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© 1999 American Society for Clinical Oncology Direct Translation of a Protracted Irinotecan Schedule From a Xenograft Model to a Phase I Trial in ChildrenFrom the Departments of Hematology-Oncology, Pharmaceutical Sciences, Biostatistics and Epidemiology, Diagnostic Imaging, and Molecular Pharmacology, St Jude Children's Research Hospital, Memphis; and the Department of Pediatrics, College of Medicine, University of Tennessee–Memphis, Memphis, TN. Address reprint requests to Wayne L. Furman, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; email wayne.furman{at}stjude.org
PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m2 (qd x 5) x 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m2, despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m2/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m2. These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.
DESPITE INCREASING cure rates for many pediatric solid tumors, metastatic disease and certain histologies carry a poor prognosis and require new therapies. Because evaluation of new therapies is limited by the relatively few children eligible for treatment on phase I trials,1 agents and schedules must be chosen carefully. Agents may be prioritized for study based on preclinical xenograft data, novel mechanisms of action, novel formulations (of established agents), and response and toxicity data from adults.1-4 However, optimal schedules of administration receive comparatively little attention, despite the highly schedule-dependent antitumor effects of some agents, such as irinotecan, in preclinical studies. In this article, we report the direct translation of preclinical findings to a pediatric phase I trial of the camptothecin prodrug irinotecan. Irinotecan (7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin) undergoes de-esterification by cellular carboxylesterases to yield a much more potent topoisomerase I inhibitor, SN-38 (7-ethyl, 10-hydroxy camptothecin).5 Irinotecan is highly active against human tumor xenografts, including those derived from pediatric tumors, such as rhabdomyosarcoma and neuroblastoma, and adult xenograft models of colon, gastric, breast, and lung cancers.6-9 However, the response rates in adult phase I10-14 and phase II15-23 trials have been lower than predicted by preclinical models.6-8,24-29 Although these results are partly explained by the greater tolerance of mice for high systemic exposures of SN-38, schedules of administration that were found to be optimal for treating human tumors in mice have not been rigorously tested in patients. The activity of camptothecin analogs, and specifically of irinotecan, is clearly schedule-dependent in human tumor xenograft studies6,7,29: a given total dose of drug, when administered on a protracted schedule, produces dramatically better responses.7 This effect is consistent with the S-phase–specific cytotoxic action of these agents. However, most phase II trials of irinotecan in adults have not used protracted schedules.6,7,29 Even the United States Food and Drug Administration (FDA)–approved schedule of irinotecan administration could not be expected to produce maximal antitumor activity when the drug's mechanism of action is considered. Data from adult phase I studies suggest that, in humans, the total irinotecan dose that can be tolerated in any period remains essentially constant, irrespective of the schedule.10-14 Thus, if the course of therapy is extended to optimize antitumor activity, the daily dose must be reduced to minimize toxicity. However, the preclinical xenograft data clearly show that in many tumor models, the dose-response relationship for irinotecan is steep (P.J. Houghton, unpublished data). Below some minimal daily systemic exposure, virtually all antitumor activity is lost. Therefore, maximal efficacy requires that the duration of therapy be prolonged while a crucial daily exposure level is maintained. This relationship between systemic exposure and tumor response to irinotecan remains poorly defined for most human cancers, although we have investigated these relationships for irinotecan and topotecan in several models of human pediatric and adult malignancies.6,7 We found previously in preclinical models that daily administration of two consecutive 5-day courses of irinotecan, repeated every 21 days, produced greater antitumor activity than did more dose-intensive schedules. We also showed, in two neuroblastoma xenograft lines, that when given on an optimal schedule, a minimal daily systemic exposure to SN-38 lactone was associated with objective responses (99 ng-h/mL for partial responses [PRs] and 257 ng-h/mL for complete responses [CRs]).29 We used these preclinical data, including the study presented here, to help identify a promising administration schedule for a phase I clinical trial in children. In this article, we present the results of a pediatric phase I trial of irinotecan that used a unique schedule of administration derived directly from preclinical studies of pediatric solid tumors in the xenograft model. Our objectives were to determine the toxicity and maximum-tolerated dose (MTD) of irinotecan given on this schedule and to seek evidence of antitumor activity. We also sought to determine whether treatment on this schedule would produce SN-38 systemic exposures in children that were comparable to those associated with antitumor effects in the xenograft model, and whether this level of SN-38 systemic exposure is tolerated in children.
Animal Studies Characteristics of the neuroblastoma xenograft used in this study (NB-1771) and methods of assessing tumor growth and tumor sensitivity were recently reported in detail.30 Animal care followed institutional guidelines. Irinotecan was formulated and administered by intravenous injection as described previously.6 Irinotecan was administered intravenously daily for a single 5-day period (designated [qd x 5] x 1) or for two 5-day periods, in each of 2 consecutive weeks (designated [qd x 5] x 2) to mice bearing bilateral tumors. These cycles were repeated three times at 21-day intervals. The cumulative dose administered per cycle remained constant (ie, 25 mg/kg given either as 5 mg/kg x 5 injections [group A] or 2.5 mg/kg x 10 injections [group B], and 6.25 mg/kg given either as 1.25 mg/kg x 5 injections [group C] or 0.625 mg/kg x 10 injections [group D]). Groups of mice treated on the single 5-day cycle received 5 or 1.25 mg/kg/d. Mice on the (qd x 5) x 2 schedule received one half of the respective daily dose used in the (qd x 5) x 1 schedule.
Statistical Analysis of Animal Studies
Patients Drug formulation and administration. Irinotecan (CPT-11 or Camptosar [Pharmacia & Upjohn, Kalamazoo, MI]) was supplied as a sterile, pale yellow, clear aqueous solution, in 100-mg, single-dose, 5-mL vials. Each milliliter of solution contained 20 mg of irinotecan hydrochloride (on the basis of trihydrate salt), 45 mg of sorbitol (National Formulary) powder, and 0.9 mg of lactic acid (United States Pharmacopeia [USP]). The drug was diluted with 5% dextrose injection (USP), or 0.9% sodium chloride injection (USP), before intravenous infusion. The schedule of administration was based on favorable antitumor responses in our xenograft studies.6,7 The drug was administered by 1-hour intravenous infusion once daily for 5 consecutive days followed by a 2-day rest and then a second 5 consecutive days of treatment ((qd x 5) x 2). The starting irinotecan dosage selected (20 mg/m2/d x 5 x 2) approximated 80% of the weekly dose used in Japanese trials that administered 40 mg/m2 daily for 3 days, repeated for up to 18 weeks.34 In the absence of grade 3 or 4 toxicity, the dosage was escalated in 20% increments (20, 24, and 29 mg/m2/d x 5 x 2) in cohorts of three patients. There was no intrapatient dose escalation.
Originally, because of possible hematologic toxicity, the study was stratified. Patients who had received prior craniospinal radiation and/or Unacceptable or dose-limiting toxicity was defined as grade 4 hematologic toxicity lasting more than 7 days, or grade 3/4 nonhematologic toxicity, in two of a cohort of three to six patients. The MTD was defined as the dose immediately below that at which dose-limiting toxicity was identified (National Cancer Institute Common Toxicity Criteria). Only the first course of treatment ((qd x 5) x 2) was used to assess dose-limiting toxicity. Treatment courses were repeated at 3-week intervals in the absence of dose-limiting toxicity. Patients were removed from the study if evidence of progressive disease was noted after any cycle of treatment. A 20% dosage reduction was permitted for subsequent cycles in patients who had reversible grade 3/4 toxicity in the absence of progressive disease. Patient evaluation. Before admission to the study, each patient underwent a complete history and physical examination. Measurable lesions (if present) were documented by imaging and/or bone marrow studies as appropriate. Laboratory studies included complete blood cell counts, urinalysis, and assays of serum blood urea nitrogen, creatinine, uric acid, bilirubin, AST, ALT, lactate dehydrogenase, alkaline phosphatase, glucose, sodium, potassium, chloride, CO2, magnesium, calcium, albumin, and phosphorus. These studies were performed before treatment, at 3- to 4-week intervals, and at the end of study. Blood urea nitrogen, creatinine, AST, and alkaline phosphatase were assayed weekly, and complete blood counts were obtained at least twice weekly.
Toxicity was assessed by the National Cancer Institute Common Toxicity Criteria. A CR was defined as complete regression of all apparent tumor masses, including lesions noted on imaging, and/or clearing of the bone marrow of tumor cells, persisting at least 4 weeks. A PR was defined as greater than 50% and less than 100% regression of all tumor masses (measured when possible in two diameters) in the absence of any new lesions, or a decrease
Pharmacokinetics SN-38 plasma protein binding. In a subset of patients, we determined the extent of SN-38 plasma protein binding. SN-38 (500 ng/mL; 0.8 µmol/L) was added to a patient plasma sample obtained before the irinotecan infusion. The plasma sample was placed in an ultrafiltration device (MPS-1; Amicon, Danvers, MA) and centrifuged at 7,200 x g for 15 minutes. The ultrafiltrate was analyzed for unbound SN-38, and SN-38 plasma protein binding was determined as the ratio of ultrafiltrable SN-38 to the SN-38 plasma concentration measured before centrifugation.
Pharmacokinetic analysis.
As previously described,36 we used a four-compartment pharmacokinetic model and maximum likelihood estimation to fit the irinotecan and SN-38 lactone concentration-time data. Irinotecan systemic clearance was calculated using accepted equations.37 The area under the plasma concentration-time curve (AUC) for hours 0 to 7 (AUC0
Animal Studies We previously showed that low-dose protracted schedules of camptothecin analogs induced optimal responses in several xenograft tumor models.6,7,29 Figure 1 shows the results of irinotecan treatment of neuroblastoma NB-1771 xenografts in mice. The experiment compared two schedules (groups A and C [(qd x 5) x 1] and groups B and D [(qd x 5) x 2]) in which the cumulative dose per 21-day cycle was identical (ie, 25 mg/kg administered either as 5 mg/kg x 5 injections [group A] or 2.5 mg/kg x 10 injections [group B], and 6.25 mg/kg administered either as 1.25 mg/kg x 5 injections [group C] or 0.625 mg/kg x 10 injections [group D]). Growth of control NB-1771 xenografts is shown in Fig 1E. Figure 1F shows the relative mean tumor volumes in each group (mean tumor volume/initial mean tumor volume). As shown in Table 1, time to tumor failure in all treatment groups was significantly greater than that in the control group (P = .004 for all tests). Notably, no mouse in treatment group B (2.5 mg/kg (qd x 5) x 2) had tumor progression; all had CRs, and five of seven maintained these responses up to week 12. In the other (qd x 5) x 2 group (group D), only one tumor quadrupled in volume (at 11 weeks); five of the seven mice achieved CRs, two of which were maintained to 12 weeks. In the two (qd x 5) x 1 groups, there was only one CR. Groups B and D ((qd x 5) x 2) differed significantly from groups A and C ((qd x 5) x 1) in terms of response distributions (P = .028 and .052, respectively). All P values were adjusted for multiple comparisons, making this analysis a conservative one.
Patients Because of possible hematologic toxicity, patients were initially stratified based on prior craniospinal irradiation. The first eight patients who had received prior radiation, as defined in Patients and Methods, received irinotecan (three at 20 mg/m2, three at 24 mg/m2, and two at 29 mg/m2) without clinically relevant hematologic toxicity. We therefore amended the study and enrolled subsequent patients at the dose level being used in nonirradiated study patients (24 mg/m2). For purposes of simplification, patients are reported without reference to this initial stratification. Thus, more than six patients were treated at the first two dose levels. The characteristics of the 23 patients who were assessable for toxicity are listed in Table 2. They received 84 courses of irinotecan at three different dosages (20, 24, and 29 mg/m2/d x 5 x 2). The median number of courses administered per patient was three (range, one to 10). Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). All patients had been extensively pretreated: 17 had received two or more multiagent chemotherapy regimens, eight had been treated with topotecan, and seven had received autologous bone marrow transplants.
Hematologic toxicity.
Nonhematologic toxicity. Of the 14 patients who did not have grade 3/4 diarrhea, 12 experienced mild diarrhea that was easily managed with early initiation of loperamide. Nausea or vomiting was also modest and was easily controlled by ondansetron given with or without dexamethasone. Another significant but non–dose-limiting toxicity included nonneutropenic sepsis in two patients (one at 20 mg/m2 and one at 24 mg/m2). Both recovered uneventfully after a course of broad-spectrum antibiotics.
Antitumor activity. Other responses were observed that did not qualify as such but were of interest. One patient with refractory hepatoblastoma presented with an alpha-fetoprotein level of 1.2 x 106 ng/mL that decreased to 1.2 x 105 ng/mL after three courses of irinotecan at 20 mg/m2. A 17-year-old patient with recurrent osteosarcoma had significant shrinkage of a metastatic pulmonary tumor from approximately 2.7 x 3.5 cm to 1.5 x 2.0 cm. This reduction in tumor size persisted for 1 month.
Pharmacokinetics.
We also compared absolute SN-38 production in our study with that reported in three adult phase I or II studies of irinotecan.13,14,39 We selected irinotecan doses from these studies that were similar to the FDA-approved dose of 125 mg/m2. In these three adult clinical trials that administered irinotecan weekly for 4 consecutive weeks of each 6-week cycle, cumulative doses of 500,39 600,14 and 60013 mg/m2 per course, respectively, yielded a cumulative SN-38 lactone AUC of 260 to 492 ng-h/mL for each course. In comparison, children in the present study who received irinotecan at the MTD had a cumulative dose of 200 mg/m2 per course. For the purpose of this comparison, we assumed that the SN-38 systemic exposure in adults and children was constant. The cumulative SN-38 lactone AUC determined at the MTD was 1,060 ng-h/mL, two-fold or more greater than that observed in the representative adult studies.
We found this protracted schedule of irinotecan administration to be well tolerated. The dose-limiting toxicity, severe diarrhea and/or abdominal cramps, occurred in six of 12 patients treated at a dose level of 24 mg/m2/d, despite the use of loperamide as outlined by Abigerges et al.40 Myelosuppression that lasted longer than 7 days was not dose-limiting at any level. The results of a variety of schedules used in adult trials10-14,41,42 suggest that the predominant toxicity may be related to the schedule of administration, with diarrhea predominating on continuous or intermittent dosing schedules13,42 and neutropenia predominating on a single-dose schedule.41 In any case, the lack of significant myelosuppression on this protracted irinotecan schedule may offer an opportunity to combine the drug effectively with more myelosuppressive chemotherapeutic agents. The optimization of such combinations would need careful evaluation in future trials. The response rate we observed (five of 23 patients) was much greater than the average 6% objective response rate observed in a review of 228 other phase I trials of antineoplastic agents,43 especially when considering the heavy pretreatment of these children. As shown in Table 2, most patients were in their second (or subsequent) relapse, and seven had undergone intensive chemotherapy with autologous bone marrow transplantation. Our response rate is still remarkable when compared with that of a recent phase I study of topotecan in a similar group of children (three PRs among 40 children enrolled).44 In addition to the PRs observed, the "near PRs" in a patient with refractory hepatoblastoma and a patient with osteosarcoma, plus significant disease stabilization for a median of 70 days in most of the other patients, make this response rate remarkable. These findings suggest that irinotecan given on this protracted schedule should be further evaluated in children, beginning at a dose of 20 mg/m2/d. Further evaluation of the schedule dependency of irinotecan in adult cancer patients is warranted. Whether tumors that become resistant to other topoisomerase I inhibitors such as topotecan will also be resistant to irinotecan (or vice versa) is a clinically important question, but one that cannot be answered by our data. Eight of our patients had been treated previously with topotecan, and only one of the eight had a significant response to irinotecan, achieving a PR that continued through four subsequent courses before disease progression. Further preclinical and clinical evaluation of the relative cross-resistance of these agents is needed. The standard method for the design and conduct of phase I trials of antineoplastic agents has evolved empirically. Discussions of alternative designs1,45-51 have not addressed the schedule on which a new agent is to be administered. Optimally, preclinical data from xenograft models of pediatric tumors can offer valuable insight for prioritizing the most promising agents and schedules to be evaluated in children. The results of this study suggest that irinotecan is a good example of this approach. In the xenograft model, daily administration of irinotecan in two consecutive 5-day courses was more efficacious than traditional, more dose-intensive schedules.6,7,29 However, no direct comparison of the 5-day and 5-day x 2 schedules has been reported. Similar results have been obtained with additional neuroblastoma and rhabdomyosarcoma xenograft models in which administration of irinotecan using the (qd x 5) x 2 schedule was markedly more effective than the 5-day schedule. Studies with 9-aminocamptothecin show a similar schedule dependence.52 We also found that a minimum threshold of SN-38 exposure must be achieved for antitumor activity, and that beyond a certain point, higher dose-intensity enhances toxicity but not tumor regression.29,53 This steep dose-response curve highlights the importance of designing a regimen for children that yields optimal systemic drug exposures. In the present study, we showed in NB-1771 neuroblastoma xenografts that the effect of a given total dose of irinotecan was significantly increased when it was administered in two 5-day cycles separated by a 2-day rest, rather than in a single 5-day cycle. The schedule used in our phase I trial was based on information gained from these studies. To compare the SN-38 lactone systemic exposures observed in our patients with those reported by other investigators, we first calculated the relative extent of irinotecan conversion to SN-38. As indicated by Rivory et al,38 this is not a direct measure of the conversion of irinotecan to SN-38 but a pharmacokinetic estimate for analysis of the dose dependence of this metabolic pathway. At the MTD of 20 mg/m2/d, the median proportion of conversion was 0.28, a value greater than values reported by Vassal et al54 in a group of children and by Rivory et al38 in adults who received high-dose irinotecan. However, because our daily irinotecan dose was, at most, one tenth of those given in the other two studies, we also compared absolute SN-38 production in our study with that reported in three adult trials using the FDA-approved schedule and dosage of irinotecan.13,14,39 At the MTD, our protracted schedule of administration yielded a cumulative SN-38 lactone systemic exposure per course that was greater than that obtained in adults with doses two to three times as high on the less protracted schedule. This enhanced SN-38 systemic exposure was consistent with the significant antitumor responses we observed, and was well tolerated in this group of children. One of our objectives was to determine whether treatment on this schedule would produce SN-38 systemic exposures in children that were comparable to those associated with antitumor effects in the xenograft model. At the MTD of 20 mg/m2/d, a 10-fold range in SN-38 lactone systemic exposure was observed. However, the median SN-38 systemic exposure was comparable to that associated with antitumor responses in the xenograft model (eg, 106 ng-h/mL in children; 99 to 256 ng-h/mL in xenografts). However, these SN-38 values represented both unbound and plasma protein–bound SN-38. Because the unbound drug is the clinically active portion, potential interspecies differences in SN-38 protein binding must be considered. In previous experiments, we showed that the median percentage of unbound SN-38 in murine plasma was 2% (range, 1% to 4%).55 Because the plasma protein binding of SN-38 is not plasma concentration dependent, we assumed a constant of 2% unbound in estimating the unbound SN-38 systemic exposure in the xenografts. The median unbound SN-38 exposure of 4.3 ng-h/mL in the five patients studied at the MTD compared favorably to the 1.3 to 2.3 ng-h/mL associated with PRs and the 3.3 to 4.3 ng-h/mL associated with CRs in mice.55 The tolerability of this regimen in heavily pretreated children, the lack of significant myelosuppression, and the remarkable number of clinically significant responses suggest that this schedule of irinotecan administration should be evaluated further. These data also suggest that preclinical xenograft models can provide useful predictors of the responses of some pediatric cancers to topoisomerase I inhibitors such as irinotecan. Similarly, principles derived from preclinical models have the potential to enhance the design of clinical trials for adults as well as children with cancer.
Supported by grants no. CA23099 and CA21765 from the National Institutes of Health, Bethesda, MD, and by the American Lebanese Syrian Associated Charities. We thank Sharon Naron for her editorial comments.
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ABSTRACT
INTRODUCTION
2; recovery from the toxic effects of prior chemotherapy; hemoglobin level greater than 8 g/dL, absolute neutrophil count greater than 1,000/µL, and platelet count greater than 100,000/µL (unless marrow was infiltrated with tumor); adequate liver function (bilirubin level 
30 Gy irradiation of more than 50% of the pelvis were treated as a separate group, with an identical treatment protocol and dose escalation scheme. After no significant hematologic toxicity was observed in eight patients who had received prior irradiation (three at 20, three at 24, and two at 29 mg/m2/d x 5 x 2), the study was amended to enroll subsequent patients without regard to prior irradiation, and the data derived from the two strata were combined. All subsequent patients were enrolled at 24 mg/m2/d x 5 x 2, the dose level of the larger, nonirradiated stratum, and subsequent toxicity at this dose level prevented further escalation. Because diarrhea was dose-limiting in many adult phase I trials, each patient was given antidiarrheal medication (loperamide) and instructed to begin treatment at the first episode of poorly formed or loose stools or at the earliest onset of bowel movements more frequent than normally expected for the patient. 
7) was calculated for irinotecan and SN-38 using the log-linear trapezoidal method. The relative extent of conversion of irinotecan was calculated by the following equation
300 to 350 mg/m2 per dose)
