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© 2002 American Society for Clinical Oncology Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group StudyByFrom the Departments of Hematology-Oncology and Pharmaceutical Sciences, St Jude Children’s Research Hospital, and Department of Pediatrics, University of Tennessee, College of Medicine, Memphis, TN; Children’s Oncology Group Research Data Center, Gainesville, FL; Department of Pediatric Hematology/Oncology, University of California San Diego Medical Center, San Diego, CA; Department of Pediatric Hematology/Oncology, Washington University Medical Center, St Louis, MO; Department of Pediatric Oncology, Baylor College of Medicine, Houston, TX; Department of Pediatric Hematology/Oncology, University of Arkansas, Little Rock, AK; and Department of Hematology/Oncology, Saint Justine Hospital, Montreal, Quebec, and Department of Pediatric Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada. Address reprint requests to Wayne L. Furman, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; email: wayne.furman{at}stjude.org
PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia. PATIENTS AND METHODS: Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m2/d for 5 days and 2.4 mg/m2/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days). RESULTS: Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m2/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m2 (range, 9.4 to 45.9 L/h/m2) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days. CONCLUSION: The MTD was 2.4 mg/m2/d for 9 days. Further testing is warranted of TPT’s schedule dependence in children with leukemia.
TOPOTECAN (TPT), A semisynthetic water-soluble analog of camptothecin, binds to the nuclear enzyme topoisomerase-I, disrupting DNA continuity and replication.1-5 Binding is dependent on the presence of a lactone moiety in the E-ring that undergoes a pH-dependent, reversible hydrolysis to form a carboxylate form that predominates at low pH values.3,5 We predicted that the antitumor activity of TPT should be highly schedule-dependent based on its unique mechanism, cell-cycle specificity, and preclinical xenograft data.5-10 TPT has shown significant antitumor activity in numerous preclinical animal models,4,5,11-13 including the mouse xenograft model,6,7 and exceptional inhibition of tumor growth or increased life spans in cases of rapidly proliferating murine leukemias.14 In many xenograft models, its activity was schedule dependent,6,8,15 with protracted exposure associated with better responses.8-10 In at least one clinical trial in patients with previously treated ovarian cancer, response rate was greater when TPT was administered on an intermittent schedule compared with a single 24-hour infusion.16 TPT has shown significant activity in many pediatric solid tumors,17-20 but little published information is available on its use in children with acute leukemia.21 Thus, we conducted two sequential Pediatric Oncology Group (POG) phase I studies of TPT in children with refractory acute leukemias. The objectives of these studies were to evaluate safety and efficacy of TPT in children with refractory acute leukemias and assess the pharmacokinetics and pharmacodynamics of TPT among those patients. In our first study, we fixed the duration of therapy and increased the TPT dosage in cohorts of children. When no dose-limiting toxicity (DLT) was defined on the initial schedule (daily x 5), we evaluated increased duration of treatment for up to 12 consecutive days in subsequent cohorts.
Eligibility Patients eligible for these protocols (POG 9275 and 9575) were younger than 21 years at study entry and had leukemias unresponsive to conventional therapy. Other eligibility requirements included life expectancy of at least 6 weeks, recovery from toxicities of previously received chemotherapies, no severe or uncontrolled infections, and adequate liver function (bilirubin  1.5 mg/dL, AST two times normal), renal function (creatinine < 1.5 mg/dL), nutritional status (weight > third percentile for age, albumin  3 g/dL), and performance status (Eastern Cooperative Oncology Group status, 0 to 2), as well as more than 3 months since bone marrow transplantation or 6 or more months since total-body irradiation and bone marrow transplantation. Informed written consent was obtained according to institutional guidelines.
Patient Evaluation Toxicities were assessed according to the National Cancer Institute common toxicity criteria, and the definition of unacceptable hematologic toxicity was an absolute neutrophil count less than 500/µL or a platelet count less than 20,000/µL for more than 5 weeks unrelated to leukemic cell regrowth. Complete response (CR) was defined as total disappearance of all measurable extramedullary disease, M-1 marrow status (< 5% leukemic blast cells) with restoration of normal hematopoiesis, and normal performance status. Patients who achieved partial responses (PR) had M-2 marrow histology (5% to 25% leukemic blast cells), absolute neutrophil count greater than 500/µL, less than 5% circulating blasts, platelet count greater than 25,000/µL, and hemoglobin level greater than 7 g/dL. Stable disease was defined when patients did not meet criteria for CR or PR but had no evidence of disease progression.
Drug Formulation and Administration
Treatment Plan We did not allow intrapatient TPT dosage escalation within the study. MTD was defined as the dosage immediately below that at which two patients of a cohort of three or more had unacceptable grade 3 or 4 toxicities as defined. Treatment courses were repeated every 3 weeks when there were no DLTs. Patients were removed from the study if there was evidence of progressive disease after any cycle of treatment.
Pharmacokinetic Analysis A two-compartment model was fit to the TPT lactone plasma concentration-time data from each patient with a Bayesian algorithm, as implemented in ADAPTII (Biomedical Simulations Resource, Los Angeles, CA).23 Estimated pharmacokinetic variables included volume of the central compartment, elimination rate constant, and intercompartment rate constants. Calculated pharmacokinetic parameters included the area under the concentration-time curve from zero to infinity, systemic clearance, beta half-life, and steady-state volume of distribution.
Pharmacodynamics Analysis
Patient Characteristics Among 25 patients with acute lymphoblastic leukemia (ALL), one had non-Hodgkin’s lymphoma that recurred primarily in bone marrow, and among 24 with refractory acute nonlymphoblastic leukemia (ANLL), two developed ANLL after the initial treatment for ALL (Table 1). Before entry, all patients received intensive multimodality treatment that included one to six multidrug chemotherapy regimens. Forty-nine patients received 70 assessable courses of TPT at 12 different dosages (2.0, 2.4, 3.0, 3.6, 4.3, and 5.2 mg/m2/d for 5 days, then 2.4 mg/m2/d for 7, 9, and 12 days, and 2.0, 1.6, and 1.4 mg/m2/d for 12 days). One patient received 11 courses, one patient four, 11 patients two, and the remaining 34 received one course. Among three patients with courses not fully assessable for toxicity, one patient was started on granulocyte colony-stimulating factor, one was taken off the study after receiving eight of 12 planned doses of TPT, and one received three doses of TPT before developing acute respiratory failure and dying of progressive leukemia the next day.
Hematologic Toxicity Most patients developed grade 4 neutropenia and thrombocytopenia usually within 7 to 10 days of beginning TPT. Many patients also were hospitalized subsequently for febrile neutropenia. However, myelosuppression was not defined as DLT in this heavily pretreated group of children with compromised marrow because of leukemic infiltrate. Only one patient, a 7-year-old with recurrent ALL and Down’s syndrome, who was treated with 2.0 mg/m2 for 12 days, had possible dose-limiting myeloid toxicity. During his approximately 5 weeks of grade 4 neutropenia, he also had a Hickman catheter infection, mucositis, and sinusitis but recovered without sequelae. He also had a PR to the first course, with improvement in percentage blasts in bone marrow from 92% to 18% on recovery from course 1. He received a second course at a reduced dosage of 1.6 mg/m2 for 12 days before he developed the progressive disease.
Nonhematologic Toxicity
Other nonhematologic toxicities were minimal ( grade 2). Most patients had mild (grade 1 or 2) nausea and vomiting. Two others had mild abdominal pain, and three had mild diarrhea. Four patients reported headaches, and six developed pruritic rashes soon after TPT treatment began. The rashes resolved within several days after therapy ended. Two patients (one treated at 5.2 mg/m2/d for 5 days; one treated at 2.4 mg/m2/d for 9 days) developed chills and fever associated with drug administration. One of them also had unexplained anemia (hemoglobin on day 1 of treatment 8.9 g/dL; on day 5, 6.7 g/dL). Symptom recurrence was prevented in this patient by pretreatment with hydrocortisone, diphenhydramine, and acetaminophen before each dose of the second course. Nonhematologic side effects were easily managed, seemed to be independent of dosage, and were not considered dose limiting.
Antileukemic Activity
Several heavily pretreated patients had transient oncolytic responses. For example, one patient had an initial leukocyte count of 218,000/µL that decreased to 6,200/µL on day 8. That rapid decrease was associated with an elevated serum uric acid value (17.5 g/dL), consistent with tumor lysis. Another patient with scalp chloroma and 63% circulating blasts on day 1 had resolution of his chloroma and clearing of peripheral blasts by day 13. Unfortunately, we evaluated his bone marrow at the end of the first course and found disease progression.
Effects of Schedule on Response
Pharmacokinetics Summarized in Table 4 are TPT lactone pharmacokinetic variables for the first and last doses. As in previous studies, we noted wide interpatient variability for TPT lactone clearance (46%); however, intrapatient variability was minimal. The median TPT lactone clearance for the first dose was 19.2 L/h/m2 (n = 33) and was not different when measured in a subset of patients (n = 15) at the end of the course (P = .79; sign test). As depicted in Fig 1, a significant linear relation was noted between TPT area under the concentration-time curve and dose over a wide range of TPT dosages (eg, 1.4 to 5.2 mg/m2/d; P < .001).
The relationship between nonnormalized TPT lactone clearance and demographic and routine measures of renal and hepatic function was assessed by simple linear regression analysis. In this analysis, single variables were evaluated to explain variability in TPT lactone clearance. Height, weight, body-surface area, and age were patient-specific variables that related to TPT lactone clearance. To evaluate further the effect of patient-specific variables on TPT clearance, a multiple stepwise regression analysis was performed on 22 patients who had complete demographic and biochemical data sets. The variables selected were body-surface area, age, and serum creatinine. This relationship is depicted graphically in Fig 2, where the actual patient values for each variable in the model were used to calculate TPT lactone clearance. The predicted (calculated) TPT lactone clearance is plotted versus the measured TPT lactone clearance; the solid line represents the line of identity. The mathematical expression of this model is included in the legend of Fig 2.
We also noted that the five patients on concomitant allopurinol therapy had median TPT lactone clearance that was 35% lower than the median value for all patients (12.5 L/h/m2). Most of these patients would have also received increased intravenous hydration and alkalization, as well. The two patients who received TPT and concomitant dexamethasone therapy had TPT lactone clearance that was greater than the median value (ie, 45.9 and 28.1 L/h/m2 v 19.2 L/h/m2, respectively).
Pharmacodynamics
The determination of the optimal dose and schedule of new chemotherapeutic drugs has been the subject of much discussion over the years.25,26 The evaluation of the biology of cell kill in in-vitro models of cancer27 led to the treatment maxim that giving increasing doses of active drugs will result in improved cure rates. As some have said, "if a little is good, then more is better."28 However, improved understanding of cancer biology has led to a recent re-examination of this concept of dose-intensity.25,28-30 For TPT, the optimal dose and schedule is not known.31 However, its cell-cycle specificity and preclinical xenograft data would predict that prolonged, intermittent32 exposure would optimize its therapeutic benefit.6-9 Studies have evaluated intermittent and continuous TPT administration in children17-19 and adults33-38 with refractory solid tumors and adults with refractory leukemia39-41 or myelodysplastic syndrome.18,19,21,33-44 Our initial study examined an intermittent, 5-day schedule and began at the MTD of children with solid tumors.19 To evaluate TPT in children with leukemia, the definition of hematologic DLT was significantly liberalized (see Patients and Methods), and although we did not identify the DLT in the initial study (POG 9275), we were able to more than double the dose tolerated in children with solid tumors.19 That dosage of 5.2 mg/m2/d was greater than the adult phase II dosage of 4.5 mg/m2/d for a similar schedule in adults with leukemia.41 In that trial, adults with refractory leukemia treated at the 5.75-mg/m2 dosage experienced dose-limiting hyperpyrexia, severe rigors, and precipitous anemia. Thus, the authors recommended a phase II dose of 4.5 mg/m2.41 In our study, one of the three patients who received 5.2 mg/m2 daily had similar but less severe toxicity. After premedication with hydrocortisone, diphenhydramine, and acetaminophen, that patient received a second course of TPT without symptoms. With only one clinically significant response in the first 21 children, and with emergence of more data on the schedule dependency of TPT,7 we elected to determine the DLT of a protracted TPT schedule rather than further escalate the dosage. More clinically significant responses (CR + PR) were observed in children who received 12 days of TPT, regardless of dosage, compared with children who received less than 12 days of TPT (six [CR + PR] of 18 who received TPT for 12 days and two [CR + PR] of 31 who received TPT for < 12 days). Had a hypothesis test been planned to detect improved response in patients who received 12 days of TPT with Fisher’s exact test, P would have been .007. Although anecdotal in this study, these data suggest improved outcome with increased duration. We emphasize that this study was not designed to examine the effect of treatment duration on response, and although the results were interesting, they require confirmation in a prospective trial. Typhlitis or neutropenic colitis is a well-described complication of cancer therapy45 and is increasingly being reported.46 The pathophysiology of typhlitis involves loss of colonic mucosal integrity, invasion of the bowel wall by bacteria, and decreased host immune defenses.45,46 Patients have developed typhlitis after treatment with cytarabine, etoposide, daunomycin, methotrexate, vincristine, and corticosteroids.45 It has not been reported as a DLT for 5-day TPT regimens; however, studies in children with solid tumors have shown that protracted TPT dosage over 12 days might be associated with it. Studies that evaluated protracted oral TPT found diarrhea as a DLT, and in fact, it was more common in the 10- and 21-day regimens than in the 5-day regimen.47-49 Likewise, our study participants who developed typhlitis received TPT for at least 9 days. However, we found no relation between TPT lactone systemic exposure and typhlitis. Stepwise multivariate regression analysis showed that body-surface area, age, and serum creatinine were significant predictors of TPT clearance. Those results were similar to larger population studies of TPT, such as that by Gallo et al,50 who reported height, weight, and serum creatinine as covariates for total TPT clearance. Our ongoing population analysis in 132 children has shown that body-surface area, serum creatinine, age, and phenytoin coadministration are important covariates for TPT lactone clearance.51 Once patient-specific covariates of TPT clearance are identified, they will help us design more individualized TPT dosage regimens. Besides patient-specific variables, pharmacokinetic studies of TPT disposition have shown potentially important drug interactions.52,53 In five children with solid tumors, we showed that concomitant administration of dexamethasone and TPT increased TPT lactone clearance by approximately 30%,54 which was consistent with our previous observations. In contrast, decreased TPT lactone clearance in patients who received concomitant allopurinol has not been described. Although most of these patients also received increased hydration and alkalization, we doubt this would explain the decreased TPT lactone clearance. We have shown that TPT undergoes tubular secretion.53 The mechanism of decreased TPT clearance might be related to excretion of alloxanthine, a metabolite of allopurinol, or effects manifested during tumor lysis syndrome, which will require further study. Animal studies are planned to better understand this potential drug interaction. The DLT in most studies of TPT has been myelosuppression, primarily neutropenia, and occasionally thrombocytopenia.17-19,33,37,38,43 Although filgrastim enabled substantial dose escalation (an increase of 2.3 times) of TPT in at least one report, no corresponding increase in tumor response was seen.37 That finding was not surprising because studies in mice that bore human solid-tumor xenografts suggested that increasing dose beyond a threshold offers no advantage in efficacy and contributes to toxicity.6,7,55 Although we are not aware of any similar data in preclinical leukemia models, we did not observe any clinically significant responses beyond the dosage level of 2.4 mg/m2/d for 5 days in the first study. Thus, we ceased escalating TPT dosage and began escalating duration of therapy. The two CRs, six PRs, and complete (although transient) clearing of peripheral blasts in additional children are results that merit further study. The surprising number of clinically significant responses, particularly in a heavily pretreated group of children, although short-lived, is encouraging. The fact that most responses were in patients who received more protracted exposure to TPT is also intriguing and warrants further investigation.
Supported by grant nos. CA 29139 and CA 31566 from the National Cancer Institute, Bethesda, MD. We thank Suzan Hanna for expert technical assistance.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
