Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study

  1. Darrell J. Yamashiro
  1. From the College of Physicians and Surgeons of Columbia University, New York, NY; Children's Hospital of Philadelphia, Philadelphia, PA; Mayo Clinic and Foundation, Rochester, MN; Genentech Inc, South San Francisco; Children's Hospital, Los Angeles; Children's Oncology Group, Arcadia, CA; Hospital for Sick Children; Sunnybrook and Women's College Health Sciences Centre, Toronto, Canada; National Cancer Institute, Bethesda, MD; and the Texas Children's Cancer Center, Houston, TX
  1. Corresponding author: Julia Glade Bender, MD, Pediatric Oncology, Irving Pavilion 7, 169 Ft. Washington Ave, New York, NY 10032; e-mail: jg589{at}columbia.edu.
 
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Abstract

Purpose We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)–neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer.

Patients and Methods BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors.

Results Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data.

Conclusion BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

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INTRODUCTION

Vascular endothelial growth factor (VEGF) is the best-characterized pro-angiogenic factor.1 A recent cascade of clinical evidence has validated antiangiogenesis by VEGF blockade as effective cancer therapy in renal, colorectal, non–small-cell lung, and other carcinomas.2-5 The humanized anti-VEGF antibody bevacizumab (BV; Avastin; Genentech Inc, South San Francisco, CA)6 was the first to demonstrate proof of principle, and has been US Food and Drug Administration–approved for adult use at doses of 5 to 15 mg/kg. Monoclonal anti-VEGF antibody (A.4.6.1 or BV) has produced inhibition of tumor angiogenesis in preclinical models of pediatric tumors, including rhabdomyosarcoma,7,8 Wilms’ tumor,9 neuroblastoma,10 and hepatoblastoma.11 These studies support the evaluation of BV in children with cancer. Findings of reversible physeal dysplasia and ovarian and uterine changes in juvenile monkeys during BV preclinical testing,12 however, have raised concerns of potential pediatric-specific adverse effects.

Between December 2003 and September 2005, the Children's Oncology Group phase I and Pilot Consortium conducted a phase I trial of BV in children with refractory extracranial solid tumors. Primary aims included estimating the maximum-tolerated (MTD) or recommended phase II dose using a restricted dose-escalation scheme bracketed around clinically efficacious doses in adults, defining dose-limiting toxicities (DLTs) and other toxicities, and describing BV pharmacokinetics in children. Secondary aims included assessment of BV antitumor activity and exploration of potential biomarkers of antiangiogenesis.

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PATIENTS AND METHODS

Study Design

BV provided by the Cancer Therapy Evaluation Program (National Cancer Institute, Bethesda, MD) was administered as a 30- to 90-minute infusion on days 1 and 15 of a 28-day course, with no interruption between courses. On the basis of adult data, the starting dose was 5 mg/kg, with cohort escalations to 10 and 15 mg/kg. Further escalations were to be undertaken, on the basis of tolerability, only if median clearance in children was at least two-fold greater than that observed in adults. Intrapatient dose escalation was not permitted. Patients with grade 3 toxicity (excluding hypertension controllable with oral medication) not resolving within 4 weeks of drug administration would not resume therapy. Courses could be repeated up to 24 times, provided that the patient had stable disease and met eligibility laboratory parameters.

A minimum of three patients was studied at each dose level. If none experienced a DLT, three subsequent patients were enrolled at the next higher dose level. If one of three patients at a given dose level experienced a DLT, up to three more were treated at the same level. The MTD was defined as the dose level at which zero of six or one of six patients experienced DLT with at least two of three or two of six patients encountering DLT at the next higher dose. At either the established MTD or the highest dose level tested, enrollment would be extended to allow up to six patients under age 12 to further evaluate toxicity in this younger patient group.

Common Terminology Criteria for Adverse Events (CTCAEv3) was used to grade toxicities. Hematologic DLT was defined as drug-related grade 4 neutropenia or thrombocytopenia, grade 3 thrombocytopenia requiring transfusion, or failure to return to grade 1 thrombocytopenia or grade 2 neutropenia resulting in delay of more than 14 days between doses. Nonhematologic DLT was defined as grade 2 arterial thrombosis, grade 2 hemorrhage, grade 3 venous thrombosis, or any grade 3 or 4 toxicity possibly, probably, or definitely related to BV excluding: grade 3 transaminase (AST/ALT) elevation that returned to grade 1 or better, or baseline, before next treatment; grade 3 fever or infection; and grade 3 hypertension well controlled with oral medication. Any drug-related adverse event that led to dose omission (eg, platelets < 75,000, proteinuria > 2 g/24 hours, hypertension uncontrollable with medication) was also considered dose-limiting, but patients could remain on study if reversible within 4 weeks.

Vital signs (including blood pressure), urinalysis, serum creatinine, liver function tests, CBC, and electrolytes were examined weekly throughout the first course of therapy and subsequently every 2 weeks. Disease evaluations were performed at the end of odd-numbered courses.

Patient Eligibility

Patients age 1 to 22 years with solid tumors refractory to standard treatment or for which no curative therapy existed who had measurable or assessable disease, were eligible. Patients with lymphoma, primary brain tumors, or CNS metastasis were excluded. Other eligibility criteria included Karnofsky or Lansky performance status of at least 50%; life expectancy more than 8 weeks; adequate bone marrow function (absolute neutrophil count ≥ 1,000/μL, platelet count ≥100,000/μL, and hemoglobin ≥ 8gm/dL); urine protein less than 500 mg/24 hours; adequate clotting, renal, and liver function; and full recovery from acute toxic effects of prior chemotherapy or radiotherapy. At least 28 days were to have elapsed between major surgery or significant trauma and enrollment, and at least 7 days between minor surgery and enrollment. Patients could not have a known history of stroke, myocardial infarction, severe angina, peripheral vascular disease, or recent (within 3 months) deep venous thrombosis. Baseline hypertension had to be well controlled on stable medication for 2 weeks; a head computed tomography scan should be negative for CNS metastasis.

Institutional review boards at participating institutions approved the study. Informed consent and child assent, when appropriate, were obtained according to individual institutional policies.

Response Evaluation

Response Evaluation Criteria in Solid Tumors13 was used for assessment. All patients with measurable disease at enrollment and who received at least one dose of bevacizumab were eligible for such assessment. Time to progression was calculated as the number of courses from enrollment to disease progression.

Growth and Development Toxicity Monitoring

A lower-extremity scanogram, a femur/tibia radiograph used to assess pediatric limb length discrepancy,14 and bone age (anteroposterior radiograph of the left hand and wrist) were obtained at baseline, every 2 months, and/or time of progression in patients who had not yet achieved adult height. Regardless of pubertal status, ovarian function in females was followed with Tanner staging; menstrual history and calendar; and luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol sampling at baseline, end of course 1, and days 3 and 21 of a menstrual cycle if possible.

Pharmacokinetic and Pharmacodynamic Studies

Subject participation in pharmacokinetic (PK) and pharmacodynamic (PD) components of the trial was voluntary according to previously published ethical guidelines for COG phase I Consortium protocols.15 For PK studies, blood samples were drawn during course 1 before treatment, and 10 minutes, 3 hours, 5 hours, and 1, 2, 4, 7, and 14 days after the day-1 infusion; 10 minutes and 14 days after the day-15 infusion; and then before day-1 infusions in subsequent courses. Samples (3 mL) were collected in tubes without added anticoagulant, placed upright (30 minutes) and centrifuged (3,000 × g for 10 minutes at 4°C). Serum was stored at −70°C until analysis. BV concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). The minimum quantifiable concentration in human serum was 78 ng/mL (Genentech Inc).

Concentration versus time data after the first dose (day 0 to day 14) were analyzed by standard noncompartmental methods using WINNonlin (Scientific Consultant, Apex, NC) Pro v.4.1 (Pharsight Corporation, Mountain View, CA). The apparent terminal elimination rate was determined by linear least-squares regression of BV serum concentration versus time data through 4 to 14 days.

PD samples were collected in EDTA tubes. One was immediately centrifuged at 4°C to separate plasma. Plasma (VEGF, basic fibroblast growth factor [bFGF], and thrombospondin-1 [TSP-1]) analysis was performed using commercially available ELISA (Quantikine VEGF and QuantikineHS bFGF kits, R&D Systems Inc, Minneapolis, MN; TSP-1 competitive ELISA kit, Neogen Corporation, Lansing, MI). Total circulating endothelial cells (tCEC), the progenitor subset (CEP), and the apoptotic fraction (aCEC) were analyzed within 24 hours of collection after shipment on ice. Mature CEC (mCEC) were calculated by deducting the number of CEP from total CEC population per sample. Cells were counted using a four-color fluorescence-activated cell sorter using anti-CD45 (to exclude hematopoietic cells), anti-CD31 and anti-CD146 (endothelial markers), anti-CD133 (a progenitor cell marker), and 7AAD (a marker of apoptosis16) with appropriate analysis gating as described previously.17-19 CEC and CEP analyses were conducted in one laboratory (R.S.K. and Y.S.) with consistent flow cytometry settings, gating, and overall procedures for each specimen evaluated. At least 100,000 events were collected to ensure accuracy of the results.

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RESULTS

Of the 21 patients enrolled, 20 were eligible, 19 of whom received at least one dose of drug, and 18 of whom were fully assessable for toxicity (Table 1). The one ineligible patient had major surgery 10 days before enrollment and was removed after the first dose. Three, three, and 12 patients were assessable at the 5-, 10-, and 15-mg/kg dose levels respectively. Two patients enrolled at the 15 mg/kg dose level were not fully assessable for toxicity: One withdrew consent before receiving the first dose of BV, and the other developed progressive disease on day 12 without experiencing DLT. In the remaining 18 fully assessable patients, a total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Interim PK analysis did not support escalating beyond the 15-mg/kg dose level.

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Table 1.

Demographic and Clinical Characteristics of Eligible Patients (n = 20)

Toxicity

No patient experienced DLT (Table 2). In general, BV was well tolerated. Only one grade 3 toxicity attributable to the agent (lymphopenia) was observed (Table 2). Common non–dose-limiting, grade 1 to 2 toxicities included infusion reaction (n = 3), rash (n = 3), mucositis (n = 2), and proteinuria (n = 3). No hemorrhage or thrombosis was reported. Non–dose-limiting increases in blood pressure (BP) were observed in the majority of children irrespective of dose level. Individually, 11 of 16 patients with complete documentation of day 1 and day 21 BP experienced an increase, whereas five of 16 had no change or decrease in BP. As a group, pediatric patients showed a statistically significant rise with a median rise of 6 mmHg (mean, 6.4 mmHg) for systolic (P = .038) and 9 mmHg (mean, 7.8 mmHg) for diastolic pressures (Wilcoxon signed rank test P = .002; Fig 1). Self-limited grade 1 CTCAEv3-defined hypertension was observed in only one patient, who entered the study while taking a longstanding antihypertensive (amlodipine).

Fig 1.
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Fig 1.

Statistically significant but clinically asymptomatic rise in systolic and diastolic blood pressure across dose levels in the majority of patients from day 1 (preinfusion) to day 21 of course 1 at each dose level.

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Table 2.

Non–Dose-Limiting Toxicities With Possible, Probable, or Definite Relationship to Protocol Therapy and Observed in More Than 10% of 19 Eligible Patients With Relapsed/Refractory Solid Tumors Who Received at Least One Dose of Drug

Growth and Development

There were three patients with open epiphyses and complete radiographic evaluation at baseline and after 1 to 2 months of therapy. None exhibited physeal expansion during this limited time period. Endocrine evaluations were available for seven of 10 eligible female patients. Of these, three were postmenarchal. One enrolled onto study with secondary amenorrhea. Another exhibited a two-fold rise in FSH and LH without concomitant change in estradiol after two courses of therapy. The third had a menstrual period that was normal in duration and flow 4 days after her first dose of BV. At the end of the first course, there was a marked rise noted in her LH and FSH, and the subsequent period was missed. No menstrual data are available after completion of therapy.

Antitumor Activity

Of the 19 eligible patients who received at least one dose of BV, 15 had Response Evaluation Criteria in Solid Tumors–measurable disease and 4 had assessable disease. There were no complete or partial responses. Five patients, all with bone or soft tissue sarcomas, received more than three courses while receiving therapy: three patients with Ewing sarcoma received four (n = 1) and nine (n = 2) courses, and patients with alveolar soft part sarcoma and mesenchymal chondrosarcoma received five and 16 courses, respectively, before disease progression.

Pharmacokinetics

The pharmacokinetics of BV were characterized with data from the first dose from 8 of 10 participating patients with sufficient sample numbers. Mean serum concentration-time profiles for the 5- and 15-mg/kg BV dose levels are shown in Figure 2. Because serum concentration-time data fit a one-compartment model in three patients and a two-compartment open model in five patients, data were analyzed by noncompartmental methods to provide comparable pharmacokinetic estimates for all patients (Table 3). Maximum serum concentration (Cmax) and area under the concentration-time curve (AUC) values were proportional to dose. BV serum clearance values varied over a five-fold range (3.1 to 15.5 mL/d/kg) with a median value of 4.1 mL/d/kg, whereas half-life (t1/2) values varied over a four-fold range (4.4 to 14.6 days) with a median value of 11.8 days.

Fig 2.
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Fig 2.

Mean serum concentration-time profiles for bevacizumab 5 (yellow circles) and 15 (blue circles) mg/kg administered by 30- to 90-minute infusion to pediatric patients. A postinfusion model that accounted for the length of infusion for each patient was used for the analysis.

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Table 3.

Bevacizumab Pharmacokinetics

Pharmacodynamics

There was significant interpatient variability in all correlative assays. No correlation was observed between baseline VEGF, TSP-1, bFGF, CEC or CEP, and clinical benefit. Three of 13 patients had two-fold rise in plasma VEGF after the first course (course 1, day 28), and two of these three, received more than three courses of therapy. However, our assay did not separate free from BV-bound VEGF. The number of mCEC increased in six of eight patients from baseline to the end of the first treatment course (Fig 3A). It has recently been reported that patients responding to antiangiogenic treatment reveal a significant increase in aCEC, and it has been speculated that these cells derive from the damaged tumor vasculature.19 Given the heterogeneity of the study population, we determined the apoptotic to total CEC ratio (aCEC/tCEC) at baseline and day 28 and associated this ratio to the number of cycles received before progression (Fig 3B).

Fig 3.
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Fig 3.

Pharmacodynamic studies were obtained at baseline, on day 28 of the first course, and then at an every-other-month interval. Each line represents one patient. (A) Mature circulating endothelial cells (CEC) seemed to rise in most patients after the first course of therapy. (B) The percentage of apoptotic CEC was used to assess CEC viability while normalizing for intrapatient variability of baseline values. The number of cycles received before disease progression follows the day-28 data point. mCEC, mature circulating endothelial cells.

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DISCUSSION

The VEGF-neutralizing antibody BV in children with refractory solid tumors was administered biweekly at doses up to 15 mg/kg. No DLTs were observed, and a MTD was not defined. Overall, BV therapy was well tolerated in these pediatric patients, with only minor complaints of infusion reaction, rash, mucositis, and proteinuria, with none requiring discontinuation of therapy. Rare but serious adverse events seen in adults, including severe hemorrhage, arterial thromboembolism, wound-healing complication, GI perforation, hypertensive crisis,20 nasal septum perforation,21 and reversible posterior leukoencephalopathy syndrome22 were not observed. However, this is not unexpected given the low incidence of these events, the small size of this pediatric cohort, and the limited number of courses administered.

Similar to findings for VEGF-blocking agents in adults, there seemed to be rise in both diastolic and systolic BP after BV administration in the majority of patients. This did not meet CTCAEv3 criteria for hypertension except in a single patient with longstanding BP elevation. These observations are again constrained by the relatively short duration of therapy, the limited availability of BP recordings, and the small sample set, which does not allow for significant conclusions regarding dose dependency or cumulative effects. Nonetheless, it suggests that pediatric-specific guidelines for the management of hypertension as a result of BV therapy may be required in the future. Although the precise mechanism of hypertension during BV therapy has not been established, adult trials suggest that this is reversible.2

Angiogenesis in general and VEGF in particular are critical for normal embryogenesis and growth. In mice, VEGF neutralization resulted in a paucity of metaphyseal vessels and failure of capillaries to invade the hypertrophic chondrocyte zone, resulting in a three- to six-fold expansion of the epiphyseal chondrocyte layer and reduced femur lengthening after 14 days of treatment. In this model, the changes seemed reversible after cessation of therapy.23 In our study, no effects on open epiphyses were detected during the limited study period. This early finding does not address long-term effects on adult height and bone health, which should be a focus of future studies. Likewise, a rise in LH and FSH levels in two of three postmenarchal girls post-BV is consistent with suppression of ovarian function, and supports further study of this effect in young women.

In our pediatric study, drug exposure was proportional to dose (Table 3). Although a large degree of interpatient variability in drug disposition was observed in children, overall, it was similar to that observed in adults.24-28 In adults, BV exhibits linear pharmacokinetics at doses ranging from 1 to 20 mg/kg and intervals from 1 to 3 weeks. Disposition is characterized by low clearance and volume of distribution consistent with limited extravascular distribution.24,25 Median values of clearance (4.1 mL/d/kg) and mean residence time (16.3 days) in children were similar to the median clearance (3.9 mL/d/kg) and mean residence time (12.4 days) values in adults.24 Although there is some evidence of a sex difference in BV pharmacokinetics for adult patients,26-28 our patient numbers precluded us from performing a similar analysis in children.

As in adults, our pediatric phase I trial of BV did not identify an MTD. The best means to determine optimum biologic dosing for VEGF-targeting strategies is unknown. Mature CEC are believed to enter the blood after sloughing from unstable, injured, or actively remodeling vessels. CEC have been shown to be elevated in adult cancer patients, increasing with progression and decreasing with remission.17 Early correlative studies in breast, lymphoma, and GI stromal tumor patients suggest that kinetics of CEC have potential as biomarkers of antiangiogenic or metronomic chemotherapy.19,29-31 This is one of the first pediatric studies to prospectively measure cellular biomarkers of angiogenesis. Comparative values for healthy controls and children with cancer are not available. Our observation that mCEC tend to increase with BV is consistent with recent adult data,19,31 and the suggestion that viability of CEC (aCEC/tCEC) may predict either host sensitivity or clinical benefit remains intriguing. Further evaluation of mobilization and viability of CEC in children may increase our understanding of response to VEGF blockade and potentially aid in clinical decision making.

In summary, this is to our knowledge the first report of a VEGF-targeted agent to complete phase I testing in children with refractory solid tumors. BV seems to have an acceptable toxicity profile when administered at doses of 5, 10, or 15 mg/kg every 2 weeks. Drug disposition in pediatric patients seems to be similar to that observed in adults; therefore, common adult BV dosing schedules of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks will be pursued in pediatrics. Although we did not observe adverse effects on growth or development, additional studies are needed to evaluate longer-term effects of this agent in children. These data, together with the experimental evidence of anti-VEGF efficacy in pediatric tumor models and the proven clinical benefit of BV in adult cancers,3,4,32 suggest that additional studies of BV in combination with chemotherapy in children are warranted. Phase II studies that include population PK analysis and biologic correlates are planned in pediatric Ewing sarcoma, soft tissue sarcoma, and brain tumors.

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Authors’ Disclosures of Potential Conflicts of Interest

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: Lu Xu, Genentech (C) Consultant or Advisory Role: Robert S. Kerbel, Genentech (C), ImClone Systems (C) Stock Ownership: Lu Xu, Genentech Honoraria: Robert S. Kerbel, Pfizer, Roche, Novartis, Amgen Research Funding: Robert S. Kerbel, ImClone Systems; Marvin D. Nelson, NCI - COG IRC Expert Testimony: None Other Remuneration: None

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Author Contributions

Conception and design: Julia L. Glade Bender, Peter C. Adamson, Helen X. Chen, Mark D. Krailo, Susan M. Blaney, Jessica J. Kandel, Darrell J. Yamashiro

Administrative support: Helen X. Chen, Susan M. Blaney

Provision of study materials or patients: Julia L. Glade Bender, Helen X. Chen, Marvin D. Nelson

Collection and assembly of data: Julia L. Glade Bender, Yuval Shaked, Robert S. Kerbel, Erin M. Cooney-Qualter, Diana Stempak, Marvin D. Nelson, Mark D. Krailo, Ashish M. Ingle, Darrell J. Yamashiro

Data analysis and interpretation: Julia L. Glade Bender, Peter C. Adamson, Joel M. Reid, Lu Xu, Sylvain Baruchel, Yuval Shaked, Robert S. Kerbel, Diana Stempak, Helen X. Chen, Marvin D. Nelson, Mark D. Krailo, Ashish M. Ingle, Susan M. Blaney, Jessica J. Kandel, Darrell J. Yamashiro

Manuscript writing: Julia L. Glade Bender, Peter C. Adamson, Lu Xu, Robert S. Kerbel, Mark D. Krailo, Ashish M. Ingle, Jessica J. Kandel, Darrell J. Yamashiro

Final approval of manuscript: Julia L. Glade Bender, Peter C. Adamson, Lu Xu, Sylvain Baruchel, Robert S. Kerbel, Diana Stempak, Helen X. Chen, Marvin D. Nelson, Jessica J. Kandel, Darrell J. Yamashiro

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Acknowledgments

We thank Elizabeth O'Connor and Carrianne Hanson of the COG phase I/Pilot Consortium Coordinating Center for outstanding administrative support throughout the development, conduct, and analysis of this clinical trial.

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Footnotes

  • Supported by Grant No. CA97452 from the National Cancer Institute, Bethesda, MD; the Pediatric Cancer Foundation, Scarsdale, NY; Genentech Inc, South San Francisco, CA; and COG Grant No. CA 98543. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm.

  • Sponsored by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program, under the Clinical Research and Development Agreement (CRADA) between NCI and Genentech Inc.

  • Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

  • Received April 12, 2007.
  • Accepted October 16, 2007.
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  1. doi: 10.1200/JCO.2007.11.9230 JCO vol. 26 no. 3 399-405
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