Camptothecin, in the Treatment of Advanced Non-Small-Cell Lung Cancer

Abstract

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

Randomised phase III trial of irinotecan combined with cisplatin for advanced non-small-cell lung cancer

“…The phase I clinical trial of CPT-11, in which CPT-11 was administered weekly, showed that the dose-limiting adverse effects were leucopenia and diarrhoea, and the recommended dose for the phase II monotherapy trial was 100 mg m À2 week À1 (Negoro et al, 1991). In the phase II clinical trial of CPT-11 monotherapy for patients with untreated advanced NSCLC, the response rate was 31.9% (23 out of 72 cases) and the MST was 42 weeks (Fukuoka et al, 1992).…”

Clinical Observations on Associations Between the UGT1A1 Genotype and Severe Toxicity of Irinotecan

“…Modified FOLFIRI regimen was used every14 days, the others were every 21days. Because toxicity of irinotecan results in leukopenia and diarrhea is dose-limiting (Negoro et al, 1991), once patients occurred grade IV toxicity, the dosage would be adjusted next chemotherapy. No restriction was put on whatever the previous chemotherapy regimens course CPT-11 in patients according to their basic clinic characters and their UGT1A1 genotypes.…”

“…Because CPT-11 causes severe diarrhea and neutropenia in 20% to 35% of patients treated (Negoro et al, 1991;Rothenberg, et al, 1993;Rougier et al, 1998;Saltz et al, 2000;Rothenberg et al, 2001;Vanhoefer et al, 2001;Fuchs et al, 2003), and fatal events (up to 5.3% prevalence) during single-agent irinotecan treatment have been reported (Vanhoefer et al, 2001). We associated these two kind side effects with UGT1A1 genotypes, clinic characters and each other to detect the relationship between them by multivariate logistic analysis We took the sex, age, KPS, number of metastasis, history of chemotherapy, UGT1A1 genotype, dosage, leucopenia, neutropenia, primary cancer and pathological type into risk factors.…”

“…Irinotecan (CPT-11) is an S-phase-specific, semisynthetic derivative of camptothecin that interferes with DNA replication and cell division by inhibiting topoisomerase I (Fukuoka et al, 1992) and is now used widely, especially for colorectal and lung cancers (Negoro et al, 1991;Cunningham, et al, 1998;Kudoh et al, 1998;Rougier et al, 1998;Masuda et al, 1999;Uygun et al, 2013;Wei et al, 2013;Wu et al, 2013;Bozkurt et al, 2014;Zhang et al, 2014). Although it prolongs survival, patients who treated with chemotherapy include irinotecan is often accompanied by unpredictable and sever side effects.…”

“…Although it prolongs survival, patients who treated with chemotherapy include irinotecan is often accompanied by unpredictable and sever side effects. It causes severe diarrhea and neutropenia in 20% to 35% of patients treated (Negoro et al, 1991;Rothenberg et al, 1993;Rougier et al, 1998;Saltz et al, 2000;Othenberg et al, 2001;Vanhoefer et al, 2001;Fuchs et al, 2003). Fatal events (up to 5.3% prevalence) during single-agent irinotecan treatment have been reported (Vanhoefer et al, 2001).…”