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© 2003 American Society for Clinical Oncology A Phase I Study of Irinotecan As a 3-Week Schedule in Children With Refractory or Recurrent Solid Tumors
From the Department of Pediatric Oncology, Institut Gustave Roussy, and UPRES EA3535 Pharmacology and New Treatments of Cancer, Institut Gustave Roussy, Villejuif, France; the Departments of Pediatric Oncology and Biostatistics, Institut Curie, and Aventis Pharma SA, Paris, France; and the Department of Pediatric Oncology, Centre Léon Bérard, Lyon, France. Address reprint requests to Gilles Vassal, MD, PhD, Department of Pediatrics, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: gvassal{at}igr.fr.
Purpose: A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors. Patients and Methods: Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts. Results: One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean ± standard deviation (SD) CPT-11 plasma clearance was 20.7 ± 9.5 L/h/m2 (range, 5 to 54). The mean ± SD SN-38 metabolic ratio was 1.5% ± 1.1% (range, 0.15% to 5.55%). Conclusion: The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.
IRINOTECAN (CPT-11) is an S phase–specific derivative of camptothecin, which interferes with DNA replication and cell division inhibiting topoisomerase I.1 In vivo, CPT-11 undergoes de-esterification by carboxylesterase to an active metabolite, SN-38 (7-ethyl, 10-hydroxy camptothecin), that contributes significantly to the antitumor activity of the drug. SN-38 subsequently undergoes conjugation to form SN-38 glucuronide.1 The use of new cytotoxic agents in children is mainly based on preclinical data from xenograft models and evaluations in adults.2 Substantial antitumor activity was observed in experimental tumor models1,3–7 including xenografts derived from pediatric tumors such as neuroblastoma, rhabdomyosarcoma, peripheral primitive neuroectodermal tumor, and CNS tumors.5–7 Moreover, topoisomerase I activity has been retrieved in neuroblastomas and medulloblastomas. In neuroblastoma, N-myc amplification, which is a factor of poor prognosis in children, was shown to be significantly associated with high levels of topoisomerase I.8,9 Thus, topoisomerase I seemed to be an interesting therapeutic target for malignant pediatric tumors. CPT-11 had been approved in a majority of countries worldwide for second-line treatment in adult patients with advanced colorectal cancer after fluorouracil-based therapy, and in first-line treatment associated with fluorouracil and folinic acid.10 In Europe, the recommended schedule of administration of CPT-11 as a single agent in adult patients is one intravenous (IV) infusion every 3 weeks at a dose of 350 mg/m2.11 This 3-week schedule was retained because it allowed the highest dose-intensity with the least toxicity and was convenient for outpatient use.12 In this article, we present the clinical and main pharmacokinetic results of a phase I trial of CPT-11 administered as a 120-minute IV infusion every 3 weeks in pediatric patients with refractory or recurrent solid tumors. The objectives of the study were to define the maximum-tolerated dose of CPT-11 for this schedule of administration and to recommend a safe dose for phase II testing. The toxicity profile, the plasma pharmacokinetics of CPT-11 and its major metabolite SN-38, and the antitumor activity were also documented according to this 3-week schedule in children.
Patient Eligibility Eligible patients were required to have cytologically and/or histologically confirmed diagnosis of malignant solid tumor (except for brainstem tumors, with clinical and radiological diagnosis), be refractory or in relapse after standard treatment, and/or be among those for whom no effective treatment was available. Two separate cohorts included less heavily pretreated (cohort 1) and heavily pretreated (cohort 2) patients, as defined by prior craniospinal irradiation and/or high-dose chemotherapy with stem cell rescue. Patients with bone marrow involvement were eligible for the study and assessable for hematotoxicity. Patients were to be between 6 months and 18 years of age, with a National Cancer Institute (NCI) performance status of 2 or less and a life expectancy greater than 6 weeks. Patients were required to have adequate blood cell counts (ie, polynuclear neutrophils > 1,500/mm3 [cohort 1], or > 1,000/mm3 [cohort 2]; and platelets > 100,000/mm3 [cohort 1], or > 75,000/mm3 [cohort 2]) except in case of bone marrow involvement, satisfactory hepatic function (ie, bilirubin  1.5 x the upper limit of normal [ULN] in the presence of hepatic metastases, or otherwise 1.25 x ULN; transaminases 2.5 x ULN), normal renal function, and no radiotherapy or chemotherapy within the last 4 weeks before study entry (6 weeks for nitrosoureas). Exclusion criteria comprised severe gastrointestinal pathology, symptomatic or evolutive intracranial hypertension, and prior abdominal or bowel irradiation exceeding 20 Gy. Before study enrollment, complete medical history and clinical examination, concomitant treatments, performance status, hematologic and biochemical profile, ECG, chest x-ray, and tumor target assessment were performed. Qualitative and quantitative analysis of the microbial agents present in stools was performed in order to guide the choice of antibiotics when needed. The study was conducted in accordance with Good Clinical Practice standards and was approved by the local ethics committee. The parents or legal representative provided a written informed consent, and patient’s assent was obtained when appropriate.
Treatment In case of grade 3 or 4 toxicity (except alopecia or nausea/vomiting) during a cycle, the next cycle was to be delayed, and/or, the dose of CPT-11 was to be reduced to the next lowest dose level according to the encountered toxicity. In case of febrile neutropenia or grade 4 neutropenia lasting more than 7 days, the dose at the following cycle had to be that of the lower level. In case of reoccurrence despite dose reduction, the treatment had to be stopped. If blood cell count at day 21 was less than 1,000/mm3 for neutrophils or less than 100,000/mm3 for platelets, the next CPT-11 cycle was delayed by 1 or 2 weeks at the same dose. In case of no recovery on day 35, the treatment was terminated, and the patient was withdrawn from the study. In case of severe delayed diarrhea (grade 3 to 4 lasting > 2 weeks despite adequate treatment), CPT-11 was stopped, and the patient withdrawn from the study. Treatment was also stopped in case of disease progression. Concomitant treatments included atropine (20 µg/kg) for cholinergic symptoms (up to the dose level of 350 mg/m2, atropine was administered on curative intent after the first infusion and on prophylactic intent for subsequent cycles; from dose levels of 420 mg/m2, all patients received atropine prophylactically) and 5-HT3 receptor antagonists as antiemetic treatment. Delayed diarrhea was treated using acetorphan, the enkephalinase inhibitor that was recently shown to be an effective and safe treatment of acute diarrhea in children.13,14 Acetorphan was orally administered as curative treatment, at 1.5 mg/kg every 8 hours as soon as the first liquid stool occurred. Corticosteroids, at a dose of 1.5 mg/kg/d or lower, were allowed for a purpose other than antiemetic treatment if the dose was stable for at least seven days.
Study Design DLT was defined for both cohorts as the occurrence of the following: grade 4 neutropenia or thrombocytopenia persistent more than 7 days; delayed grade 3 to 4 diarrhea (despite appropriate treatment for more than 48 hours or requiring hospitalization for rehydration); any nonhematologic and nondigestive grade 4 toxicity (except alopecia); any nonhematologic grade 3 toxicity (except vomiting in absence of adequate treatment, transient hepatic toxicity, fever without infection, or mucositis); a grade 4 infection; or any life-threatening or fatal toxicity.
Toxicity and Response Evaluation
Pharmacokinetics Pharmacokinetic analyses were performed using APIS (MIIPS, Marseille, France) and WinNonlin (Scientific Consulting Inc, Cary, NC) softwares. CPT-11 plasma concentration-versus-time curves were analyzed using both compartmental and noncompartmental methods. The following parameters were calculated: area under the plasma concentration–time curve (AUC) up to the last measured data point by the trapezoidal method, AUC extrapolated to infinity, half-lives, volume of distribution at steady state, and body clearance. For SN-38, the maximal concentration, the time required to reach it, the AUC (determined using the trapezoidal method), and elimination half-life were determined. The extent of metabolism of CPT-11 to SN-38 in plasma was expressed by a metabolic ratio value, defined as the ratio of the SN-38 AUC, over the CPT-11 AUC.
Statistical Analysis
Patient Characteristics Between April 1996 and December 1999, 81 patients were included in the study, in three French centers, and with 48 patients in the less heavily pretreated cohort 1 and 33 patients in the heavily pretreated cohort 2. All patients were eligible except for one patient in cohort 2 who presented with grade 4 thrombocytopenia (in absence of any bone marrow involvement) at study entry. Patients’ characteristics at inclusion are summarized in Table 1  . Compared with cohort 1 patients, patients in cohort 2 presented diminished chances of hematologic recuperation, having received prior cerebrospinal irradiation in 24% (n = 8) and high-dose chemotherapy with autologous stem cell transplantation in 76% (n = 25). Concomitant treatments included paracetamol in 41 patients (51%), and corticosteroids in 37 patients (46%). Few patients received antiepileptics (n = 4) or known CYP3A4 inhibitors (n = 4).
MTD In cohort 1, 122 cycles were administered, with a median of two cycles (range, one to nine cycles) at dose levels ranging from 200 to 720 mg/m2. The main DLTs reported on first cycle (from the 500 mg/m2 to 720 mg/m2 dose levels) were grade 3 and grade 4 delayed diarrhea, grade 3 neutropenia infection, grade 3 cholinergic syndrome (despite atropine treatment), and grade 3 cardiac failure (Table 2 ). The patient with the latter toxicity was heavily pretreated with anthracyclines (cumulative dose of 400 mg/m2 epirubicin) and left thoracic irradiation (24 Gy). Three of six patients experienced DLT at the 720 mg/m2 dose level. The recommended dose for less heavily pretreated children was subsequently defined as 600 mg/m2.
Eighty-one cycles were administered in cohort 2, with a median of 2 cycles (range, one to eight cycles) at dose levels ranging from 200 to 600 mg/m2. The DLT reported on first cycle (from the 350 mg/m2 dose level) was one case of persistent grade 4 neutropenia occurring in the ineligible patient (Table 2  ). This DLT was not taken into consideration for dose escalation. One case of grade 3 nausea/vomiting, despite adequate preventive treatment, was described at a dose level of 500 mg/m2. At the dose level of 600 mg/m2, two patients experienced persistent grade 4 neutropenia. Considering the results obtained in cohort 1 and according to CRM, dose escalation was stopped, and 600 mg/m2 was considered to be the recommended dose in heavily pretreated children.
Compliance to Treatment In cohort 2, the percentage of cycles delayed for between 4 and 7 days was 17% (8 of 48 cycles), and a reduction of dose was performed in 2% (1 of 48 cycles; due to hematologic toxicity). The most frequent reasons for treatment delay were toxicity not related to study drug (four cycles) and hematologic toxicity (three cycles). In both cohorts, the median relative dose-intensity was excellent, and comprised between 90% and 100% of the planned dose-intensity regardless of the dose level.
Hematologic Toxicity
Nonhematologic Toxicities Acute cholinergic syndrome. Cholinergic syndrome (as described in Table 4 ) was encountered at all dose levels. The events were generally mild or moderate. In cohort 1, grade 3 cholinergic syndrome occurred in four patients at 350, 500, and 720 mg/m2 dose levels (8%) and in four cycles (3%). Occurrences included abdominal cramps (one cycle at 350 and one cycle at 500 mg/m2), early diarrhea (one cycle at 720 mg/m2), and visual disturbances (one cycle at 720 mg/m2). No grade 3 or 4 toxicity occurred in cohort 2 (Table 4). Preventive atropine, which was administered systematically from dose level 420 mg/m2 and above, might explain the relatively low incidence or absence of severe events.
Delayed diarrhea. In cohort 1, delayed diarrhea occurred in 32 patients (67%) and 54 cycles (44%). Hospitalization was necessary in 11 patients and 12 cycles, with a median duration of 4.5 days (range, 1 to 12 days); only three patients had to receive an intravenous rehydration. Grade 3 to 4 delayed diarrhea occurred in seven patients (15%) and seven cycles (6%; Table 5 ).
In cohort 2, delayed diarrhea occurred in 21 patients (64%) and 34 cycles (42%). Hospitalization was necessary in three patients and three cycles, with a median duration of 4 days (range, 1 to 4); two patients had to receive an intravenous rehydration. Two patients (6%) experienced two cycles (2.5%) of grade 3 to 4 toxicity (Table 5 ). Grade 3 to 4 delayed diarrhea occurred from the 350 mg/m2 level in both cohorts, and frequency increased with the administered dose with a more marked increase in patients of the first cohort (Table 5). However, the duration of episodes remains stable and relatively short, with a median duration of 1 day in both cohorts (range, 1 to 9 days in cohorts 1 and 2). In both cohorts, the daily dose of acetorphan administered was inferior to that recommended (4.5 mg/kg/d) with a median dose of 1.5 mg/kg/d (range, 0 to 7.5 mg/kg) in cohort 1, and 1.6 mg/kg/d (range, 0 to 8.6 mg/kg) in cohort 2.
Other toxicities.
In cohort 1, the main other nonhematologic toxicities related to the study drug included nausea/vomiting (79% of patients and 66% of cycles), asthenia (75% of patients and 57% of cycles), alopecia (50% of patients, 48% of cycles), and abdominal cramps not linked to cholinergic syndrome or diarrhea (40% of patients, 26% of cycles). Grade 3 to 4 adverse events included nausea/vomiting (7% of cycles), asthenia (7% of cycles), and abdominal cramps (3% of cycles; Table 5
In cohort 2, the other main, related, nonhematologic adverse events included nausea/vomiting (79% of patients; 63% of cycles), asthenia (67% of patients; 48% of cycles), abdominal cramps not linked to cholinergic syndrome or diarrhea (45.5% of patients; 20% of cycles), and alopecia (36% of patients; 43% of cycles). Grade 3 to 4 events remained uncommon; included nausea/vomiting, asthenia (three cycles), and abdominal cramps (one cycle; Table 5
Pharmacokinetics
Efficacy Partial responses (confirmed and not confirmed) were noted at the dose level of 600 mg/m2 in one high grade glioma, one rhabdomyosarcoma, one neuroblastoma, and one medulloblastoma and persisted for four, five, nine, and 28 courses, respectively (Table 7 ). Actually, the last patient treated in the study experienced a partial response after two courses (medulloblastoma) and did continue the treatment after the study cutoff for 25 additional courses until disease progression. Twenty-one patients presented minor response or stable disease at all dose levels with 14 patients in cohort 1 and seven patients in cohort 2. Eight patients had a stable disease that persisted for five to nine courses. These were mainly observed with neuroblastoma (n = 2), high-grade glioma (n = 2), ependymoma (n = 2), medulloblastoma (n = 1), and desmoplastic round cell tumor (n = 1).
The primary goal of this phase I trial was to determine the MTD of CPT-11 administered intravenously every 3 weeks to children with refractory or recurrent solid tumors. Eighty-one children were included in the study, with brain tumors and neuroblastoma as predominant tumor types. Two separate cohorts included less heavily (48 patients), and heavily (33 patients) pretreated patients as defined by previous cerebrospinal irradiation and/or high-dose chemotherapy with autologous stem cell rescue. Myelosuppression was dose limiting in the heavily pretreated patients, and delayed diarrhea was dose limiting in the less heavily pretreated children. No difference was observed between the 120- and 60-minute durations of infusion at the MTD. Thus, the recommended phase II dose of CPT-11 as a 3-week schedule is 600 mg/m2 administered as a 60-minute infusion for less heavily, and heavily pretreated children with solid tumor. CPT-11 has been developed according to different schedules in adults and in children in Europe and in the United States. In a previous phase I study18 in adults (N = 64) following the same schedule of 30-minute infusion every 3 weeks, dose escalation reached levels of 750 mg/m2. Delayed diarrhea was one of the limiting toxicities from dose level 350 mg/m2, but could be easily dealt with allowing high-dose loperamide to reach subsequent levels. Neutropenia then seemed to be dose limiting, with increased severity at higher doses and 100% of patients suffering from grade 4 neutropenia at 750 mg/m2. The MTD was then defined as having a 600-mg/m2 dose level, with a recommended dosage of 350 mg/m2 for safety reasons. The author mentioned that a higher dose of 500 mg/m2 could be recommended in good-risk patients with careful monitoring of gastrointestinal toxicities. This was confirmed in the feasibility study from Merrouche et al,19 which evaluated high-dose CPT-11. The recommended dose of CPT-11 seemed higher in our study, with similar types of toxicities encountered. The incidences of grade 3 to 4 neutropenia were comparable between adult and pediatric patients, but the incidence of nonhematologic toxicities seemed to be lower in children, especially for grade 3 to 4 delayed diarrhea (11% in the 81 children in the present study, compared with 19% in the 64 adults treated with high-dose loperamide). In the feasibility study of high-dose-intensity of CPT-11, performed by Merrouche et al,19 this difference in the incidence of delayed diarrhea was confirmed. At the dose of 600 mg/m2, 50% of adult patients (9 of 18) experienced grade 3 to 4 diarrhea, versus 15% of children (4 of 26) in the present study. The physiopathology of the CPT-11–induced delayed diarrhea remains unclear, involving both secretory and exsudative mechanisms. In addition, the treatment in adults is based on early administration of high doses of loperamide.20 Delayed diarrhea seemed less severe, had a shorter duration of episodes in children, and was well controlled with the orally administered enkephalinase inhibitor, acetorphan. Moreover, in the majority of children, the daily dose of acetorphan was clearly inferior to that recommended by the protocol. As acetorphan is not available in all countries, loperamide is currently evaluated for use in children in phase II studies. Cholinergic syndrome was well controlled by atropine treatment. No patient exhibited grade 4 toxicity, and only four patients experienced a grade 3 in cohort 1. In the same way, nausea/vomiting was well controlled with antiemetic treatment. One patient of the first cohort experienced a grade 3 cardiac failure after the first cycle with CPT-11 500 mg/m2. This patient, who had nephroblastoma, previously received a cumulative dose of epirubicin of 400 mg/m2 and a left thoracic irradiation at 24 Gy, and it was probable that subclinical cardiac toxicity was not detected at inclusion. Therefore, this cardiac toxicity seems to be the more likely cause of symptomatic left ventricular ejection function decrease and cardiac failure in this 13-year-old patient, than the therapy with CPT-11. No case of cardiotoxicity was noted in other clinical trials either in adult or in pediatric patients. Concerning pharmacokinetic parameters, the mean ± SD plasma clearance of CPT-11 observed in children (20.7 ± 9.5 L/h/m2) was higher than the mean value (15.0 L/h/m2) reported in adult patients treated using the same schedule, at doses ranging from 100 to 750 mg/m2.18 Mean plasma levels of SN-38 ranged from 15 to 286 ng/mL in children, and from 32 to 299 ng/mL in adults.18 The SN-38 metabolic ratio (mean, 1.5%; individual range, 0.15% to 5.55%) was lower than in adults treated following the same 3-week schedule (mean, 3%).18 The SN-38 metabolic ratio appeared low when compared with the ratio reported in children treated according to a protracted schedule, as reported by Ma et al.21 However, the absolute systemic exposures to SN-38 cannot be compared since Ma et al quantified lactone forms of CPT-11 and metabolites, whereas total compound forms were measured in the present study. CPT-11 disposition seems to be different in children and adults, and to occur according to the schedule of administration. However, the metabolism of CPT-11 may be influenced by coadministration of drugs metabolized by the same enzymes (CYP3A4 and UDPGT), as previously described, in adult or pediatric glioma patients.22,23 In this study, almost half the children (46%) received corticosteroids, but very few patients received antiepileptics or CYP3A4 inhibitors. The safety profile of CPT-11 in children treated in this study on a 3-week schedule was similar to that reported in children treated with protracted dosing schedules (ie, daily for 5 consecutive days, every 21 days,24 daily x2 for 5 days every 21 days,25 or daily for 3 consecutive days every 25 days26) with diarrhea and myelosuppression being the predominant toxicities. In the phase I trial evaluating a 60-minute IV infusion of CPT-11 administered daily for 5 days every 21 days in 35 patients, myelosuppression was dose-limiting in heavily pretreated patients at 50 mg/m2/dose, and diarrhea was dose-limiting in less heavily pretreated children at 65 mg/m2/dose.24 Grade 4 neutropenia occurred in 20% of overall patients, and grade 4 thrombocytopenia occured in less than 15% of patients. Grade 3 diarrhea occurred in 17% of patients. In the phase I trial evaluating a 60-minute IV infusion of CPT-11 at 20, 24, and 29 mg/m2 (qdx5) x2 every 21 days in heavily pretreated children,25 the DLT was grade 3 to 4 diarrhea and/or abdominal cramps at 24 mg/m2 despite aggressive use of loperamide. Neutropenia grade 3 to 4 occurred in 11% of cycles and no case of severe thrombocytopenia was observed. Grade 3 to 4 diarrhea occurred in 39% of patients and 11% of cycles. In the Japanese phase I study which evaluated 2-hour infusion of CPT-11 at 50 to 200 mg/m2 administered during 3 consecutive days every 25 days in 28 patients, grade 4 hematopoietic toxicity occurred in 23.5% of 3-day courses of CPT-11 and grade 3 diarrhea in 11.8% of 3-day courses.26 Although tumor response was not the primary end point of this study, the antitumor activity was very encouraging, especially when considering pretreatment of these children. Four patients had partial response and 21 patients had minor response or stable disease over the 79 assessable patients. The objective responses were observed in patients with high grade glioma, neuroblastoma, rhabdomyosarcoma or medulloblastoma. This latter patient had followed CPT-11 treatment after the study enclosure (until 28 cycles) and the disease remained stable during 2 years. These results were in accordance with preclinical data obtained in xenograft models of pediatric tumors.5–7 CPT-11 was shown to be highly effective on rhabdomyosarcoma, neuroblastoma and medulloblastoma xenografts. In the five-day course of CPT-11, two partial responses (one neuroblastoma and one hepatocellular carcinoma) were observed in 35 children with refractory solid tumors,24 whereas five patients over the 23 treated with the two times 5-day course underwent partial responses.25 In the Japanese study, four partial responses (three neuroblastoma and one leiomyosarcoma) were noted out of 28 children.26 The heterogeneity of the types of solid tumors and of the prior therapies in children of phase I trials does not allow to draw any conclusion in terms of optimal schedule of administration. In summary, CPT-11 administered as a single infusion every 3 weeks is well tolerated in children with recurrent or refractory solid tumors. The dose limiting toxicities of CPT-11 differ according to pretreatment of children, with neutropenia as DLT in heavily pretreated patients and delayed diarrhea as DLT in less heavily pretreated patients. A prospective multicenter European phase II trial is currently ongoing in children with neuroblastoma, rhabdomyosarcoma, or CNS primitive neuroectodermal tumor (medulloblastoma and supratentorial) using CPT-11 administered as a 60-minute IV infusion every 3 weeks at the recommended dose of 600 mg/m2.
The authors indicated no potential conflicts of interest.
We thank Maryse Berlion for preparing and editing the manuscript.
Presented at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15–18, 1999.
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13. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, et al: Racecadotril in the treatment of acute watery diarrhea in children. N Engl J Med 343:463–467, 2000 14. Cezard JP, Duhamel JF, Meyer M, et al: Efficacy and tolerability of racecadotril in acute diarrhea in children. Gastroenterology 120:799–805, 2001[CrossRef][Medline] 15. O’Quigley J: Continual Reassessment Method in cancer clinical trials, in Crowley J (ed): Handbook of Statistics in Clinical Oncology. New York, NY, Marcel Dekker, 2001, pp 35–72 16. Rivory LP, Haaz MC, Canal P, et al: Pharmacokinetic interrelationships of irinotecan and its three major metabolites in patients enrolled in phase I/II trials. Clin Cancer Res 3:1261–1266, 1997[Abstract]
17. Santos A, Zanetta S, Cresteil T, et al: Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 6:2012–2020, 2000
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25. Furman WL, Stewart CF, Poquette CA, et al: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815–1824, 1999 26. Mugishima H, Matsunaga T, Yagi K, et al: Phase I study of irinotecan in pediatric patients with malignant solid tumors. J Pediatr Hematol Oncol 24:94–100, 2002[CrossRef][Medline] Submitted August 29, 2002; accepted July 28, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% for at least 4 weeks. Stable disease was defined as a regression of the tumor size lower than 50%, or progression less than 25%; and minor response was defined as a regression of the tumor between 25% and 50%. Progressive disease comprised all stages not already defined, including the appearance of any new lesion. 
, AUC extrapolated to infinity. AUC values reported as ng.h/mL.
