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© 2002 American Society for Clinical Oncology Phase I Study of Combination Topotecan and Carboplatin in Pediatric Solid TumorsByFrom the Departments of Hematology-Oncology, Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN; and Hospital St Justine, Montreal, Quebec, Canada. Address reprint requests to R.L. Heideman, MD, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105; email: richard.heideman{at}stjude.org
PURPOSE: We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children. PATIENTS AND METHODS: Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m2/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 µg/kg/d starting on day 4. RESULTS: Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m2/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m2/d for 3 days, and 0.6 mg/m2/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease. CONCLUSION: Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.
APPROXIMATELY 50% of children with malignant solid tumors will experience relapse after current multimodal therapy. Salvage therapy for these patients is often unsatisfactory and is associated with a generally low overall response rate and survival.1 Thus it is important to identify and investigate novel therapeutic agents, singly or in combination, for their potential incorporation into frontline clinical trials. Here we describe a phase I trial of topotecan (TOPO) in association with fixed dose of carboplatin (CARBO). Unique to this study was a CARBO dose based on targeted systemic exposure and the exploration of the maximum-tolerated dose (MTD) of TOPO with or without granulocyte colony-stimulating factor (G-CSF). This is the first report of this combination in children. CARBO was chosen because of its activity against a variety of pediatric solid tumors, either alone or in combination therapy, and because it possesses fewer nonhematologic toxicities than cisplatin (CDDP).2-14 Furthermore, in contrast to most other agents, CARBO has a mechanism of clearance that is easily assessable with standard clinical measures; approximately 90% of an administered dose of CARBO is eliminated by glomerular filtration.15 Thus it is possible to individualize the dose of CARBO in each patient based on their renal clearance as estimated either by creatinine clearance or by technetium-99m diethylenetriaminepentaacetic acid (99Tc DTPA) plasma clearance. The therapeutic efficacy of CARBO as well as its major toxicity, thrombocytopenia, correlates well with its area under the (concentration x time) curve (AUC) in plasma ultrafiltrate.7,16,17 AUC-based drug delivery reduces interpatient systemic drug exposure and toxicity by accounting for individual variability of drug clearance, thus improving the ability to judge patient response and toxicity. TOPO, a water-soluble semisynthetic camptothecin derivative, is a specific inhibitor of the intracellular enzyme topoisomerase I and is capable of producing lethal damage during the course of DNA replication.18-20 TOPO and its congeners have been shown to possess broad antitumor activity in both in vitro and in vivo tumor models as a single agent.20-23 Phase I trials of TOPO in adult and children with malignancies have suggested broad antitumor activity.20,24-26 The use of TOPO after a DNA damaging agents such as CARBO is appealing in that TOPO may prevent repair of CARBO-induced damage. For the above reasons, TOPO and CARBO seemed a rational combination for clinical exploration in pediatric malignancies. The goals of this study were (1) to determine the MTD of TOPO in association with a fixed dose of CARBO (based on targeted systemic exposure) with or without G-CSF, (2) to describe and quantitate the toxicities of this drug combination, and (3) to study the pharmacokinetics and pharmacodynamics of TOPO in children receiving 72 hours’ continuous infusion of TOPO.
Eligibility Patients younger than 21 years with nonhematologic malignancies recurrent or refractory to standard therapy or for which no standard chemotherapy existed were eligible for protocol therapy. The study was later amended to include patients with solid tumors who had received no prior myelosuppressive treatment (eg, surgery alone or local radiotherapy). Other eligibility criteria included histologic confirmation of malignancy (except for those patients who met the conventional neuroimaging criteria of diencephalic or brainstem tumors), Eastern Cooperative Oncology Group performance status of 2 or less, a life expectancy of at least 8 weeks, and no other concurrent antineoplastic therapy. Patients must also have recovered from all toxicities associated with any prior therapy, be at least 6 weeks beyond prior nitrosurea therapy, have a bilirubin level less than 1.5 mg/dL, ALT less than 100 U/dL, have an absolute neutrophil count (ANC) of at least 1,000/µL, have a platelet count more than 100,000/µL, and have normal renal function for age. Patients with prior radiation therapy to whole spine or radiation dose of 30 Gy or more to more than 50% of bony pelvis, those who underwent prior bone marrow transplantation (autologous or allogeneic), and pregnant or lactating mothers were ineligible for study. Written, informed consent conforming to institutional and federal guidelines indicating that patients or their legal guardians were aware of the investigational nature of the study was also required.
Treatment The study was conducted in two parts. Part I was designed to determine the MTD of TOPO in association with CARBO among patients with refractory or recurrent tumors (stratum I). Once this MTD was known, it was to become the starting dose for patients with newly diagnosed tumors for which there was no standard chemotherapy and for those with no prior myelosuppressive therapy (stratum II). Determination of the MTD for TOPO for both patients groups was performed by evaluating individual cohorts of three to six patients at each dose level. If none of the first three patients had dose-limiting toxicities (DLT) at a given dose, then the dose was escalated to the next level in a subsequent cohort. If DLT occurred in one of three patients, an additional three patients were evaluated at the same level; if none of these additional three patients experienced DLT, then the TOPO dose was escalated. If two or more of a cohort of three to six patients had DLT, then accrual at that level was stopped and the next lower level was declared the MTD. A minimum of six patients were treated at the MTD, and no intrapatient dose escalation was allowed.
The MTD of TOPO was determined with and without G-CSF. G-CSF was given at a dose of 5 µg/kg/d as a subcutaneous injection starting on day 4 of each cycle of treatment and continued for at least 10 days or thereafter until the ANC was
Patient Evaluation and Follow-Up 99Tc-DTPA plasma clearance was repeated after every fourth cycle, with an increase in serum creatinine of 0.2 mg/dL or more, or more often as clinically indicated. Patients had clinical and radiographic response evaluation after every two cycles of therapy.
Toxicity
Response Definitions
Pharmacokinetics Studies
Between November 1993 and December 1998, 55 patients were enrolled at two participating institutions. Of these, 51 patients were eligible. Four patients were ineligible because of age more than 21 years (n = 2), Eastern Cooperative Oncology Group score more than 2 (n = 1), and prior lomustine therapy within 6 weeks of starting the first course of therapy (n = 1). The clinical characteristics and prior treatment of the eligible patients are shown in Table 1. Table 2 lists the dose levels studied in both strata of patients.
Previously Treated Stratum I A total of 19 eligible patients were enrolled onto the stratum for previously treated patients (stratum I). Eighteen of the 19 patients were assessable for toxicity. One patient with early progressive disease was not eligible for evaluation of toxicity. Table 2 shows the DLT observed during the first course of therapy in relation to the TOPO dose levels in these patients. Among those in the previously treated stratum, all three patients treated at the first dose level (level I-1, 0.50 mg/m2/d) of TOPO without G-CSF developed hematologic DLTs (one each had dose-limiting neutropenia and thrombocytopenia and one patient had both). Two of the three also had nonhematologic DLT (one with grade 4 infection and one with grade 3 cellulitis). These results led to a reduction of TOPO dose to 0.4 mg/m2/d (level I-2) in the next patient cohort. At this level, hematologic DLT was again noted in three patients. One other patient had nonhematologic DLT in the form of grade 3 hematuria (this patient had previous ifosfamide therapy and hemorrhagic cystitis) and one other had grade 3 infection. Dose level I-3 (TOPO 0.4 mg/m2/d) added G-CSF. Among three assessable patients, one developed dose-limiting thrombocytopenia and another had both dose-limiting thrombocytopenia and neutropenia. A further TOPO dose reduction to 0.3 mg/m2/d with G-CSF was evaluated at level I-4. Of six assessable patients at level I-4, two patients had dose-limiting thrombocytopenia and neutropenia, and two others had nonhematologic DLTs (one with grade 3 infection and one with grade 4 seizure). No further TOPO dose levels were studied in this previously treated group.
Previously Untreated Stratum II No dose-limiting events were noted in the first three patients enrolled at level II-1 of TOPO at 0.4 mg/m2/d dose without G-CSF. Subsequent escalation to dose level II-2 (0.5 mg/m2/d of TOPO) without G-CSF was associated with dose-limiting neutropenia in one patient; no DLTs were observed in an additional three patients enrolled at this level. The TOPO dose was escalated further to 0.6 mg/m2/d in level II-3. At this level, two events of dose-limiting neutropenia and one of thrombocytopenia were observed. Thus the MTD of TOPO in combination with CARBO without G-CSF was 0.5 mg/m2/d, and neutropenia was the DLT. Subsequent dose levels of TOPO were evaluated with G-CSF. Dose level II-4 employed TOPO at a dose of 0.6 mg/m2/d with the addition of G-CSF. At this level, six patients were enrolled and no DLT was observed. Hence, the dose of TOPO was further escalated to 0.75 mg/m2/d with G-CSF in level II-5a. None of the three patients enrolled on this level had DLT, and a further dose escalation to level II-6 with TOPO 0.9 mg/m2/d of with G-CSF was performed. Among five patients enrolled, two experienced dose-limiting thrombocytopenia and one had both neutropenia and thrombocytopenia. Thus an additional cohort of patients was investigated at the previous dose level of 0.75 mg/m2/d (level II-5b). Two patients at dose level II-5b had both dose-limiting neutropenia and thrombocytopenia. At this point the study was closed, and the MTD of TOPO in combination with a systemically targeted dose of CARBO with G-CSF was determined to be 0.6 mg/m2/d. The total number of treatment cycles received in 50 patients varied from one to eight among the previously treated group and from one to six in the untreated group. In all, 16 patients (31%; seven previously treated and nine untreated) could receive only one cycle of treatment because of either progression of disease (n = 14) or toxicity (n = 2). In the previously untreated group, 14 (27%) of 52 cycles were delivered on day 21 as planned; 24 (46%) were delivered before day 28 from the last cycle. Thus 73% of cycles were delivered on or before day 28. In the previously untreated group, at the MTD of TOPO without G-CSF (0.5 mg/m2/d), 59% of cycles were delivered before day 28. With the addition of G-CSF, the MTD of TOPO was marginally increased to 0.6 mg/m2/d, and 100% of cycles were given on or before day 28% and 50% of cycles were given on time at day 21.
Tumor Response
Pharmacokinetics Pharmacokinetic (PK) studies were completed during the first TOPO course in eight boys and eight girls. As defined by the study entry criteria, all patients had normal age-adjusted renal and hepatic function. The clinical diagnoses of these patients were representative of all patients on study. Three patients were studied at the 0.3 mg/m2/d dosage level, four were studied at the 0.4 mg/m2/d dosage level, and nine were studied at the 0.5 mg/m2/d dosage level. The TOPO lactone pharmacokinetic parameters determined in these patients are summarized in Table 4. Steady-state plasma TOPO lactone concentrations ranged from 0.6 to 2.14 ng/mL (mean, 1.09 ng/mL). The mean TOPO lactone clearance was 18.10 L/(hr x m2) (range, 8.68 to 26.91 L/[hr x m2]).
The combination of a topoisomerase I inhibitor and DNA damaging agents such as alkylating or platinating agents has been shown to possess synergistic antitumor activity in multiple in vitro and in vivo studies.13,30-33 Because of this, there has been much interest in phase I and II trials of such combinations; in adult non–small-cell lung carcinoma patients, such combinations have been reported to be associated with response rates as high as 85%.34,35 This is the first report of a phase I trial of such a combination in children. In contrast to other studies reported in adults, the current study determined the MTD of TOPO given as a 72-hour continuous infusion rather then as five daily bolus doses after CARBO. A further differentiating feature of the current study is that the CARBO was individually dosed, based on each patient’s renal clearance, rather than being given based on surface area alone. In general, patients tolerated the infusion of TOPO and CARBO very well. In the previously untreated group, myelosuppression was the major DLT of this drug combination, and nonhematologic DLT was not observed. Although the addition of G-CSF did not allow for dose escalation in previously treated patients, its use was associated with a modest increase (approximately 20%) of the TOPO MTD from 0.5 to 0.6 mg/m2/d in the previously untreated/no prior myelosuppressive stratum. Among the group of patients who had received prior myelosuppressive therapy, an MTD of TOPO in association with a CARBO AUC of 6.5 could not be defined with or without G-CSF. Dose-limiting hematologic and nonhematologic toxicities persisted despite de-escalation of the TOPO from 0.5 to 0.3 mg/m2/d. At this point it was felt that further reductions were unwarranted and would be unlikely to result in clinically relevant TOPO concentrations. The explanation for the inability to find an MTD among this group is uncertain and may relate to heavy prior therapy (most patients had received prior treatment with ifosfamide and/or cisplatin [data not shown]) or to changes in drug clearance resulting from the combination of agents used, as discussed below. Significant myelotoxicity and the inability to escalate the dose of TOPO or other topoisomerase I inhibitors such as irinotecan in concert with the use of other antineoplastic agents with which they have been paired (cyclophosphamide, cisplatin, or CARBO) has been a constant theme in recent adult phase I studies.30,36,37 It is possible that the CARBO dose (AUC of 6.5) used in this study was too high to permit the escalation of TOPO. However, even at a substantially lower CARBO AUC of 4, as used in the study of Simpson et al,38 the combination with TOPO at 0.5 mg/m2/d for 5 days was associated with excessive hematologic toxicity. Similar problems are present in multiple other studies that have used conventional (or even lower than conventional) doses of other platinating or alkylating agents with a topoisomerase I inhibitor.26,30,34-36 The additive toxicity of this combination does not seem to be related to alteration in the PK of TOPO. Rowinsky et al25 reported delays in renal TOPO clearance as a result of prior treatment with nephrotoxic agents such as cisplatin. However, the PK of TOPO among the patients in the current study do not differ from what we have observed and reported in prior studies of TOPO alone, and no consistent pattern of drug interaction or alteration in the PK parameters of any of these agents has been seen in other studies.13,35,38-40 Thus changes in TOPO PK are an unlikely explanation. Another possible explanation for the observed toxicity of these combinations may relate to the potential for DNA-damaging agents to increase intracellular topoisomerase I. Murren et al35 have reported that treatment with cyclophosphamide markedly increased peripheral-blood mononuclear-cell topoisomerase I. Similarly, in vitro studies reported by Fukuda et al41 suggest that increased topoisomerase I inhibitory activity is present after CDDP exposure. However, later and more detailed studies by Ma et al42 showed no relationship between topoisomerase I levels and the cytotoxic synergy of topoisomerase I inhibitors with CDDP. Thus it seems unlikely that treatment-induced increase in the amount of the target topoisomerase I/DNA complex is a major contributor to the enhanced cytotoxic activity of these combinations. A potentially more plausible explanation for the observed synergy between these agents is that topoisomerase I inhibitors are related to an increased retention of the DNA interstrand cross-links after platinum exposure and interaction with the topoisomerase I cleavable complex and the DNA replication forks involved in repairing the cross-links.43-45 Rowinsky et al44 have suggested that the lethal event associated with topoisomerase I inhibitors occurs when a DNA replication fork meets a topoisomerase I enzyme stabilized by the topoisomerase I inhibitor in its covalent complex with DNA. Most of the above-noted studies explored a treatment sequence in which DNA damaging agents were given before a topoisomerase I inhibitor. Only two phase I studies have explored alternative schedules of administration of these agents in which a topoisomerase I inhibitor is used before a DNA-damaging agent.25,38 Both studies have suggested that these alternate sequences of drug administration are associated with significantly less myelotoxicity. However, there is yet limited data regarding the clinical activity of these alternate sequences. Although Simpson et al38 suggest that the rate of objective response and disease progression did not differ between the TOPO before or after CARBO schedules of administration in their phase I study, only six assessable patients were studied in each arm. In the only other trial comparing alternative sequences of administration, Rowinsky et al25 reported only one patient with an objective response; this occurred in the TOPO before cisplatin arm. Of potential importance to the design of future studies is compelling data that suggest that the use of topoisomerase inhibitors in protracted single daily dose schedules (daily for 5 to 10 days) possesses superior antitumor activity compared with shorter courses or continuous infusion.22,37 Further clinical investigation of alternative schedules and sequences is warranted to better define their place in current cancer therapy. Our results confirm that G-CSF does not allow any meaningful TOPO dose escalation in the conventional schedule of a platinating agent followed by a topoisomerase I inhibitor. Further, within the setting of a phase I trial, the response rate noted in the present trial (six objective responses and 19 patients achieving stable disease) is indicative of useful antitumor activity for this drug combination in pediatric solid tumors. Although our results suggest further investigation of this drug combination, we would encourage studies using alternative TOPO schedules, as well as consideration of alternative sequences of drug administration.
Supported in part by grant nos. CA-23099 and CA-81445 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, and by American-Lebanese-Syrian Associated Charities, Memphis, TN.
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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
5,000/µL. 
