Pediatr Blood Cancer
Phase I Trial and Pharmacokinetic Study of Sorafenib in Children With
Neurofibromatosis Type I and Plexiform Neurofibromas
AeRang Kim, MD, PhD,1,2* Eva Dombi, MD,1Kathleen Tepas, RN,1Elizabeth Fox, MD,3Staci Martin, PhD,1
Pamela Wolters, PhD,1Frank M. Balis, MD,3Nalini Jayaprakash, MS,1Baris Turkbey, PhD,4Naira Muradyan, PhD,5
Peter L. Choyke, MD,4Alyssa Reddy, MD,6Bruce Korf, MD, PhD,7and Brigitte C. Widemann, MD1
One of the most debilitating complications of neurofibromato-
sis type 1 (NF1) is the development of complex, benign nerve
sheath tumors called plexiform neurofibromas (PN). Surgery, the
only treatment for PN, often is not feasible, and recurrence is high
. Increasing knowledge of the molecular pathways involved in
the growth of NF1 related tumors and the advent of molecularly
targeted anti-cancer drugs have resulted in the development of
potential medical treatments for NF1-associated PN.
PN are composed of neoplastic Schwann cells that lack NF1
gene expression [2,3] and exhibit activation of Ras , which
initiates several signaling cascades that lead to cell proliferation.
Tumor microenvironment  and angiogenesis [6,7] may also
play a role in PN development and proliferation. Sorafenib is
an oral agent that potently inhibits CRAF, BRAF, and receptor
tyrosine kinases including VEGFR-2,3, PDGFR-b, c-kit, and Flt3.
Pre-clinical testing of sorafenib in a genetically susceptible mouse
model for NF1-associated neurofibroma demonstrated significant
decreases in tumor volume .
Sorafenib is FDA approved for adults with advanced renal cell
 or unresectable hepatocellular carcinoma . Most common
sorafenib related toxicities include reversible skin rash, hand-
foot skin reaction, diarrhea, anorexia, alopecia, abdominal pain,
fatigue, and hypertension [11–14]. Prolonged administration of
sorafenib has been associated with cumulative toxicities of
rash or hypertension [15–17]. Sorafenib has been evaluated in a
Children’s Oncology Group (COG) phase I trial for children with
refractory solid tumors . Toxicity and the pharmacokinetic
profile were similar to adult studies, and the maximum tolerated
dose (MTD) in solid tumors was 200 mg/m2/dose BID ,
comparable to the adult recommended fixed dose of 400 mg BID.
When retrospectively compared to children with refractory can-
cers who enroll on phase I trials, children with NF1 were younger
(median 8 vs. 14 years), had better performance status, received
less prior medical therapy, remained on experimental therapy
longer (median 10 vs. one cycle), and survived their disease
. Therefore children with NF1 may require longer duration
of therapy to define tolerability, differing definitions of dose lim-
iting toxicities (DLT), and more conservative starting dose and
escalation schemas than children or adults with refractory cancers.
We conducted a phase I trial of sorafenib in children with NF1
and inoperable PN. The objectives of our study were to determine
the acute and chronic toxicities, DLT, MTD defined over the
first three cycles, pharmacokinetics and pharmacodynamics of
Background. Sorafenib targets multiple pathways thought to be
crucial in growth of plexiform neurofibroma (PN) in children with
neurofibromatosis type 1 (NF1). Sorafenib has been tolerated with
manageable toxicities in adults and children with refractory cancer.
We conducted a separate study in this population. Monitoring long-
term toxicities such as effects on growth and obtaining additional
pharmacokinetic data were of importance due to the young age and
long duration of therapy seen in previous phase I trials in children
with NF1. Procedure. Children ?3 and ?18-year-old with NF1 and
inoperable PN were eligible. Sorafenib was administered orally
twice daily for consecutive 28-day cycles. Maximum tolerated
dose (MTD) was determined from toxicities observed during the
first three cycles. Results. Nine children enrolled, median age 8
(6–12) years. At the starting 115 mg/m2/dose (n ¼ 5), two experienced
dose-limiting grade 3 pain in their PN. At the de-escalated
80 mg/m2/dose (n ¼ 4), approximately 40% of the pediatric solid
tumor MTD, two had dose-limiting toxicity (grade 3 rash and grade
4 mood alteration), exceeding the MTD. At 80 mg/m2/dose, the
median AUC0–12 hoursat steady-state was 39.5 mg hours/ml. Toxic-
ities appeared to correspond with decreases in quality of life (QOL).
No tumor shrinkage was observed. Conclusions. Children with NF1
and PN did not tolerate sorafenib at doses substantially lower than
the MTD in children and adults with malignant solid tumors. Future
trials with targeted agents for children with NF1 may require a more
conservative starting dose and separate definitions of dose limiting
toxicities (DLT) than children with cancer. Pediatr Blood Cancer
? 2012 Wiley Periodicals, Inc.
neurofibromatosis type I; phase I; plexiform neurofibromas; sorafenib
1Pediatric Oncology Branch, NCI, CCR, Bethesda, Maryland;
2Children’s National Medical Center, Washington, District of
phia, Philadelphia, Pennsylvania;
NCI, Bethesda, Maryland;
6University of Alabama at Birmingham, The Children’s Hospital,
3Division of Oncology, Children’s Hospital of Philadel-
4Molecular Imaging Program,
5iCAD, Inc., Nashua, New Hampshire;
7University of Alabama at Birmingham,
Grant sponsor: Intramural Research Program of the NIH; Grant sponsor:
National Cancer Institute; Grant sponsor: Center for Cancer Research;
Grant sponsor: Children’s Tumor Foundation Clinical Trial Award.
Presented in part at the International Society of Pediatric Neuro-
Oncology Meeting, 2010, Vienna, Austria.
Disclaimer: The views expressed do not necessarily represent views
of the National Institutes of Health or the US government.
Conflict of interest: AeRang Kim served as a consultant on the
Nexavar pediatric advisory board. Pamela Wolters owns common
stock in Bristol-Myers Squibb Co., General Electric Co., and Zimmer
Holdings Inc. Bruce Korf serves as the site PI for Novartis trial and is
on the Novartis NF advisory board.
*Correspondence to: AeRang Kim, MD, PhD, Center for Cancer and
Blood Disorders, Children’s National Medical Center, 111 Michigan
Avenue, N.W. Washington, DC 20010.
Received 22 March 2012; Accepted 12 July 2012
? 2012 Wiley Periodicals, Inc.
Published online in Wiley Online Library
sorafenib in children with NF1 and PN. Sorafenib resulted in
growth plate thickening and impairment of trabecular bone for-
mation in pre-clinical models of juvenile, but not mature animals
[20–23]. Thus monitoring skeletal toxicity was of particular im-
portance due to the young age and long duration of therapy seen
in previous phase I trials in children with NF1. Tumor response
was evaluated using a semi-automated method of volumetric MRI
analysis. Standard methods used to measure tumor size and assess
response in cancer trials (RECIST  and WHO  criteria)
were inadequate to quantify clinically meaningful changes in PN
 and recently volumetric methods [27–29] were developed for
response evaluation and have been incorporated in most PN trials
[19,30,31]. Pharmacodynamic endpoints such as plasma VEGF,
VEGFR2, and dynamic contrast enhanced (DCE) MRI to evaluate
tumor blood flow were evaluated in a pilot fashion. Quality of life
(QOL) was assessed because of the potential impact of sorafenib-
related toxicities or benefits on patient functioning. Medication
adherence was monitored as sorafenib is an oral agent, and assur-
ance of adherence was essential in determining if a patient was
assessable for toxicity and efficacy.
Patients age ?3 and ?18 years with a clinical diagnosis of
NF1 based on NIH consensus criteria  and presence of an
inoperable measurable PN defined as a lesion of ?3 cm measured
in one-dimension that has the potential to cause significant
morbidity  were eligible. Adequate organ function and prior
therapy similar to previously published criteria were required
. Diastolic blood pressure within 95th percentile for age and
gender, no anti-hypertensive medication, and ability to swallow
whole tablets were required. The study was approved by Institu-
tional Review Boards from each participating center. Informed
consent and assent, as appropriate, were obtained according to
local institutional guidelines.
Drug Administration and Study Design
Sorafenib was supplied by the Cancer Therapy Evaluation
Program (National Cancer Institute, Bethesda, MD) as 50 and
200 mg tablets. The starting dose was 115 mg/m2/dose BID
with planned dose escalations to 150 and 200 mg/m2/dose, and
de-escalation to 80 mg/m2/dose if the starting dose was not toler-
ated. No escalation beyond the pediatric solid tumor MTD
(200 mg/m2/dose) was planned. Doses were prescribed using a
dosing nomogram capped for a body surface area of >1.8 m2. In
the absence of disease progression or unacceptable toxicity, each
28-day course was repeated without interruption.
A 3 þ 3 phase I dose escalation scheme was used. A patient
was considered evaluable for MTD if DLT was observed at any
time during cycles 1–3, or in absence of DLT, if at least 70% of
the prescribed dose had been administered during cycles 1–3
based on adherence diary review and pill count of returned
drug. Toxicity was graded according to the NCI Common Termi-
nology Criteria for Adverse Events (CTCAE) v3.0. DLT was
defined as any grade ?3 toxicity during cycles 1–3 excluding
grade 3 nausea and vomiting of <5 days, ALT or AST elevations
that recovered to grade ?1 within 7 days of stopping drug.
Persistent (?7 days) grade 2 toxicities could be considered dose
Pediatr Blood Cancer DOI 10.1002/pbc
limiting if they are intolerable with standard supportive measures.
A previously described algorithm for the management and grad-
ing of sorafenib-related hypertension was used . The follow-
ing skeletal changes were considered dose limiting: (1) femoral
growth plate volume expansion on MRI greater than 2 times from
baseline, performed centrally at the NCI . (2) Patients with a
>6% bone mineral density (BMD) decrease on lumbar spine
dual-energy X-ray absorptionmetry (DEXA) scan relative from
baseline and a BMD Z-score of <2.5. For patients with open
growth plates, sorafenib was discontinued if <1 cm growth
was noted prior to cycle 8, <2.5 cm growth in first 12 months,
or <2 cm/year annualized growth velocity following the first
Patients were monitored with history, physical, and laboratory
evaluations (complete blood count and differential count, compre-
hensive chemistries including lipase and amylase) every other
week during cycle 1, and then prior to cycles 2, 3, 4, 8, 12, and
then every three cycles. Specific evaluations for skeletal toxicity
included growth measurements, lower extremity scanogram,
unilateral knee MRI for volumetric growth plate analysis ,
laboratory measurements of bone metabolism (serum calcium,
phosphorus, bone specific alkaline phosphatase, osteocalcin, para-
thyroid hormone, vitamin D levels), and DEXA scan. Blood
pressures were performed weekly during cycle 1, every other
week during cycles 2–3, and then prior to each cycle. In between
visits, the research nurse performed review of patient diary along
with adherence questionnaire by phone weekly during the first
cycle, every other week during cycles 2 and 3, and prior to
each cycle. MRI for disease evaluation was performed at baseline,
prior to cycles 4, 8, 12, and then every six cycles using volumetric
analysis. A ?20% increase in volume from baseline of at least
one monitored PN was considered disease progression .
Pharmacokinetic and Pharmacodynamic Studies
Participation in pharmacokinetic and pharmacodynamic eval-
uations was voluntary. Pharmacokinetic analysis was the same as
performed for the COG study. Initially, pharmacokinetic evalua-
tion was designed to be performed after the first dose. However,
based on observations from the COG trial that day 1 pharmacoki-
netics could not adequately estimate half-life, after the first pa-
tient, pharmacokinetic samples were collected at steady-state.
One milliliter of heparinized blood was collected pre-treatment.
The first steady-state sample was collected exactly 12 hours after
the last dose of sorafenib on any 1 day after day 10 of cycle 1.
The dose of sorafenib was given, and then samples were collected
at 0.5, 1, 2, 3, 5, and 8 hours after the dose. Sorafenib plasma
concentrations were measured using a validated HPLC/MS/MS
method . Sorafenib pharmacokinetic parameters were calcu-
lated using non-compartmental methods. The pre-trough concen-
tration was also used as the 12 hours post-value based on the
assumption that at steady-state the trough concentration should
be constant. Pharmacokinetic parameters were analyzed using
descriptive statistics. Plasma VEGF and soluble VEGFR2
(sVEGFR2) were quantified at baseline and at steady-state on
day 28 ? 1 of cycle 1 using commercial available human VEGF
and sVEGFR2 immunoassay kits (QuantikineTM, R&D Systems,
Target lesions for DCE MRI were identified and imaging was
performed on a 1.5T MR system (Philips Achieva, Best, The
2 Kim et al.
Netherlands). After three baseline unenhanced scans, gadopente-
tate dimeglumine (Magnevist; Bayer Healthcare Pharmaceuticals,
Wayne, NJ) was injected. A total of 23 phases were acquired
at 30-second intervals. Post-processing was performed using
CADvue software (iCAD, Inc. Nashua, NH) employing the Tofts
pharmacokinetic model [36,37] to quantify vascular permeability
as Ktrans(the transfer constant) and kep(efflux rate) and initial area
under gadolinium concentration curve (iAUGC) at 90 seconds.
QOL was assessed with the PedsQL 4.0 Generic Core Scales
 at baseline and prior to cycles 4, 8, 12, 18, and 24. This
23-item questionnaire yields subscale scores representing physi-
cal, emotional, social, and school functioning and a total scale
score. Raw scores are linearly transformed to a 0–100 scale, with
higher scores indicating better QOL.
At each study visit prior to cycles 2, 4, 8 12, and subsequently
every six cycles, a research nurse collected sorafenib pill bottles
to calculate adherence based on pill counts. Also collected at each
study visit were patient diaries, where parents of patients recorded
the dates and times of all doses taken, and reasons for any missed
Patient characteristics are described in Table I. Of the nine
eligible patients enrolled, two patients withdrew during cycle 1
for non dose-limiting toxicities and thus were not fully assessable
for toxicity. One patient developed grade 2 hypertension on cycle
1 day 8. Rather than beginning anti-hypertensive treatment as
recommended per protocol, the patient held drug with normaliza-
tion of blood pressure and withdrew from treatment. The other
patient developed grade 2 facial PN pain on cycle 1 day 11. The
patient had no previous baseline pain, declined supportive care,
held sorafenib with resolution of pain, and withdrew from
Table II summarizes the DLTs observed. Patient 1 reported
baseline tumor pain and received narcotic medication on an as
needed basis. He developed grade 3 pain in his pre-existing large
abdominal, pelvic, and thigh PN on day 7 cycle 1. His pain
persisted despite scheduled narcotics, and required hospitalization
for intravenous analgesia. Sorafenib was held with full recovery.
He elected not to receive further sorafenib at a reduced dose and
withdrew from treatment. Patient 5 had a large facial PN and
reported no baseline pain. He developed grade 3 tumor pain
with grade 2 facial edema day 4 of cycle 1. Treatment with
non-steroidal anti-inflammatory medication provided minimal
benefit. Sorafenib was held with resolution of pain, and he
resumed treatment at a reduced dose. Six weeks into therapy,
he again developed grade 3 tumor pain, and was taken perma-
nently off sorafenib.
Since two out of three patients developed DLT, sorafenib was
de-escalated to the 80 mg/m2dose level, which is approximately
40% of MTD in the pediatric solid tumors . Patient 6 devel-
oped dose-limiting grade 3 rash day 10 of cycle 1, which resolved
5 days after holding drug. The patient tolerated sorafenib at
reduced dose. Patient 7 had a history of bipolar disease, and in
cycle 3, she developed dose-limiting grade 4 mood alteration,
suicidal ideation, which required immediate psychiatric care.
She was taken off therapy and returned to baseline within 2 weeks.
The MTD was again exceeded and no MTD was determined.
Most frequent non-DLTs were tumor pain, anorexia, rash, and
hand-foot syndrome. Patient 6 developed grade 1 behavior
changes with emotional lability. Hypertension was not frequently
observed. Among patients that were on drug for more than three
cycles (n ¼ 4), two patients had greater than 10 mmHg increases
in either systolic or diastolic blood pressures that occurred within
7 days of starting therapy and appeared to stabilize during the
remainder of their course.
Bone toxicity. Four patients (ages 5–7 years) had received at
least seven cycles of therapy. Their median baseline femoral
growth plate volume was 4279 mm3(range, 3236–4910). The
median volume change from baseline to off therapy was
?205 mm3(?810 to 389) with an average percent change of
negative 6.6%. Patients’ growth ranged from 0.4 to 2.1 cm during
seven cycles of therapy. Patient 2 experienced grade 1 anorexia
with 9% of weight loss prior to cycle 8. She did not meet growth
requirements of at least 1 cm at the time of evaluation prior to
cycle 8, and sorafenib was discontinued. Upon re-evaluation
3 months off therapy, she had grown 2 cm with recovered weight
loss. No meaningful differences in measurements were observed
in patients’ DEXA scans or laboratory measurements of bone
TABLE I. Baseline Characteristics for Eligible Patients
Patient characteristicn ¼ 9
Performance status, mean
Prior medical regimens directed at PN
Prior radiation therapy
Plexiform neurofibroma characteristicn ¼ 11a
Tumor volume (ml)
aPatients 3 and 5 had two plexiform neurofibromas measured.
Sorafenib in Plexiform Neurofibromas3
Pediatr Blood Cancer DOI 10.1002/pbc
No tumor shrinkage was observed. The median number of
cycles was seven (range, <1 to 12). Three patients discontinued
protocol therapy during cycle 1, 2, and 3 respectively due to
toxicity and were not assessable for response. One came off
therapy due to toxicity with stable disease after seven cycles
(16% volume increase); two due to progressive disease after seven
and 12 cycles (volume increases of 25% and 27% respectively);
and one due to clinical progression not assessable for response
due to surgical intervention.
80.9 mg hours/ml) was higher than expected derived from the
results of the COG trial . The patient had normal bilirubin,
but Gilbert’s disease, which affected his drug metabolism ,
and the protocol was amended subsequently to exclude patients
with Gilbert’s disease. Four patients had steady-state pharmacoki-
netics (Table III). All were treated at 80 mg/m2/dose twice daily
except for patient 6, who had a sorafenib dose reduction to once
daily dosing. There was little inter-patient variability (coefficient
of variationfor apparentclearance
AUC0–12 hoursand apparent clearance was 39.5 mg hours/ml and
1 day1 drug exposure(AUC0–24 hours
Among paired samples for plasma VEGF and sVEGFR2
(n ¼ 5), there were no statistically significant changes from
baseline to steady-state (Wilcoxon signed-rank test P ¼ 0.7 and
0.2). Baseline DCE MRI was performed in six patients with target
lesions volumes ranging from 67 to 560 cm3. All tumors appeared
relatively hypovascular. The mean (SD) baseline Ktransand
iAUGC(90 seconds) was 0.043 (0.017) minutes?1and 5.50
(1.25) mMseconds. The low Ktransand iAUGC(90 seconds) num-
bers reflect poor enhancement, but there was considerable varia-
tion. Patients with both baseline and follow up scan (n ¼ 3)
demonstrated a slight increase in both Ktransand iAUGC.
Quality of Life Evaluation
Parents of nine patients completed the baseline QOL evalua-
tion, and four completed the pre-cycle 4 evaluation. Parent ratings
indicated that three of these four patients had declines of 9, 17,
and 27 points in the PedsQL Total scale score indicating worse
QOL. One patient decreased on all four subscales and the other
two decreased on three of the four subscales. These decreases
appeared to correspond to toxicities experienced by these patients
between the baseline and pre-cycle 4 evaluations, including rash,
itching, pain, and irritability. The patient whose QOL scores
remained relatively stable over time reported similar types of
symptoms that were well-controlled in a timely manner; thus
she remained on study longer than any other patient (until her
pre-cycle 12 evaluation).
Adherence was calculated based on tablet counts for patients
who returned all pill bottles as instructed (n ¼ 5), and patient
TABLE II. Summary of Dose-Limiting Toxicities Over First Three Cycles
Dose level mg/m2/dose Patients entered Patients evaluablePatient number
Dose limiting toxicity
CTC toxicity term (grade)
Pain, tumor (3)
Pain, tumor (3)c
Mood alteration (4)
aEquivalent to an adult fixed dose of 207 mg based on average adult body surface area of 1.8 m2;bTwo patients were not evaluable due to
patient elected early withdrawal due to grade 2 toxicities (hypertension (n ¼ 1) and pain (n ¼ 1));cPatient was dose reduced to 80 mg/m2/dose
and developed grade 3 tumor pain again.
TABLE III. Sorafenib Pharmacokinetics at Steady-State
(mg/m2) Patient no.Age (years)BSA (m2) Dose (mg)
Abbreviations: BSA, body surface area; Cmax, peak sorafenib concentration; AUC, area under the curve; CL/F, apparent clearance; SD, standard
deviation;aPatient was initially on 115 mg/m2/dose every 12 hours and was dose reduced to 80 mg/m2/dose every 12 hours when pharmaco-
kinetics were preformed;bPatient was initially on 80 mg/m2/dose every 12 hours and was dose reduced to 80 mg/m2/dose once daily when
pharmacokinetics were performed;cThe mean, SD, and median values do not include patient 6.
4 Kim et al.
Pediatr Blood Cancer DOI 10.1002/pbc
diaries (n ¼ 7). The mean (range) overall adherence rate was 96%
(87–100%) per tablet count and 99% (97–100%) per medication
Sorafenib targets multiple pathways thought to be crucial in
the growth of PN with promising results in a genetically suscep-
tible mouse model for NF1-associated neurofibroma  making
this agent attractive to study in this population. It has been toler-
ated in adults and children with refractory cancer with mild to
moderate manageable toxicities.
The MTD of sorafenib in children with NF1 and PN could not
be determined. The DLTs in this population were tumor pain,
rash, and mood alteration. Dose-limiting tumor pain was not
observed in the pediatric refractory cancer trial , nor was
tumor pain a DLT in adults . All but one DLT occurred early
in the first cycle of treatment. Decreases in parent-reported QOL
appeared to correspond to reported toxicities and suggested that
the side effects had a substantial impact on patients’ physical,
emotional, social, and school functioning. Also, adherence data
obtained from both tablet counts and parent-completed diaries
suggest that, even with considerable side effects, adherence to
sorafenib was high.
One may hypothesize that tumor pain could be a pharmacody-
namic marker for response, much like rash [41,42], and hyperten-
sion [43,44]. However, tumor pain in this study was dose-limiting
and a relationship with response could not be correlated. No
associations with pain to drug exposure, VEGF or sVEGFR2,
or DCE MRI findings could be explored due to sample size.
Although this disease has high morbidity, only one patient
reported baseline pain, and most patients took minimal concomi-
tant medications. The use of daily narcotics use to ameliorate
toxicity related to a drug with unknown benefit was difficult to
substantiate especially in the setting of phase I trial where deter-
mination of tolerability is the primary objective. For the one
patient with history of baseline pain, increasing his oral narcotic
medication did not help reduce his pain. Patients with NF1 may
be less willing to tolerate toxicity from treatment for their non-
malignant tumors compared to those with refractory cancers as
two patients with non-DLT withdrew from the study. They also
may be less willing to accept standard supportive care measures
such as anti-hypertensives and pain medications often given to
refractory cancer patients without hesitation.
The children in this trial were younger than those with refrac-
tory cancer (median 8 vs. 14 years). No clear relationship of
clearance and age was observed in this study, but only four
patients had steady-statepharmacokinetics.
AUC0–12 hoursat 80 mg/m2, which is approximately 40% of the
adult and pediatric solid tumor MTD, was 39.5 mg hours/ml.
Although, drug exposure may be greater than what would be
expected with this substantial dose decrease, it is below the
AUC0–12 hours range of 47.8–76.5 mg hours/ml reported in the
literature in adults treated at the recommended fixed dose of
400 mg BID [11–14]. Insufficient drug exposure may be associ-
ated with absent tumor response substantiated by lack of pharma-
codynamic marker modulation in our trial.
Differences in organ sensitivity due to underlying genetic
mutations in this population may explain differences in tolerability
to this medication. There is growing evidence suggesting
downstream effectors of Ras are involved in the enhanced sensi-
tivity of sensory neurons . Responses to inflammatory medi-
ators are altered by mutation of the Nf1 gene in pre-clinical
models , which may explain abnormal painful sensations
such as hyperalgesia, dyesthesias, and allodynia often experienced
by patients with NF1 particularly in response to injury or trauma
[46,47]. It may be hypothesized that injury to the vessels may be
caused by the anti-angiogenesis mechanism of sorafenib resulting
in increased pain sensation, and warrants further investigation.
Pre-clinical testing of sorafenib in a genetically susceptible
mouse model for NF1-associated neurofibroma demonstrated sig-
nificant decreases in tumor volume . The mice were treated
with 45 mg/kg of sorafenib daily by oral gavage. This dose was
chosen based on pre-clinical studies, but is approximately half the
adult recommended dose equivalent using surface area dosage
conversion factors . The median Cmax was 23.7 mg/ml in
mice with PNs treated with sorafenib in the pre-clinical model
. Interestingly, this was about fivefold fold greater than
the Cmaxobserved in this trial.
Only four patients received greater than seven cycles and the
objectives to determine chronic toxicities were unmet. Although a
thorough and comprehensive evaluation for bone toxicity was
incorporated into the study design, we were unable to truly eval-
uate bone toxicity due to small sample size, the emergence of
other DLTs, and early discontinuation of protocol therapy. Based
on the tablet sizes available, further dose de-escalation was not
feasible. Future studies with sorafenib for this specific population
are not planned at this time.
Children with NF1 and PN did not tolerate sorafenib at doses
substantially lower than the MTD in children with refractory
cancer. Children with NF1 on phase I trials may be less willing
to accept potential mild to moderate toxicities in comparison to
children refractory cancer that have life-threatening diseases with
poor survival outcome. Standard supportive care guidelines may
need to be adjusted for children with NF1. The MTD of targeted
agents in patients with cancer may not apply to children with NF1
and PN. Future NF1 trials in children with targeted agents may
require a more conservative starting dose and separate definitions
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Pediatr Blood Cancer DOI 10.1002/pbc