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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2274-2280 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.2388 Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors
From the Departments of Oncology, Pharmaceutical Sciences, Biostatistics, and Radiological Sciences, St Jude Children's Research Hospital; and the Department of Pediatrics and the Center for Pediatric Pharmacokinetics and Therapeutics, The University of Tennessee College of Medicine, Memphis, TN Address reprint requests to Sheri L. Spunt, MD, Department of Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; e-mail: sheri.spunt{at}stjude.org
Purpose To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity. Patients and Methods Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]). Results Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed. Conclusion The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.
Oxaliplatin (trans-l-1,2-diaminocyclohexane oxalatoplatinum), an antineoplastic platinum derivative, forms DNA adducts that block DNA replication and transcription.1 Its unique 1,2-diaminocyclohexane (DACH) carrier ligand makes oxaliplatin a highly effective inhibitor of DNA synthesis2; DACH-platinum adducts are more cytotoxic than those formed by cisplatin and carboplatin.2,3 The DACH carrier ligand also slows the rate of conversion of monoadduct to diadduct,4 and counteracts other mechanisms that allow cells to tolerate unrepaired platinum (Pt-) -DNA adducts.5,6 Oxaliplatin has demonstrated in vitro and in vivo activity against a range of human tumors.3,7-10 Although it forms significantly fewer Pt-DNA adducts than cisplatin, oxaliplatin induces apoptosis more potently.11-14 Thus, the in vitro cytotoxicity of the two compounds is similar. Oxaliplatin is also active against some cisplatin-resistant human tumor cell lines,3,7,10 and clinical responses to oxaliplatin in patients with cisplatin-resistant tumors have been reported.15 Two mechanisms explain the noncrossresistance of cisplatin and oxaliplatin. First, loss of a functional DNA mismatch repair system leads to cisplatin resistance but not to oxaliplatin resistance.16 Computer modeling suggests that the large DACH ring sterically prevents binding of the mismatch repair enzyme complex to oxaliplatin adducts.17 Second, enhanced replicative bypass has been observed in cisplatin-resistant cell lines but not in oxaliplatin-treated cell lines.18 Oxaliplatin also differs from other platinum compounds in its adverse effect profile. In adults, the dose-limiting toxicity (DLT) was transient peripheral neuropathy.19 Oxaliplatin neurotoxicity appears to be cumulative, but, unlike cisplatin neuropathy, is apparently usually reversible.19 The mechanism of oxaliplatin neurotoxicity remains unclear. However, recent in vitro studies suggest that oxaliplatin influences the kinetics of voltage-gated sodium channels and that carbamazepine 0.07 mcg/mL significantly reduces this effect by slowing sodium channel recovery.20 In a clinical trial in adults, 200 mg of carbamazepine given three times daily from 5 days before to 2 days after oxaliplatin administration achieved serum levels above 6.7 mcg/mL in nine of 10 patients but failed to ameliorate oxaliplatin neurotoxicity.21 Gastrointestinal toxicity (nausea/vomiting and diarrhea) is a common adverse effect of oxaliplatin and other platinum compounds.22,19 Oxaliplatin's hematologic toxicity is generally mild, although immune hemolytic anemia has been reported.19,22,23 Unlike cisplatin and carboplatin, oxaliplatin appears not to cause significant nephrotoxicity or ototoxicity.22,24,25 Oxaliplatin is active against a variety of malignancies in adults and is widely used to treat colorectal carcinoma.26-30 The recommended dose (based on adult phase I studies) is 135 mg/m2 administered intravenously (IV) over 2 hours every 3 weeks.19 An equally dose-intensive regimen of 85 mg/m2 every 2 weeks has also been used in adults.27,28,31 In children, some solid tumors are inherently resistant to cisplatin and carboplatin or become resistant after treatment,32-39 and cumulative ototoxicity and nephrotoxicity from these agents may be problematic.40,41 We conducted a phase I study of oxaliplatin in pediatric patients because of its potential activity in platinum-refractory tumors and because its toxicity profile differs from those of other platinum compounds. We first established the maximum-tolerated dose (MTD) and DLT of a 2-hour infusion of oxaliplatin administered every 3 weeks to pediatric patients with refractory solid tumors. We then evaluated whether coadministration of carbamazepine allows further dose escalation by reducing neurotoxicity. Finally, we evaluated the tolerability of oxaliplatin administered every 2 weeks at a dose intensity equivalent to that of the MTD given every 3 weeks. Concomitant pharmacokinetic studies evaluated the disposition of oxaliplatin in pediatric patients.
Study Design Eligibility criteria are shown in Table 1. This study was approved by our institutional review board, and patients or their legal guardians provided written informed consent. Oxaliplatin was supplied by the manufacturer, Sanofi-Aventis (Malvern, PA).
Patients were enrolled on one of three consecutive treatment regimens that were designed sequentially. Regimen A was designed to determine the MTD of oxaliplatin administered at 3-week intervals as a 100, 130, or 160 mg/m2 2-hour IV infusion. A minimum of three patients assessable for toxicity were to be treated at each dose level. If DLT was not observed among the first three assessable patients treated at a dose level, the dose was escalated. If one of three patients experienced DLT, an additional three patients were treated at that dose level. In the absence of further DLT, the dose was escalated. The MTD was defined as the dose level immediately below that at which two or more patients experienced DLT during the first course of treatment. Six assessable patients were to be treated at the MTD. There was no intrapatient dose escalation. Patients who experienced DLT could continue treatment at the next lower dose level after resolution of toxicity. Regimen B was designed to determine whether carbamazepine would allow further oxaliplatin dose escalation by reducing dose-limiting neurotoxicity. Six patients assessable for toxicity were to receive oxaliplatin as in regimen A, at a fixed dose one level higher than the MTD. Carbamazepine was given orally twice daily, from one day before oxaliplatin treatment began to 48 hours after it ended at doses of 2.5 mg/kg twice per day (age, < 6 years), 100 mg twice per day (age, 6 to 12 years), and 200 mg twice per day (age >12 years). Blood was drawn for trough serum carbamazepine determination immediately before the third dose of carbamazepine (just before oxaliplatin). We then enrolled six assessable patients on Regimen C, which evaluated the tolerability of a fixed dose equivalent to two thirds the MTD of oxaliplatin given every 3 weeks, administered IV every 2 weeks over 2 hours (three doses per course). A maximum of six courses (Regimens A and B) or three courses (Regimen C) was permitted in the absence of DLT or progressive disease. All patients received prophylactic antiemetics. Granulocyte colony-stimulating factor was not prescribed.
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Because of the unique nature of oxaliplatin neurotoxicity, sensory neuropathy was graded according to a specialized scale designed by the drug manufacturer (Table 2). Only toxicity during the first course of treatment was used to determine the MTD. Grade 4 neutropenia or thrombocytopenia (or thrombocytopenia requiring platelet transfusion) that persisted for longer than 7 days was classified as hematologic DLT. Nonhematologic DLT included all grade 3 or 4 nonhematologic toxicity except grade 3 nausea or vomiting that resolved with antiemetics, grade 3 diarrhea that resolved with loperamide therapy, and grade 3 hepatic toxicity that returned to baseline or
Patient Evaluation Before starting therapy, each patient underwent a complete history and physical examination, including a detailed examination by a pediatric neurologist. Laboratory studies included a complete blood count, serum chemistries, measures of renal (blood urea nitrogen and creatinine) and hepatic function, and urinalysis. Brainstem auditory evoked potentials or audiography and disease-appropriate staging evaluations were performed at baseline. During treatment, patients received weekly physical examinations, complete blood counts, and serum chemistry assays, including blood urea nitrogen and creatinine. A formal evaluation by a pediatric neurologist was performed before each cycle of chemotherapy. Audiometry and appropriate staging evaluations were performed after every two courses and at the end of treatment. Response was assessed after two courses of therapy. A complete response (CR) was defined as the disappearance of all apparent tumors for a minimum of 4 weeks. A partial response (PR) was defined as a greater than 50% reduction in the sum of the products of the greatest perpendicular diameters of all measurable lesions for a minimum of 4 weeks and the appearance of no new lesions. Progressive disease (PD) was defined as an increase of 25% or more in the sum of the products of the greatest perpendicular tumor diameters, or the development of new lesions. Stable disease (SD) was defined as response that did not meet the criteria for CR, PR, or PD.
Pharmacokinetic Studies
Initially, a three-compartment model was fit to the platinum ultrafiltrate concentration data using maximum-likelihood (ML) estimation as implemented in ADAPT II.45 Only the subgroup of patients with adequate data were used in this analysis. For the purposes of this study, adequate was defined by visual inspection of the data by the study pharmacologist, the presence of at least two measured concentration-time data points in each of the three distribution phases, and the last scheduled time point (ie, week 2 and week 3 samples in the every 2-week and every 3-week dosing groups, respectively). Estimated model parameters included volume of the central compartment (Vc), elimination rate constant, and intercompartment rate constants (k12, k21, k13, and k31). The clearance and terminal half-life (T1/2
Patient Characteristics Between September 2000 and April 2003, 26 patients were enrolled. The median age was 11 years (range, 5 to 21 years); 17 patients were male, 16 were white, eight were black, and two were of other races. The most common diagnoses were neuroblastoma/ganglioneuroblastoma (n = 7) and medulloblastoma (n = 5; Table 3) . Patients had received a median of two prior chemotherapy regimens (range, none to nine).
Regimen Toxicity Table 4 shows the toxicity of the first course of oxaliplatin therapy. Of 11 patients treated on regimen A, one who received 130 mg/m2 every 3 weeks experienced dose-limiting myositis. The first two patients treated at 160 mg/m2 every 3 weeks also experienced DLT. Both had grade 3 pharyngolaryngeal dysesthesias (tingling, numbness, a lump in the throat sensation), sensory neuropathy, and ataxia attributed to oxaliplatin. Therefore, 130 mg/m2 every 3 weeks was determined to be the MTD. The two patients who experienced DLT at 160 mg/m2 subsequently received 130 mg/m2 without DLT. At the MTD, hematologic toxicity was mild. Sensory neuropathy was common and, as expected, often exacerbated by cold. Five of 11 patients on regimen A received four or more cycles (range, four to six; 100 mg/m2, n = 2; 130 mg/m2, n = 3) and none experienced cumulative hematologic, neurologic, or other toxicity.
Six patients were treated on regimen B (160 mg/m2 of oxaliplatin every 3 weeks given with carbamazepine). The trough serum carbamazepine level before the third dose of carbamazepine (before oxaliplatin administration) was in the range therapeutic for seizure control (range, 4 to 12 µg/mL) in five of six patients and was 2.5 µg/mL in the remaining patient. None of these six patients experienced DLT. However, one experienced grade 3 ataxia associated with a toxic serum carbamazepine level of 14.8 µg/mL the day after oxaliplatin administration, despite protocol dosage compliance. This toxicity resolved rapidly after correction of the serum carbamazepine level. As in regimen A, hematologic toxicity was mild and sensory neuropathy was common. Nine patients were treated on regimen C (85 mg/m2 oxaliplatin every 2 weeks without carbamazepine). Only six of these patients were assessable for toxicity; the others had failed to complete a full course of therapy because of early disease progression (n = 2) or a chemotherapy ordering error (n = 1). DLT was not encountered and the toxic effects were similar to those in regimens A and B. All patients underwent audiometric testing. At study entry, 22 patients had normal hearing and four had grade 2 or 3 hearing loss; follow-up audiometric testing found no decrement in hearing in any patient.
Oxaliplatin Pharmacokinetics
Of the 26 patients, we chose 12 who had adequate sampling (as defined in Patients and Methods) and used the ML results from these patients as the prior density for the subsequent MAP analysis. The ultrafiltrable Pt concentration-time data for all patients were then modeled by using a three-compartment MAP Bayesian approach. The ML and MAP parameter estimates were highly concordant in the 12 patients whose data were used as the prior density. Because the MAP Bayesian method is more robust than ML estimation for modeling sparse data, the MAP Bayesian analysis offered the most reliable parameter estimates for this group. Table 5 summarizes the MAP Bayesian-estimated pharmacokinetic parameters. The clearance rate of ultrafiltrable Pt in patients receiving concurrent carbamazepine and oxaliplatin 160 mg/m2 was not found to differ significantly from that of other patients (Mann-Whitney U test, P = .36).
Tumor Responses Table 3 presents tumor response according to treatment regimen and disease type. Among the 23 assessable patients, tumor responses were SD (n = 7) and PD (n = 16). Three patients on regimen C did not receive a full course of therapy due to early disease progression (n = 2) or a chemotherapy ordering error (n = 1) and thus were unassessable for response. The seven patients with SD had received 100 mg/m2 every 3 weeks (n = 2), 130 mg/m2 every 3 weeks (n = 1), 160 mg/m2 every 3 weeks (n = 2; because of DLT, subsequent cycles were 130 mg/m2), and 85 mg/m2 every 2 weeks (n = 2). Three patients with SD received more than two courses of therapy; disease progression occurred after four, five, and six courses, respectively.
The MTD of oxaliplatin administered to pediatric patients with refractory solid tumors as a 2-hour IV infusion every 3 weeks was 130 mg/m2. The DLT was acute neurotoxicity (pharyngolaryngeal dysesthesia, sensory neuropathy, and oxaliplatin-induced ataxia). At the MTD, hematologic toxicity was mild and low-grade sensory neuropathy (often exacerbated by cold) was common. Nephrotoxicity and ototoxicity were not observed. These findings are similar to those in adults.19,22 A phase I clinical trial in adults recommended a dose of 135 mg/m2 using the same schedule; the DLT was cumulative sensory neuropathy.19 As in our study, significant nephrotoxicity and clinically apparent ototoxicity were not observed, and hematologic toxicity was mild. Nausea and vomiting in children and adults were not dose limiting with appropriate antiemetic therapy. Among the five patients in our study who received four or more cycles of oxaliplatin, there was no evidence of cumulative neurologic toxicity. However, most of these patients' cumulative doses were near the threshold (500 mg/m2) for disabling neuropathy in adults.19 Therefore, chance may explain the absence of cumulative neurotoxicity. Interestingly, the oxaliplatin dose could be escalated beyond the MTD with concomitant administration of carbamazepine, which achieved serum levels therapeutic for seizure control in five of six patients. Although preclinical data suggested that carbamazepine could reduce oxaliplatin neurotoxicity,20 it had not ameliorated clinical neurotoxicity in adults at concentrations exceeding those that were effective in vitro.21 More recently, calcium and magnesium infusions have been used to chelate oxalate, an oxaliplatin metabolite implicated in neurotoxicity.46 In a retrospective study of adults receiving combination chemotherapy including oxaliplatin, calcium and magnesium infusions diminished the incidence and intensity of neuropathy.47 Because of these findings and the potential complications of carbamazepine administration, we did not further escalate the oxaliplatin dose. Because the MTD and DLT of oxaliplatin administered every 3 weeks were similar to those in adults, we also evaluated the tolerability of a fixed dose of 85 mg/m2 (two thirds of the MTD of oxaliplatin given every 3 weeks) administered every 2 weeks. We encountered no DLT, and toxic effects were similar to those seen in the other patients. In this pediatric cohort, the pharmacokinetics of ultrafiltrable Pt were similar to those observed in adults.43 Whereas many adult studies have used a two-compartment model, a three-compartment model adequately described the ultrafiltrable Pt data obtained through our extensive and protracted sampling strategy. Clearance of ultrafiltrable Pt in adult studies has ranged from 9.3 to 25.7 L/h (5.3 to 14.6 L/h/m2 if normalized to average adult body-surface area, 1.76 m2, which is consistent with our results).43 As in adults, plasma-free Pt had a long terminal half-life (range, 87 to 743 hours).43 We observed no CRs or PRs, but approximately one third of assessable patients (seven of 23) experienced disease stabilization. Although these results might understandably discourage further evaluation of oxaliplatin in children, experience in adults with colorectal carcinoma suggests otherwise. Phase II studies of oxaliplatin monotherapy in adults with previously untreated colon carcinoma demonstrated disappointing response rates (range, 9% to 24%)31,48,49; however, but in later phase III studies, oxaliplatin given with fluorouracil and leucovorin was superior to standard therapy with fluorouracil and leucovorin alone and to fluorouracil given with leucovorin and irinotecan.28,50 Four other pediatric oxaliplatin studies have been completed or are in progress. A phase II evaluation of single-agent oxaliplatin in pediatric brain tumors documented two PRs in 15 patients with a first recurrence of medulloblastoma.51 The Children's Oncology Group has recently completed two studies whose results are not yet available: a phase I study of oxaliplatin and irinotecan and a phase II single-agent study. A fourth study evaluating oxaliplatin in combination with etoposide is ongoing at St Jude Children's Research Hospital (Memphis, TN). In summary, the MTD, PK, and adverse effect profile of oxaliplatin are similar in children and adults. Although carbamazepine appeared to diminish dose-limiting neurotoxicity, its adverse effects suggest that other approaches (eg, calcium and magnesium infusions) are preferable. Because oxaliplatin is not associated with nephrotoxicity or ototoxicity and may be active against tumors resistant to cisplatin and carboplatin, oxaliplatin should be evaluated in pediatric malignancies routinely treated with platinum agents. Additional studies are needed to identify oxaliplatin-containing combination regimens that are active against pediatric malignancies and to determine the role of this novel platinum compound in pediatric oncology.
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. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Sheri L. Spunt, Sanofi-Synthelabo; Charles B. Pratt, Sanofi-Synthelabo Testimony: N/A Other: N/A
Conception and design: Sheri L. Spunt, Catherine A. Billups, Charles B. Pratt, Clinton F. Stewart Administrative support: Valerie McPherson Provision of study materials or patients: Sheri L. Spunt, Charles B. Pratt Collection and assembly of data: Sheri L. Spunt, Burgess B. Freeman III, Catherine A. Billups, Valerie McPherson, Raja B. Khan, Charles B. Pratt, Clinton F. Stewart Data analysis and interpretation: Sheri L. Spunt, Burgess B. Freeman III, Catherine A. Billups, Charles B. Pratt, Clinton F. Stewart Manuscript writing: Sheri L. Spunt, Burgess B. Freeman III, Catherine A. Billups, Raja B. Khan, Clinton F. Stewart Final approval of manuscript: Sheri L. Spunt, Burgess B. Freeman III, Catherine A. Billups, Valerie McPherson, Raja B. Khan, Clinton F. Stewart
We thank S. Percy Ivy, MD, of the National Cancer Institute, Investigational Drug Branch, for facilitating the development of this clinical trial. We also thank Sharon Naron, ELS, for editorial assistance.
 Deceased.  Supported by Cancer Center Grant No. CA 23099 and Cancer Center Support Grant No. P30 CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 1 before the next course of chemotherapy. Grade 2 neuropathy that did not resolve before the next cycle of therapy was also considered dose limiting, as was a delay in treatment 
4 weeks. 
) were calculated using model parameters. The area under the concentration-time curve (AUC0-
) was calculated by using the log-linear trapezoidal method. Finally, the parameter distribution from the subgroup of patients with adequate platinum ultrafiltrate data was used to apply a maximum a posteriori (MAP) Bayesian approach to the entire study group to generate final parameter estimates. 
