VOLUME 26
`
`NUMBER 3
`
`-
`
`JANUARY 20 2008
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`
`
`O R I G I N A L
`
`R E P o R T
`
`Phase I Trial and Pharmacokinetic Study of Bevacizumab in
`Pediatric Patients With Refractory Solid Tumors: A
`Children’s Oncology Group Study
`Iulia L. Glade Bender, Peter C. Adamson, Ioel M. Reid, Lu Xu, Sylvain Baruchel, Yuval Shaked,
`Robert S. Kerbel, Erin M. Cooney—Qualter, Diana Stempak, Helen X. Chen, Marvin D. Nelson, Mark D. Krailo,
`Ashish M. Ingle, Susan M. Blaney, Jessica I. Kandel, and Darrell]. Yamashiro
`
`ABSTRACT
`
`Purpose
`We conducted a pediatric phase l 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 Iymphopenia.
`Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for
`Adverse Events (CTCAEVS) 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.
`
`J Clin Oncol 26:399-405. © 2008 by American Society of Clinical Oncology
`
`From the College of Physicians and
`Surgeons of Columbia University, New
`York, NY; Children's Hospital of Phila-
`delphia, Philadelphia, PA; Mayo Clinic
`and Foundation, Rochester, MN;
`Genentech lnc, South San Francisco;
`Children's Hospital, Los Angeles; Chil-
`dren'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.
`
`Submitted April 12, 2007; accepted
`October 16, 2007.
`
`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 P06 before initiation of the COG
`grant in 2003 is available online at
`http://www.childrensoncologygrouporgl
`admin/grantinfo.htm.
`Sponsored by the National Cancer Insti-
`tute (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 26, 2006,
`Atlanta, GA.
`
`Authors' disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: Julia Glade
`Bender, MD, Pediatric Oncology, Irving
`Pavilion 7, 169 Ft. Washington Ave.
`New York, NY 10032; e—mail: jg'589@
`columbiaedu.
`
`© 2008 by American Society of Clinical
`Oncology
`0732-1 83X/08/2603-399l$20.00
`DOl: 10.1200/JCO.2007.11.9230
`
`INTRODUCTION
`
`Vascular endothelial growth factor (VEGF) is the
`best-characterized pro—angiogenic factor.1 A recent
`cascade of clinical evidence has validated antiangio-
`genesis by VEGF blockade as effective cancer ther—
`apy in renal, colorcctal, non-small—cell lung, and
`other carcinomas?5 The humanized anti-VEGF
`
`antibody bevacizumab (BV; Avastin; Genentech
`Inc, South San Francisco, CA)6 was the first to dem—
`onstrate 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 an-
`tibody (A.4.6.1 or BV) has produced inhibition of
`tumor angiogenesis in preclinical models of pediat-
`
`rhabdomyosarcoma,7’8
`including
`tumors,
`ric
`Wilms’ tumor,9 neuroblastoma,lo and hepatoblas-
`toma.11 These studies support the evaluation of BV
`in children with cancer. Findings of reversible phy-
`seal 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 concluded a phase I trial of BV in chil—
`dren with refractory extracranial solid tumors. Pri-
`mary aims included estimating the maximum—
`tolerated (MTD) or recommended phase II dose
`using a restricted dose-escalation scheme bracketed
`Genentechfl2091
`Hospira v. Genentech
`|PR2017-OO737
`
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`Genentech 2091
`Hospira v. Genentech
`IPR2017-00737
`
`

`

`Glade Bender et 31
`
`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 Tumors' 3 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, ‘4 and bone age (anteroposterior radiograph
`of the left hand and wrist) were obtained at baseline, every 2 months, and/or
`time ofprogression in patients who had not yet achieved adult height. Regard-
`less of pubertal status, ovarian function in females was followed with Tanner
`staging; menstrual history and calendar, and luteinizing hormone (LH),
`follicle-stimulating hormone (PSI-I), 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 ofthe trial was voluntary according to previously published
`ethical guidelines for COG phase I Consortium protocols.ls 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 X g for 10
`minutes at 4°C). Serum was stored at — 70°C until analysis. BV concentrations
`
`
`Table 1. Demographic and Clinical Characteristics of Eligible Patients (n = 20)
`No.
`Characteristic
`
`
`Age, years
`Median
`Range
`Sex
`Male
`Female
`Race
`White
`African American
`Other
`Unknown
`Ethnicity
`Non-Spanish, non-Hispanic
`Hispanic NOS, Spanish NOS
`Unknown whether Spanish or Hispanic
`Diagnosis
`Alveolar soft part sarcoma
`Clear cell sarcoma of kidney
`Ewing sarcoma
`Fibrosarcoma
`Hepatoblastoma
`Mesenchymal chondrosarcoma
`Neuroblastoma
`Osteosarcoma
`Rhabdoid tumor, extrarenal
`Synovial sarcoma
`Wilms’ tumor
`
`%
`
`
`
`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 poten—
`tial biomarkers of antiangiogenesis.
`
`7
`
`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. Ifone ofthree 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 ofthree or two ofsix 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. Nonhe—
`matologic DLT was defined as grade 2 arterial thrombosis, grade 2 hemor-
`rhage, 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
`(cg, platelets < 75,000, proteinuria > 2 g/24 hours, hypertension uncontrol-
`lable 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 treat-
`ment or for which no curative therapy existed who had measurable or assess-
`able 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 fimction (absolute neuu'ophil count .> 1,000/uL,
`platelet count 2100,000/uL, and hemoglobin 2 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
`
`13
`1-21
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`10
`
`13
`3
`1
`3
`
`17
`1
`2
`
`1
`1
`5
`1
`2
`1
`2
`3
`1
`1
`2
`
`
`
`
`
`
`
`
`
`50
`50
`
`65
`15
`5
`15
`
`85
`5
`1O
`
`5
`5
`25
`5
`1O
`5
`1 0
`1 5
`5
`5
`
`10
`
`
` Abbreviation: NOS, not otherwise specified.
`
`400
`
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`Convright © 2017 American Society of Clinical OncoloEV. All rights reserved.
`
`

`

`Pediatric Phase I and Pharmacokinetic Study of Bevacizumab
`
`-°- 5 mg/kg
`-- 10 mg/kg
`
`
`
`Day 1
`
`Day 21
`
`140
`
`A 120
`CD
`
`IE E e
`
`:7w
`u:
`E
`g_
`'c:
`
`o2C
`
`D
`
`100
`
`80
`
`60
`
`40
`
`
`
`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.
`
`
`
`1
`
`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 apoptosis‘é) with appropriate analysis gating as described
`previously.”"9 CBC and CEP analyses were conducted in one laboratory
`(RSK. and Y3.) with consistent flow cytometry settings, gating, and overall
`procedures for each specimen evaluated. At least 100,000 events were collected
`to ensure accuracy ofthe results.
`
`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 l). The one ineligible patient had major surgery 10 days
`before enrollment and was removed after the first dose. Three, three,
`
`
`
`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
`
`Maximum Grade of Toxicity (No)
`
`Course 1 (total,
`Courses 2-16 (total, 48.5
`18.5 courses;
`n = 19)
`courses; n = 19)
`
`Grade 2 Grade 3
`Grade 1 Grade 2 Grade 1
`
`
`
`
`
`
`
`
`0
`
`1 5
`
`Platelets
`
`1O
`
`1 5
`
`Infusion reaction
`
`10
`
`1 5
`
`Weight loss
`
`1 5
`
`Rash
`
`10
`
`1 5
`
`M ucositis
`
`1 5
`
`Nausea
`
`
`10
`1 5
`
`
`AST/ALT
`
`
`1 5
`
`
`Proteinuria
`
`
`1 5
`
`
`Cough
`
`
`1 O
`
`
`1 5
`
`
`
`2
`
`’l
`
`1
`
`2
`
`1
`
`1
`1
`
`2
`
`1
`
`1
`
`1
`
`1
`
`'
`
`1
`
`I
`
`|
`
`1
`
`1
`
`1
`1
`
`1
`1
`
`1
`1
`
`1
`
`1
`
`1
`
`Toxicity and Dose Level
`(mg/kg)
`
`Leukocytes (total WBC)
`5
`10
`1 5
`Lymphopenia
`10
`1 5
`Neutrophils/granulocytes
`
`5 1
`
`were determined using an enzyme-linked irnmunosorbent assay (ELISA). The
`. minimum quantifiable concentration in human serum was 78 ng/mL (Genen-
`tech Inc).
`Concentration versus time data after the first dose (day 0 to day 14) were
`analyzed by standard noncompartmental methods using WINNonlin (Scien-
`tific Consultant, Apex, NC) Pro v.4.1 (Pharsight Corporation, Mountain
`View, CA). The apparent terminal elimination rate was determined by linear
`least-squares regression ofBV serum concentration versus time data through 4
`to 14 days.
`PD samples were collected in EDTA tubes. One was immediately centri—
`fuged at 4°C to separate plasma. Plasma (VEGF, basic fibroblast growth factor
`[bFGF] , and thrombospondin-l [TSP-1]) analysis was performed using com-
`mercially available ELISA (Quantilcine VEGF and QuantikineHS bFGF kits,
`R&D Systems Inc, Minneapolis, MN; TSP-1 competitive ELISA kit, Neogen
`Corporation, Iansing, MI). Total circulating endothelial cells (tCEC), the
`progenitor subset (CEP), and the apoptotic fraction (aCEC) were analyzed
`within 24 hours ofcollection 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
`
`www.jco. org
`
`
`Bevacizumab
`
`SerumConcentration(ug/mL)
`
`
`
`6
`
`8
`
`10
`
`12
`
`14
`
`I
`
`16
`
`Time (days)
`
`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.
`
`401
`
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`
`

`

`Glade Bender at al
`
`and 12 patients were assessable at the 5-, 10—, and lS—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 ofBV, and the other developed progressive disease on day 12
`without experiencing DLT. In the remaining 18 fully assessable pa-
`tients, 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 lS-mg/kg dose level.
`
`Toxicity
`No patient experienced DLT (Table 2). In general, BV was well
`tolerated. Only one grade 3 toxicity attributable to the agent (lym-
`phopenia) 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 pres
`sure (BP) were observed in the majority of children irrespective of
`dose level. Individually, 11 of 16 patients with complete documenta—
`tion ofday 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 of6 mmHg (mean, 6.4
`mmHg) for systolic (P = .038) and 9 mmHg (mean, 7.8 rang) 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 anti-
`hypertensive (amlodipine).
`
`Growth and Development
`There were three patients with open epiphyses and complete
`radiographic evaluation at baseline and after 1 to 2 months oftherapy.
`None exhibited physeal expansion during this limited time period.
`Endocrine evaluations were available for seven of 10 eligible female
`patients. Ofthese, 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 ofBV. At the end ofthe 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
`Ofthe 19 eligible patients who received at least one dose ofBV, 15
`had Response Evaluation Criteria in Solid Tumors—measurable dis-
`ease 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 (11 = 1) and nine (n = 2) courses, and
`patients with alveolar soft part sarcoma and mesenchyrnal chondro-
`sarcoma received five and 16 courses, respectively, before disease pro-
`gression.
`
`Pharmacokinetics
`
`The pharmacokinetics of BV were characterized with data
`from the first dose from 8 of 10 participating patients with suffi-
`cient 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 pro—
`vide 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 of4.1 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.
`
`Pharmacodynamics
`There was significant interpatient variability in all correlative
`assays. No correlation was observed between baseline VEGF, TSP-1,
`bFGF, CBC 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.
`
`Table 3. Bevacizumab Pharmacokinetics
`
`t1/2 (daVSl
`
`MRT (days)
`
`AUC (ng/mL - d)
`
`CL (mL/d/kg)
`
`vs. (mL/kg)
`
`Dose (mg/kg)
`5 (n = 3)
`Patient 1
`Patient 2
`Patient 3
`Mean
`Median
`SD
`15 (n = 5)
`4.4
`230
`Patient 10
`89.6
`15.5
`966
`5.8
`5.7
`275
`Patient 12
`58.1
`7.9
`1,893
`7.3
`117
`425
`Patient 15
`49.5
`3.1
`4,769
`15.7
`11.9
`299
`Patient 17
`63.4
`3.8
`3,971
`16.8
`14.6
`388
`Patient 18
`70.3
`3.5
`4,299
`20.1
`9.6
`323
`Mean
`66.2
`6.8
`3,180
`13.2
`11.7
`299
`Median
`63.4
`3.8
`3,971
`15.7
`4.4
`81
`SD
`15
`5.3
`1.655
`6.3
`—————_———_——__—_—
`
`volume of distribution; SD, standard deviation.
`
`Cmax (ILQ/m L)
`
`90.8
`109
`117
`106
`109
`13
`
`9.9
`12.9
`12.8
`11.9
`12.8
`1.7
`
`13.6
`17.7
`17.1
`16.2
`17.1
`2.2
`
`839
`1,366
`1,141
`1,115
`1,141
`264
`
`6.0
`3.7
`4.4
`4.7
`4.4
`1.2
`
`81.3
`64.8
`75.1
`73.7
`75.1
`8.3
`
`Abbreviations: Cmax, maximum serum concentration; t1,2, half-life; MRT, mean residence time; AUC, area under the concentration-time curve; CL, clearance; V55,
`
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`Copyright © 2017 American Society of Clinical Oncolozv. All rights reserved.
`
`JOURNAL or CLINICAL ONcouocv
`
`

`

`Pediatric Phase I and Pharmacokinetic Study of Bevacizumab
`
`
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`h.
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`
`ELI
`
`
`
`
`
`However, our assay did not separate free from BV-bound VEGF. The
`number ofmCEC increased in six ofeight patients from baseline to the
`end ofthe first treatment course (Fig 3A). It has recently been reported
`that patients responding to antiangiogenic treatment reveal a signifi-
`cant increase in aCEC, and it has been speculated that these cells derive
`from the damaged tumor vasculature. ‘9 Given the heterogeneity ofthe
`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).
`
`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 re-
`quiring discontinuation of therapy. Rare but serious adverse events
`seen in adults, including severe hemorrhage, arterial thromboembo-
`lism, wound-healing complication, GI perforation, hypertensive
`crisis,20 nasal septum perforation,21 and reversible posterior leu—
`koencephalopathy 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 admin-
`istration in the majority of patients. This did not meet CTCAEV3
`criteria for hypertension except in a single patient with longstand-
`ing 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 ofmetaphyseal vessels and failure ofcapillaries
`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 ofthis 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.”28 In adults, BV exhibits linear pharmacokinet—
`ics 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
`
`-
`
`www.j:o.org
`
`Baseline
`
`Day 23
`
`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 endo-
`thelial cells.
`
`Downloaded from ascopubsorg by Reprints Desk on December 11, 2017 from 216.185.156.028
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Glade Bender et al
`
`distribution consistent with limited extravascular distribution.”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 pharmaco-
`kinetics for adult patients,”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 re—
`mission.l7 Early correlative studies in breast, lymphoma, and GI stro-
`mal tumor patients suggest that kinetics of CEC have potential as
`biomarkers of antiangiogenic or metronornic chemotherapy.‘9’29'3’
`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,”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 ofa 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 develop-
`ment, 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,“32 suggest that addi—
`tional 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.
`
`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 relatidnships marked
`with a “U” are thosefor which no compensation was received; those
`relationships marked with a “C” were compensated. For a detailed
`description ofthe disclosure categories, orfor more information about
`ASCO’S conflict ofinterest policy, please refer to the Author Disclosure
`Declaration and the Disclosures ofPotential Conflicts ofInterest 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
`
`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 I. 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 I. Yamashiro
`
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