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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 563-570 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.2847 Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid TumorsFrom the Departments of Hematology-Oncology, Pharmaceutical Sciences, Biostatistics, and Molecular Pharmacology, St Jude Children's Research Hospital; Departments of Pharmacy and Pharmaceutical Sciences, College of Pharmacy, and Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN; and Miami Children's Hospital, Miami, FL Address reprint requests to Wayne L. Furman, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794l; e-mail: wayne.furman{at}stjude.org
PURPOSE: Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. PATIENTS AND METHODS: In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. RESULTS: Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ngxh/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). CONCLUSION: Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.
Irinotecan is highly active against adult and pediatric tumor xenografts1-3 and colon carcinoma.4 Protracted exposure to irinotecan at low doses increases its therapeutic efficacy and may attenuate its myelotoxicity.1,2,5-8 However, diarrhea occurring during early or late treatment is dose limiting in many phase I studies.6,9-24 The mechanism of the more severe late-onset secretory diarrhea is unknown but may reflect biliary excretion of SN-38, irinotecan's active metabolite. There are two postulated routes of intestinal damage. First, the parent drug may be excreted in bile and activated by intestinal carboxylesterase.25,26 Second, noncytotoxic SN-38 glucuronide (SN-38G) may be excreted in bile and converted back to SN-38 in the gut by bacterial beta-glucuronidase. In animal studies, irinotecan-induced diarrhea is accompanied by cecal and colonic mucosal damage consistent with direct cytotoxicity27; damage is not observed in the duodenum and jejunum, where carboxylesterase activity could convert irinotecan to SN-38. More importantly, beta-glucuronidase activity was highest in cecal contents and negligible in duodenal and jejunal contents.28,29 A combination of penicillin and streptomycin reduced irinotecan-induced cecal damage and diarrhea in these animals.28,29 If irinotecan-induced diarrhea is caused by bacterial deglucuronidation of SN-38G in the intestine, then beta-glucuronidase–producing flora are a plausible target for preventive therapy. We reasoned that an antibiotic active against aerobic beta-glucuronidase–producing organisms (cefixime) would spare the anaerobic flora and be better tolerated by children than the penicillin-streptomycin combination. A prolonged regimen of irinotecan administered at low doses is most amenable to oral administration. We present the results of the first pediatric phase I trial of orally administered irinotecan. We first determined the toxicity and maximum-tolerated dose (MTD) of oral irinotecan administered on a unique schedule derived directly from preclinical studies (a schedule we previously evaluated for intravenous irinotecan).6 We then evaluated whether coadministration of cefixime allows greater escalation of the irinotecan dose and produces SN-38 systemic exposure in children comparable to that achieved with intravenous irinotecan.30 We also report the first bioavailability data for irinotecan administered orally to children.
Eligibility Eligible patients were less than 21 years of age with recurrent solid tumors for which conventional treatment had failed. Other eligibility criteria included the following: a life expectancy of at least 8 weeks, Eastern Cooperative Oncology Group performance status score of  2, recovery from the toxic effects of prior chemotherapy, hemoglobin concentration more than 8 g/dL, absolute neutrophil count more than 1,000/µL, platelet count more than 50,000/µL (unless marrow was infiltrated with tumor), adequate liver function (bilirubin < 1.5x normal and ALT 3x normal), adequate renal function (serum creatinine 3x normal for age), and normal metabolic parameters (serum electrolytes, glucose, calcium, and phosphorus). Patients were ineligible if they had active infection, peptic ulcer disease, any GI condition that could alter motility or absorption, or allergy to cefixime or cefpodoxime or were receiving phenytoin, carbamazepine, or phenobarbital. The study was approved by our institutional review board, and informed written consent was obtained from patients, parents, or guardians, as appropriate.
Drug Formulation and Administration
Treatment and Dose Escalation DLT was defined as grade 4 hematologic toxicity lasting more than 7 days or grade 3 or 4 nonhematologic toxicity in two patients of a cohort of three to six patients. The MTD was defined as the dose immediately below the dose at which the DLT was identified. Only the first course of treatment was used to assess DLT. Courses were repeated at 3-week intervals in the absence of DLT. Patients were removed from the study if progressive disease was noted. Patients who experienced an increase of four or more stools per day over baseline for more than 2 consecutive days during course 1 began receiving oral cefixime 5 days before course 2 began. The irinotecan dose was not reduced for this second course, and cefixime was continued for the duration of study participation. After the MTD of oral irinotecan alone was established, the study was amended to allow subsequent cohorts to receive prophylactic cefixime 8 mg/kg/d (maximum, 400 mg daily) once daily, beginning 5 days before the start of course 1 of irinotecan and continuing daily for the duration of protocol therapy. Cefixime (Suprax; Wyeth, Madison, NJ) is supplied as 200-mg and 400-mg tablets and as a 100 mg/5 mL suspension. Every effort was made to use cefixime. However, if cefixime was not available, patients received cefpodoxime (Vantin; Pfizer) 10 mg/kg/d bid orally, administered as described for cefixime. Cefpodoxime, a third-generation cephalosporin with antibacterial activity like that of cefixime,31,32 comes as scored 100-mg and 200-mg tablets and as a 50 mg/5 mL or 100 mg/5 mL suspension. Because great variability was observed in systemic exposure at each irinotecan dose level in the first part of the study, the dose-escalation increment was increased in the second part of the study (45, 60, and 75 mg/m2/d).
Patient Evaluation Toxicity was assessed by the National Cancer Institute Common Toxicity Criteria (version 2.0). A complete response was defined as complete regression of all appreciable tumor masses, including lesions noted on imaging, and/or clearance of tumor cells from the bone marrow for a period of at least 4 weeks. A partial response was defined as a more than 50% and less than 100% regression of all tumor masses (measured when possible in two diameters) in the absence of any new lesions. A mixed response was defined as a more than 50% reduction in the size of one or more masses, with no progression of other lesions. Stable disease was defined as the absence of complete or partial response and the absence of progressive disease. Progressive disease was defined as a more than 25% increase in the sum of the products of the maximum length and width of indicator lesions or the appearance of new lesions. Responses were classified as such only if they were observed at two or more evaluations separated by at least 4 weeks.
Plasma Sampling and High-Performance Liquid Chromatography Analysis for Pharmacokinetics Studies
Pharmacokinetics Analysis
Fecal Beta-Glucuronidase Activity
Statistical Methods
Patients Forty patients were enrolled. One patient withdrew because of parental preference after treatment with cefixime alone and was not included in the demographic data (Table 1) or pharmacokinetic analyses. Of the remaining 39 patients, 18 were male, and 24 had a normal performance status (Eastern Cooperative Oncology Group score = 0). The predominant diagnoses were brain tumor (n = 13) and neuroblastoma (n = 10). Three patients had fewer than 10 irinotecan doses; one patient stopped after 5 days because of rapid disease progression, one patient receiving 75 mg/m2 stopped irinotecan after 7 days because of severe vomiting (DLT), and one patient stopped after eight doses because the parents changed their decision about participation in the study. The 39 patients received a total of 127 courses of irinotecan at five doses (15, 25, 35, 40, and 45 mg/m2) without cefixime and at three doses (45, 60, and 75 mg/m2) with cefixime. The median number of courses per patient was two (range, one to 23 courses). Most patients had been extensively pretreated; 28 had received two or more multiagent chemotherapy regimens, 30 had received radiation therapy, and 13 had received autologous bone marrow transplantations.
In the first part of the study (without cefixime prophylaxis in course 1), three patients received cefixime with one to four subsequent courses of irinotecan. Diarrhea was not seen with these additional courses. In the second half of the study, using cefixime prophylaxis in an attempt to escalate irinotecan doses, cefpodoxime was substituted for cefixime for eight of 19 patients because of difficulty with the cefixime supply. An additional patient had cefpodoxime substituted for cefixime with her 23rd course of treatment. No patient complained of inability to tolerate cefixime or cefpodoxime. However, one patient at 75 mg/m2 was noncompliant with daily cefixime (Table 2).
Hematologic Toxicity Clinically significant neutropenia (ANC < 500/µL) was seen in only two patients during their second course of therapy (one was neutropenic for 9 days at 40 mg/m2 and one was neutropenic for 6 days at 45 mg/m2). No clinically significant drug-related thrombocytopenia (platelet count < 50,000/µL) was observed in this heavily pretreated group.
Nonhematologic Toxicity An 11-year-old boy with recurrent rhabdomyosarcoma experienced severe cramps, diarrhea, and flushing shortly after his first dose of irinotecan (intravenous, 60 mg/m2). His symptoms resolved with intravenous atropine. He subsequently had grade 3 diarrhea 3 days after completing his 10-day course of irinotecan; it resolved without incident after 5 days. He was found to be noncompliant with his oral treatment regimen (cefixime and loperamide hydrochloride). Narcotic use was examined as an explanation for absence of diarrhea. In addition to cefixime, we adjusted for irinotecan dose and laxative use. There was no evidence that narcotic use was significantly predictive of diarrhea (P = .10; data not shown).
Antitumor Activity
Pharmacokinetics
Pre- and post-treatment stool samples were available for 11 of 19 patients who received cefixime or cefpodoxime for prophylaxis of diarrhea with course 1. Five of these 11 patients received cefixime, and six received cefpodoxime. Mean fecal beta-glucuronidase activity was significantly higher in pretreatment samples (mean, 2.1 µg/mg; SD, 1.7 µg/mg) than in samples obtained after 5 days of antibiotic administration (mean, 0.96 µg/mg; SD, 0.95 µg/mg; P = .037; Fig 2). The mean pretreatment–post-treatment change in fecal beta-glucuronidase activity did not differ between patients who received cefixime (mean, 1.8 µg/mg; SD, 2.7 µg/mg) versus cefpodoxime (mean, 0.68 µg/mg; SD, 1.4 µg/mg; P = .39).
This is the first study to assess the bioavailability of oral irinotecan by administering the drug orally and intravenously to each patient. We showed that significantly more prodrug is converted to its active metabolite after oral administration, probably because of presystemic conversion of irinotecan to SN-38 by carboxylesterase in the GI tract and liver.16,26,39 The low bioavailability of orally administered irinotecan had previously limited its usefulness. However, by using cefixime to reduce or prevent diarrhea, we were able to increase the MTD by 50% and increase the mean systemic exposure to SN-38 achieved with oral dosing by 87%. Because the optimal schedule and route of administration of irinotecan have not been conclusively determined, the most patient-friendly schedules have been chosen for clinical trials. However, studies in pediatric tumor xenografts1,2 showed that protracted exposure at low doses yields superior results. A protracted schedule also seems to be less myelotoxic than other regimens evaluated.6,7 In our opinion, the encouraging clinical responses to intravenous irinotecan observed previously with this protracted schedule6,40,41 and the reported absence of significant myelosuppression are compelling reasons for further evaluation. The oral route, if equally efficacious, would be the most patient-convenient method for protracted irinotecan administration. One of our objectives was to determine whether this regimen would produce the systemic exposure to SN-38 associated with antitumor effects in phase II pediatric trials. The oral MTD of 60 mg/m2/d, which was achieved with cefixime diarrheal prophylaxis, resulted in a median SN-38 lactone exposure similar to that achieved in other trials of irinotecan administered intravenously on this protracted schedule at the MTD of 20 mg/m2/d.30 This dose and schedule has significant antitumor activity, particularly in pediatric rhabdomyosarcoma,41 and oral administration should improve its convenience.
Some authors have shown that aggressive use of loperamide can be effective against late-onset diarrhea.10 Other investigators have tried a Japanese herbal remedy (Kampo medicine),42 thalidomide,43 budesonide,44 or oral alkalinization agents.45 However, none of these agents are palatable to children, and all, except possibly oral alkalization, treat only the symptoms and, therefore, do not reduce mucosal damage. In animal studies,28,29 oral administration of penicillin and streptomycin with irinotecan completely inhibited deglucuronidation and prevented irinotecan-induced diarrhea. Similarly, six of seven adult cancer patients who experienced diarrhea Despite the demonstrated success of antibiotic treatment, we were faced with two problems in designing this study. The first was the need to simplify the antibiotic regimen and make it as palatable as possible to children. The second was to minimize the risk of fungal overgrowth resulting from long-term antibiotic use. Aerobes comprise less than 1% of the normal GI flora. Among them, Escherichia coli and other Gram-negative bacteria are the principal producers of beta-glucuronidase. We reasoned that selective decontamination would spare the anaerobic flora and should be better tolerated by children than the penicillin-streptomycin combination. We chose cefixime for its tolerability, its bacteriacidal spectrum, and its once-daily dosing. This approach significantly reduced beta-glucuronidase activity in the evaluated stools, suggesting that it targeted the intended flora. We also considered the possibility that our results were confounded by antibiotic-induced diarrhea. In a review of 1,575 adults and 615 children treated with cefixime, diarrhea was seen in 13.4% of patients, usually during the first 4 days of treatment.47 None of our patients discontinued drug because of an adverse event during the first 5 days of treatment with antibiotic alone. Furthermore, no serious fungal infections were seen, and only two patients were observed to have Clostridium difficile infection, despite daily administration of cefixime for as long as 17 months (23 courses). The antibiotic was administered daily for the duration of study participation for patient convenience. However, we cannot confidently recommend long-term antibiotic use, especially in combination with more myelosuppressive regimens. Because reduction of beta-glucuronidase–producing bacteria is likely to be needed only while SN-38G is in the GI tract, cefixime could probably be discontinued 1 day after the last dose of irinotecan is administered. We are evaluating a shortened course of antibiotic. The tolerability of this regimen in heavily pretreated children, the absence of significant myelosuppression, and the SN-38 systemic exposure achievable at the MTD of 60 mg/m2/d are compelling reasons to evaluate this oral regimen further. Additionally, these results suggest that cefixime should similarly ameliorate dose-limiting diarrhea caused by intravenous irinotecan.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank Sharon Naron for editorial assistance and Dana Hawkins and Kristen Molina for facilitating data collection.
Supported by Grants No. CA23099 and CA21765 from the National Institutes of Health, by a grant from the Pharmacia UpJohn and Pfizer corporations, and by the American Lebanese Syrian Associated Charities. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Alimonti A, Satta F, Pavese I, et al: Prevention of irinotecan plus 5-fluorouracil/leucovorin-induced diarrhoea by oral administration of neomycin plus bacitracin in first-line treatment of advanced colorectal cancer. Ann Oncol 14:805-806, 2003 47. Tally FP, Desjardins RE, McCarthy EF, et al: Safety profile of cefixime. Pediatr Infect Dis J 6:976-980, 1987[Medline] Submitted June 30, 2005; accepted November 4, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
grade 2 with irinotecan (350 mg/m2 intravenously every 3 weeks) showed improvement when neomycin was administered with the second course.
