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Phase I Study of Weekly Oxaliplatin in Relapsed or Refractory Pediatric Solid Malignancies

Birgit Geoerger, François Doz, Jean-Claude Gentet, Michele Mayer, Judith Landman-Parker, Fabienne Pichon, Pascal Chastagner, Hervé Rubie, Didier Frappaz, Anne Le Bouil, Sunil Gupta, Gilles Vassal

From the Institut Gustave-Roussy, Villejuif; Institut Curie, Hopital Saint-Vincent de Paul, and Hopital Trousseau, Paris; Hopital de la Timone, Marseille; Centre Oscar Lambret, Lille; Hopital d’Enfants, Nancy; Hopital Purpan, Toulouse; Centre Léon Bérard, Lyon; Centre Hospitalier Universitaire, Angers, France; and Sanofi-aventis, Malvern, PA

Corresponding author: Birgit Geoerger, MD, PhD, Department of Pediatrics, Institut Gustave-Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France; e-mail: geoerger{at}igr.fr

	ABSTRACT

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Purpose To explore feasibility, maximum-tolerated dose (MTD), and recommended dose (RD) for phase II studies of weekly oxaliplatin for the treatment of relapsed or refractory pediatric solid malignancies.

Patients and Methods Eligible patients were 6 months to 21 years old, had a diagnosis of a solid malignancy, and had experienced treatment failure with at least two or more previous lines of therapy. The phase I study was multicentric, open-label, and nonrandomized. It foresaw two phases: a dose-escalation phase (comprising six levels) to find the RD and an extension at the RD to evaluate the cumulative toxicity. Oxaliplatin was administered intravenously over 2 hours on days 1, 8, and 15 of a 28-day cycle.

Results Forty-five patients were enrolled: 29 patients in the dose-escalation phase and 16 patients in the extension at the RD. Median age was 9.5 years (range, 2.8 to 20.0 years) and 7.8 years (range, 1.8 to 19.2 years), respectively. The dose-limiting toxicities during the first treatment cycle were grade 3 (G3) sepsis at 50 mg/m², G3 dysesthesia at 90 mg/m², and G3 dysesthesia and G3 paresthesia at 110 mg/m², thus the MTD and RD was 90 mg/m². No case of ototoxicity was reported. Stable disease was reported in seven patients (16.3%), and confirmed partial response was observed in two patients (4.7%), one with neuroblastoma and one with osteosarcoma.

Conclusion Oxaliplatin administered in a weekly schedule has an acceptable safety profile, different from cisplatin and carboplatin, and shows activity in children with relapsed or refractory solid tumors, suggesting further investigation in pediatric malignancies.

	INTRODUCTION

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Oxaliplatin-based chemotherapy is a standard for adjuvant and advanced treatment of colorectal cancer in adults.^1-3 Like other platinum compounds, oxaliplatin forms platinum-DNA adducts, leading to cell death.⁴ In addition, it is active in cell lines with acquired or intrinsic cisplatin resistance and in tumors resistant to first line platinum-based therapy.^5,6

Cisplatin and carboplatin are key chemotherapeutic components in a variety of pediatric malignancies but are associated with severe renal or neuronal toxicities, myelosuppression,⁷ and ototoxicity,^8-11 the latter possibly leading to a poor quality of life, especially for children.

Oxaliplatin exhibits a different toxicity profile, mainly related to sensory neuropathy, which generally resolves over time.¹² Lack of renal and ototoxicity would be an important benefit and may potentially allow platinum dose intensification. Furthermore, a weekly schedule of oxaliplatin given at a lower total dose may enable prolonged exposure to active compound and reduce adverse effects.

To explore whether weekly oxaliplatin is a feasible treatment option for relapsing or refractory pediatric solid malignancies, we conducted a multicenter, open-label, noncomparative, nonrandomized phase I study.

	PATIENTS AND METHODS

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Eligibility
Eligibility criteria included patient age of 6 months to 21 years; histologic or cytologic diagnosis of solid malignancy; two or more previous lines of chemotherapy and/or no effective treatment available; life expectancy 6 weeks; no concomitant anticancer or investigational drug; Eastern Cooperative Oncology Group performance status 2 or Lansky play score more than 50%; completion of anticancer therapy 4 weeks before study entry; no clinical evidence of peripheral sensory or motor neuropathies; adequate bone marrow; AST/ALT 2.5x the upper limit of normal (ULN); bilirubin 1.5x the ULN; creatinine less than 3x the ULN for age; no organ toxicity, including ototoxicity grade 2; and informed consent signed. The protocol was approved by institutional review board/independent ethics committee.

Treatment Design
The study was articulated in two phases: a dose-escalation phase to determine the maximum-tolerated dose (MTD) and the recommended dose (RD) and an extension to evaluate activity and cumulative toxicity at the RD. Dose escalation was started at 40 mg/m² (80% of adult RD intensity/wk), then escalated to 50, 60, 75, 90, and 110 mg/m². For each dose level, at least three patients were to be treated. If none developed a dose-limiting toxicity (DLT), the next patient received the following dose level. If at least one developed a DLT, up to three additional patients were to be treated at the same dose. If two or more DLTs occurred at a given dose level, escalation was stopped, leading to three additional patients treated at the previous dose level. Intrapatient dose-escalation was not allowed. MTD and RD were thus defined as the dose level immediately below the dose at which at least two patients experienced DLT during cycle 1. In the extension phase, at least 10 patients were to receive no fewer than four cycles at the RD to evaluate cumulative toxicity.

Oxaliplatin was administered intravenously over 2 hours on days 1, 8, and 15 of a 28-day cycle. Antiemetic treatment, including anti-5-HT₃ with corticosteroids, was allowed. Treatment was to be continued until disease progression, unacceptable toxicity, patient or parental refusal, or treatment delay of more than 3 weeks.

Toxicity
A DLT was defined as grade 4 neutropenia lasting more than 7 days, grade 4 thrombocytopenia (< 10.0 x 10⁹/L) lasting more than 7 days, documented infection during grade 4 neutropenia, any grade 3 or worse nonhematologic toxicity (except grade 3 nausea/vomiting in absence of optimum antiemetic treatment, transient AST/ALT, fever, or mucositis), grade 2 peripheral neuropathy not resolved before initiation of the following cycle, or life-threatening toxicity.

Adverse events and laboratory variables were assessed using the National Cancer Institute Common Toxicity Criteria version 2.0, with the exception of neurotoxicity, which was graded to an oxaliplatin neurotoxicity scale: grade 1, paresthesias/dysesthesias, possibly cold-induced, interfering with function; grade 2, paresthesias/dysesthesias interfering with function but not with activities of daily living; grade 3, paresthesias/dysesthesias with pain or functional impairment and also interfering with activities of daily living; and grade 4, paresthesias/dysesthesias that are disabling or life-threatening. An audiometric test was conducted every four cycles.

If a grade 4 neutropenia or grade 3 to 4 thrombocytopenia occurred on day 8 or day 15, treatment was omitted. The next cycle began at day 29 after recovery to grade 2 neutropenia and grade 2 thrombocytopenia. In case of nonhematologic toxicity, treatment was delayed until less than grade 1 or recovery. Paresthesias/dysesthesias were required to be grade 2 before the next cycle. No treatment was administered in case of grade 2 sensory neuropathy on days 8 or 15. In the event of pharyngolaryngeal dysesthesia, the infusion duration was to be increased from 2 to 6 hours. Doses that were reduced for toxicity were not re-escalated. If grade 4 toxicity kept persisting despite dose reduction, treatment was to be discontinued, but safety and efficacy evaluations were to be continued.

Neurophysiologic Evaluation
Neurophysiologic evaluation was performed at baseline and after at least four cycles of treatment or if neurologic toxicity occurred. It consisted of comprised measurement (Viking II and Spirit machines; Nicolet Biomedical Sarl, Trappes, Yvelines, France) of conduction velocity in the median nerve and somesthetic-evoked potentials (SEPs) in the median and posterior tibial nerves. For each test, at least two recordings were obtained and the results were compared with previously established normative laboratory values (M. Mayer, personal communication, August 2005).

Pharmacokinetics
Blood samples for plasma and plasma ultrafiltrate (PUF) platinum concentrations were collected at selected collection times during cycle 1 and immediately before starting cycle 2. Five mL of blood were drawn and immediately centrifuged at 1,000 x g for 10 minutes at 4°C. A total of 500 µL of plasma was removed and frozen for total platinum analysis. Two mL of the remaining plasma was loaded onto Amicon micropartition filters (Millipore S.A., Saint-Quentin, France) and centrifuged at 2,000 x g for 30 minutes (4°C). The protein-free ultrafiltrate was stored at –20°C until analysis. Platinum concentrations were determined using a validated Inductively Coupled Plasma Mass Spectrometry method that measures atomic platinum with a limit of quantification of 1 ng/mL for PUF.

Oxaliplatin-associated platinum concentrations in PUFs were analyzed using a noncompartmental pharmacokinetic analytic method (WINNonlin Professional, version 4.01; Scientific Consultant, Apex, NC). Maximum concentrations (C_max) were obtained directly from experimental observations. The area under the concentration-time curve (AUC) from time 0 to 48 hours (AUC_{0-48 hours}) was calculated using the trapezoidal method. The AUC from time 0 to infinity was calculated as a function of time from 0 to the real time t_last, with time corresponding to the last concentration above the limit of quantification (AUC_last) plus (last concentration [C_last]/slope of the regression line of the terminal phase of the plasma concentration versus time curve, on a semi-logarithmic scale [z]). AUC values were retained only if the percent of extrapolated AUC was less than 10%. The plasma clearance (CL) was calculated as dose/AUC. The volume of distribution at steady-state (Vss) was calculated as CL times the mean residence time (MRT = AUMC/AUC – t/2; where t is the infusion duration and AUMC is the area under the curve of moments calculated using the trapezoidal method).

In addition, PUF platinum terminal half-life (t_1/2, t_1/2β, and t_1/2) was calculated by compartmental analysis (WINNonlin Professional, version 4.01). Best fit was assessed by visual analysis of residuals. A three-compartment model best fitted the PUF concentration-versus-time data after multiple dosing. A weighted least squares computation (1/y²) was used for PUF.

Tumor Response
Tumor response was assessed according to WHO criteria^13,14 every two cycles. Objective responses were to be confirmed at 4 to 6 weeks. Efficacy parameters included complete response (CR), partial response (PR), duration of response (time from CR or PR to disease progression), and progression-free survival (PFS; time from first treatment to disease progression, death, or cutoff date).

	RESULTS

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Patient Characteristics
Twenty-nine patients were enrolled in the dose-escalation phase, and 16 patients were enrolled in the extension phase (Table 1). Median age at enrollment was 9.5 years and 7.8 years, respectively. The majority of patients had Eastern Cooperative Oncology Group performance status 0 to 1, metastatic disease, and had experienced relapse after prior therapy (median, two chemotherapy regimens, with nearly all including platinum compounds). Overall, 46% of patients had bone and 36% had bone marrow involvement.

In the extension, 15 patients were treated with oxaliplatin 90 mg/m² and were assessable for efficacy and safety. One patient discontinued because of disease progression before baseline measurements and did not receive study treatment. One patient received only partial cycle 1 treatment because of tumor progression and early death and was not assessed for DLT.

DLTs
During the first treatment cycle, one of six patients experienced dose-limiting grade 3 sepsis at 50 mg/m²; of three patients treated at 110 mg/m², one patient had grade 3 dysesthesia and one had grade 3 paresthesia. Therefore, the dose was de-escalated to 90 mg/m², where one of six patients treated experienced grade 3 dysesthesia (Appendix Table A1, online only). The MTD and RD for the oxaliplatin phase II study was established as 90 mg/m² administered as a 2-hour infusion on days 1, 8, and 15 of a 28-day cycle. Furthermore, during cycle 2, four patients with neuroblastoma experienced dose-limiting grade 3 thrombocytopenia, of whom two patients also experienced grade 4 neutropenia, one patient experienced grade 3 dehydration after vomiting, and one patient experienced grade 3 laryngospasm.

Safety
A total of 59 cycles were administered (median, two cycles/patient; range, one to six cycles) during the dose-escalation phase, and 28 cycles (median, two cycles/patient; range, one to four cycles) were administered in the extension phase at the RD. The mean cumulative normalized dose was 389 mg/m² (range, 120 to 1,220 mg/m²) and 425 mg/m² (range, 180 to 1,080 mg/m²) in the dose-escalation and extension phases, respectively. Seven patients (three patients during dose-escalation and four patients at the RD) had received cumulative oxaliplatin doses greater than 500 mg/m² (range, 720 to 1,220 mg/m²). Six patients (21%) and three patients (20%) in the dose-escalation and RD phases, respectively, had treatment delays of more than 5 days, most because of adverse events. Twenty-three patients (82%) and 11 patients (73%) in the dose-escalation and RD phases had a grade 3 to 4 adverse event, respectively.

Adverse events are listed in Table 2. During the dose-escalation phase, the most common toxicities reported were all grades paresthesia (50%), abdominal pain (39%), and pyrexia (36%). During extension at the RD, the most common toxicities reported were all grades paresthesia (60%), pyrexia (40%), and thrombocytopenia (40%). Grade 3 to 4 thrombocytopenia was reported in 27% of all patients. Grade 1 creatininemia was noted at baseline or during study treatment in seven patients; none experienced grade 2 to 4 renal toxicity. No case of ototoxicity was observed in all six patients receiving four or six treatment cycles as determined by audiometric test (five patients) or clinically (one patient).

View this table: [in this window] [in a new window]   Table 2. Adverse Events Occurring in 10% of Patients in Either Phase of the Study*

Neurophysiologic Evaluation
Thirty-four of 45 patients underwent a neurophysiologic evaluation before oxaliplatin administration. Three of six patients who had received four or more complete cycles of study treatment had a second evaluation 2 to 4 weeks after the last oxaliplatin dose and cumulative doses of 720, 900, and 1,220 mg/m². One evaluation was performed after two cycles and a cumulative dose of 480 mg/m² in a child that had experienced dose-limiting dysesthesia at 110 mg/m². None of the four children reported clinical symptoms at the time of neurophysiologic evaluation.

The amplitude of the response in the sensory axons of type II fibers was reduced after treatment in two patients who had received 900 and 1,220 mg/m²(50% and 36% reductions compared with the initial amplitudes). Both patients had evidence of pre-existing electrophysiologic alterations in sensory axons of type II fibers (88% of the lower limit of normal and at the lower limit of normal). No changes were observed in the two children who received 480 and 720 mg/m². Electrophysiologic changes in motor nerves were not observed.

Median nerve SEPs showed an alteration in the type I fibers of all four patients; however, at baseline, in three children, the SEP amplitudes were already reduced compared with normal values, and they remained stable after oxaliplatin treatment. Similar results were observed for posterior tibial nerve SEPs: one patient had normal (144% of the lower limit of normal) amplitude at baseline, which decreased to 33% of initial value after 1,220 mg/m² of oxaliplatin treatment. The other three patients had subnormal amplitudes at baseline; one of whom underwent a further marked decrease after 720 mg/m² oxaliplatin treatment.

Pharmacokinetics
Because of irreversible binding of platinum complexes to plasma protein and erythrocytes, PUF platinum is considered to represent all the platinum species with antitumor and toxic properties after administration of oxaliplatin.

Forty-one patients were analyzed for pharmacokinetic parameters. Thirty-one of 36 patients having PUF samples available were assessed for PUF platinum clearance. Platinum was highly bound to plasma proteins, with a plasma binding of 66.5% ± 9% (mean ± standard deviation) at the end of infusion, 86.8% ± 4.2% at 1 hour, and 98.1% ± 1.6% at 168 hours. Comparative mean (± standard deviation) platinum concentrations in PUF (0 to 168 hours and 0 to 26 hours), after the first infusion, are shown in Figure 1. Table 3 lists the main PUF pharmacokinetic parameters. PUF clearance was dose-independent (Kruskal-Wallis test, P = .3366), whereas AUC increased linearly with dose (Appendix Fig A1, online only). In two of the three patients experiencing neurologic DLT, pharmacokinetic samples were available. Both patients had high AUCs, although higher levels were found in patients where no DLT was observed. PUF clearance corrected for body-surface area did not seem different according to age groups (Appendix Fig A2, online only).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Platinum concentration-time profiles in plasma ultrafiltrate (mean ± standard deviation) from 0 to 168 hours and 0 to 26 hours after the first infusion.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Correlation of free platinum plasma clearance with pretreatment glomerular filtration rate (GFR) in 21 children treated with oxaliplatin. (——), linear regression line; (–– ––), 95% CIs. Mean ± SE = 1.47 ± 0.16 for the slope and 0.87 ± 0.86 for the intercept. Correlation coefficient r2 = 0.81, P < .0001. PUF, plasma ultrafiltrate.

	DISCUSSION

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The MTD and RD of oxaliplatin for phase II clinical studies in children is 90 mg/m² given as a 2-hour infusion, administered weekly for 3 consecutive weeks of a 4-week cycle. Despite the fact that eligible patients carried advanced disease and were heavily pretreated with myelosuppressive/neurotoxic compounds and radiotherapy, all doses of oxaliplatin were tolerable. As for adults,^15,16 and recently for children,^17,18 we detected a high incidence of peripheral sensory neuropathy (paresthesia and dysesthesia), which resolved over time. Although the second phase of the study aimed to achieve more information on cumulative toxicity, this failed as a result of rapid disease progression in most children. Nevertheless, six patients received cumulative doses between 720 and 1,220 mg/m². No cumulative neurologic toxicity was reported, and further investigation is needed.

Similar to the study of Fouladi et al,¹⁸ a high rate of grade 3 to 4 thrombocytopenia was observed. Most of these children had metastatic neuroblastoma and had received intensive prior treatment. Nausea and vomiting were generally mild. This may be attributed to the concomitant use of 5-HT₃ antagonists (received by 98% of patients), which suggests that these adverse effects can be easily managed with standard antiemetic medications. DLTs were sepsis at 50 mg/m², dysesthesia at 90 mg/m², and dysesthesia and paresthesia at 110 mg/m². Neither renal nor ototoxicity was observed in systematically performed audiometric evaluations after prolonged treatment.

Pharmacokinetic evaluations showed that for a 2.75-fold increase in oxaliplatin dose (40 mg/m² to 110 mg/m²), mean C_max and AUC of platinum in PUF increased by approximately 2.69- and 3.53-fold, respectively. The pharmacokinetic parameters C_max, AUC_0-48, and AUC after oxaliplatin infusion seem to be similar to values observed in adults¹⁹ and those reported recently in two studies in children with every 2 weeks or every 3 weeks oxaliplatin administrations.^17,18

Electrophysiologic evaluations indicate a high incidence of cumulative neurotoxicity on type I and II fibers owing to prior treatments. No evidence of oxaliplatin toxicity was observed on the axons of peripheral motor nerves or on those of central pathways. Data of the four patients who underwent both pre- and post-treatment neurophysiologic evaluations showed evidence of oxaliplatin toxicity on the axons of peripheral sensory type II fibers; however, the neurophysiologic alterations were subclinical.

In the present study, the weekly schedule allowed higher dose-intensity compared with the every 2 weeks or every 3 weeks schedules commonly used (67.5 mg/m²/wk v 42.5 and 43.3 mg/m²/wk, respectively). However, because of the long half-life of oxaliplatin,¹⁸ the weekly schedule was limited by increasing neurotoxicity and thrombocytopenia.

Tumor control was achieved in nine patients, with confirmed PRs reported for two patients at the 110 mg/m² dose level, which was, however, the dose level above the MTD. Considering the advanced disease stage and high level of previous platinum therapy in this population, the efficacy of single-agent oxaliplatin should be further explored, particularly in osteosarcoma and neuroblastoma.

In conclusion, single-agent oxaliplatin administered in a weekly schedule demonstrated acceptable safety (similar to that reported for adults) and activity in pediatric relapsed or refractory solid malignancies. The profile of oxaliplatin seems to be distinct from that of cisplatin and carboplatin in that it is not associated with cumulative renal or ototoxicities. Further investigations are warranted to establish its potential in the treatment of childhood malignancies.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Sunil Gupta, Sanofi-aventis (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Birgit Geoerger, Gilles Vassal

Provision of study materials or patients: Birgit Geoerger, François Doz, Jean-Claude Gentet, Judith Landman-Parker, Fabienne Pichon, Pascal Chastagner, Hervé Rubie, Didier Frappaz, Sunil Gupta

Collection and assembly of data: Birgit Geoerger, Anne Le Bouil, Michele Mayer, Sunil Gupta, Gilles Vassal

Data analysis and interpretation: Birgit Geoerger, Michele Mayer, Anne Le Bouil, Sunil Gupta, Gilles Vassal

Manuscript writing: Birgit Geoerger, Sunil Gupta, Gilles Vassal

Final approval of manuscript: Birgit Geoerger, François Doz, Jean-Claude Gentet, Michele Mayer, Judith Landman-Parker, Fabienne Pichon, Pascal Chastagner, Hervé Rubie, Didier Frappaz, Anne Le Bouil, Sunil Gupta, Gilles Vassal

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Area under concentration-time curves (AUC) values of platinum in plasma ultrafiltrate stratified by dose level in 31 patients after the first oxaliplatin administration. DLT, dose-limiting toxicity.

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Individual plasma ultrafiltrate (PUF) clearance corrected for body-surface area in 31 patients stratified by age groups.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A3. Computed tomography in a 11-year-old patient with a pleural osteosarcoma metastasis showed confirmed partial response after one treatment cycle (right panel) compared with baseline evaluation (left panel).

	ACKNOWLEDGMENTS

 
We thank all patients and their parents who participated in the trial and the teams of the treating centers.

	NOTES

 
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted February 13, 2008; accepted June 11, 2008.

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