VOLUME
28
䡠
NUMBER
22
䡠
AUGUST
1
2010
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Pediatric Phase I Trial and Pharmacokinetic Study of
Vorinostat: A Children’s Oncology Group Phase I
Consortium Report
Maryam Fouladi, Julie R. Park, Clinton F. Stewart, Richard J. Gilbertson, Paula Schaiquevich, Junfeng Sun,
Joel M. Reid, Matthew M. Ames, Roseanne Speights, Ashish M. Ingle, James Zwiebel, Susan M. Blaney,
and Peter C. Adamson
From the St Jude Children’s Research
Hospital, Memphis, TN; Seattle Children’s Hospital, Seattle, WA; Children’s
Oncology Group Operations Center,
Arcadia, CA; Mayo Clinic College of
Medicine, Rochester, MN; Baylor
College of Medicine; Texas Children’s
Cancer Center/Baylor College of Medicine, Houston, TX; Cancer Therapy
Evaluation Program, National Cancer
Institute, Bethesda, MD; and the Children’s Hospital of Philadelphia, Philadelphia, PA.
Submitted September 3, 2009;
accepted May 17, 2010; published
online ahead of print at www.jco.org on
July 6, 2010.
Supported by Grants No. U01 CA97452
and NCRR M01 RR00188 from the
National Cancer Institute.
Clinical Trials repository link available on
JCO.org.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Maryam Fouladi,
MD, Division of Hematology-Oncology,
Cincinnati Children’s Hospital Medical
Center, 3333 Burnet Ave, Cincinnati,
OH, 45229; e-mail: maryam.fouladi@
cchmc.org.
© 2010 by American Society of Clinical
Oncology
A
B
S
T
A
C
T
Purpose
The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting
toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in
combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the
tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the
pharmacokinetics of a vorinostat suspension in children.
Patients and Methods
Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30%
increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3)
accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).
Results
Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was
230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d.
DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia,
neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4
times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide
interpatient variability was noted in vorinostat disposition, with area under the concentration-time
curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL ⫻ hr) and oral suspension
(range, 1,186 to 4,780 ng/mL ⫻ hr). Significant accumulation of acetylated H3 histone in PBMC
was observed after administration of vorinostat, particularly at higher doses. One patient with
neuroblastoma experienced a complete response to the combination.
Conclusion
In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest
dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar
to that observed in adults.
J Clin Oncol 28:3623-3629. © 2010 by American Society of Clinical Oncology
0732-183X/10/2822-3623/$20.00
DOI: 10.1200/JCO.2009.25.9119
R
INTRODUCTION
Deregulation of histone acetylation plays an important role in the pathogenesis of many malignancies by altering chromatin structure and gene
transcription.1-7 Thus, histone deacetylase (HDAC)
inhibition leads to histone acetylation, an open
chromatin structure, and expression of previously
silenced genes.8 In preclinical studies, HDAC inhibitors induce growth arrest, activate apoptotic pathways, autophagic cell death, and cell death through
induction of reactive oxygen species.9 Vorinostat,
an oral HDAC inhibitor of class I and II HDACs,
has antitumor activity in vitro7 and in vivo10 and
can alter vascular endothelial growth factor signaling.11,12 When evaluated in the Pediatric Preclinical Testing Program, activity was observed in
an in vitro panel of tumors and significant differences in event-free survival were noted in 16 of 30
solid tumor xenografts.10 Additive or synergistic
preclinical and/or clinical activity of vorinostat has
also been reported in combination with antiangiogenic agents,13 5-aza-2⬘-deoxycytidine,14,15 and 13cis-retinoic acid (13cRA).7,16-18 Vorinostat, indicated
for the treatment of cutaneous T-cell lymphoma,19,20 is well-tolerated by adults at daily doses of
400 mg.4,20 Dose-limiting toxicities (DLTs) include
fatigue, anorexia, diarrhea, nausea, vomiting, and
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3623
Fouladi et al
thrombocytopenia. Recent trials have demonstrated activity in acute
myeloid leukemia4 and B-cell lymphoma.21
We report the results of a phase I trial of vorinostat alone and in
combination with 13cRA in children with recurrent or refractory
malignancies. The primary objectives were (part A) to estimate the
maximum-tolerated dose (MTD), determine the DLTs, and characterize the pharmacokinetics of single-agent vorinostat in children with
solid tumors; (part B) to assess the tolerability of vorinostat administered at the solid tumor MTD in patients with recurrent or refractory
leukemia; (part C) to estimate the MTD and determine the DLTs of
vorinostat administered in combination with 13cRA in patients with
recurrent neuroblastoma, medulloblastoma, CNS primitive neuroectodermal tumor (PNET) or atypical teratoid rhabdoid tumor
(ATRT); and (part D) to characterize the pharmacokinetics of vorinostat when administered as a suspension at the solid tumor MTD for
the capsule formulation. The secondary objectives were to assess the
biologic activity of vorinostat by measuring histone acetylation status
in peripheral blood mononuclear cells (PBMCs) and to preliminarily
evaluate its antitumor activity.
PATIENTS AND METHODS
Patient Eligibility
Patients older than 12 months and younger than 22 years with measurable or evaluable tumors refractory to therapy were eligible. Histologic verification of malignancy was required except for patients with intrinsic brainstem
glioma. Eligible diagnoses included patients with recurrent or refractory solid
tumor (parts A, D); leukemia with more than 25% blasts in the bone marrow
(part B); neuroblastoma, medulloblastoma, CNS PNET or ATRT (part C).
Other eligibility criteria included: Lansky or Karnofsky score ⱖ 60; bodysurface area of ⱖ 0.5 m2; recovery from the acute toxic effects of prior therapy;
ⱖ 3 months since total-body irradiation, craniospinal or hemi-pelvic radiation
and ⱖ 2 months since a stem-cell transplant; adequate bone marrow function
for patients with solid tumors (peripheral absolute neutrophil count ⱖ 1,000/
L, platelets ⱖ 100,000/L [transfusion independent], hemoglobin ⱖ 8.0
g/dL), for patients with leukemia (part B) platelets ⱖ 20,000/L, hemoglobin ⱖ 8.0 g/dL; adequate renal function (age-adjusted normal serum creatinine or a glomular filtration rate ⱖ 70 mL/min/1.73 m2), adequate liver
function (total bilirubin ⱕ 1.5⫻ institutional upper limit of normal for age,
ALT ⱕ 5⫻ institutional upper limit of normal for age and albumin ⱖ 2 g/dL).
Patients who were to receive 13cRA (part C) had to have ⱕ grade 1 skin
toxicity, serum triglycerides lower than 300 mg/dL, a negative urine dipstick
for protein, or lower than 1,000 mg/24 hour urine collection, and no gross
hematuria. Patients were excluded if they had received valproic acid in the
previous 2 weeks, were on enzyme-inducing anticonvulsants, or other noncytotoxic anticancer agents, were pregnant or lactating or had uncontrolled
infections. Patients with solid tumor with bone marrow involvement and
patients with active CNS leukemia were excluded. Patients with CNS malignancies receiving dexamethasone had to be on a stable or decreasing dose
for ⱖ 7 days before study enrollment.
The institutional review boards of participating institutions approved
the protocol. Informed consent and assent, as appropriate, were obtained
according to local institutional guidelines.
Drug Administration and Study Design
Vorinostat was supplied by the Cancer Therapy Evaluation Program
(National Cancer Institute, Bethesda, MD) as a white, opaque gelatin capsule,
containing 100 mg of vorinostat. A dosing nomogram was used to minimize
interpatient dosing variability. For part D, a suspension was prepared locally by
the investigational pharmacists by mixing 20 mL of OraPlus (Humco, Texarcana, TX) with the contents of twenty 100 mg vorinostat capsules in a 4 ounce
glass bottle. After shaking for up to 3 minutes to disperse, an additional 20 mL
of OraSweet (Paddock Lab, Minneapolis, MN) was added. The container was
3624
again shaken to disperse, resulting in a final concentration of 50 mg/mL. The
suspension was stored at room temperature and based on manufacturer’s
recommendation was stable for a maximum of 2 weeks. Vorinostat was administered orally each day, preferably with food.
The starting vorinostat dose for part A (patients with recurrent or refractory solid tumor) was 180 mg/m2/d (approximately 80% of the adult recommended dose of 400 mg daily) with dose escalations in 30% increments. Once
the MTD for vorinostat was defined, vorinostat was administered to six patients with recurrent or refractory leukemia to assess its tolerability at the solid
tumor MTD (part B). In part C, additional cohorts of patients with recurrent
neuroblastoma, medulloblastoma, PNET, or ATRT were enrolled to determine the MTD of vorinostat administered in combination with standard
Table 1. Patient Characteristics for Eligible Patients (n ⫽ 63)
Patients
Characteristic
Age, years
Median
Range
Sex
Male
Female
Diagnosis part A
CNS tumors
Malignant glioma
Medulloblastoma
Astrocytoma, mixed glioma
Ependymoma, NOS
Atypical teratoid/rhabdoid tumor
Non-CNS tumors
Soft tissue sarcomas
Ewing’s sarcoma
Neuroblastoma
Osteosarcoma
Rhabdomyosarcoma,
Diagnosis part B
Acute lymphoblastic leukemia
Acute promyelocytic leukemia
Acute lmyeloid leukemia FAB M1
Diagnosis part C
CNS tumor
Medulloblastoma
Primitive neuroectodermal tumor
Pineoblastoma
Atypical teratoid rhabdoid tumor
Non-CNS tumor
Neuroblastoma
Diagnotic part D
CNS tumor
Malignant glioma
Ependymoma
Medulloblastoma
Pineoblastoma
Non-CNS tumor
Rhabdomyosarcoma
Endodermal sinus tumor
Osteosarcoma
Prior therapy
Median No. prior regimens
Range
Prior radiation therapy
No.
%
11
2.6-22
40
23
63.5
36.5
7
3
2
2
1
23.3
10.0
6.6
6.7
3.3
6
2
2
2
3
19.9
6.7
6.7
6.7
9.9
4
1
1
66.6
16.7
16.7
5
4
2
1
35.7
28.5
14.3
7.1
2
14.29
3
2
1
1
23.1
15.4
7.7
7.7
3
1
2
23.1
7.7
15.4
2
1-7
45
Abbreviations: NOS, not otherwise specified; FAB, French-American-British.
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JOURNAL OF CLINICAL ONCOLOGY
Pediatric Phase I Trial of Vorinostat
neuroblastoma dosing of 13cRA (80 mg/m2/dose twice per day for 14 days).22
The starting dose for vorinostat in part C was 180 mg/m2/dose daily. In part D,
patients with recurrent or refractory solid tumor received vorinostat as a 50mg/mL suspension at the part A MTD in order to characterize the pharmacokinetics of the suspension compared with the capsule.
In the absence of disease progression, and if laboratory parameters as
defined in the eligibility section were met, each 28-day course was repeated
without interruption for up to 12 courses. In parts A and C, a minimum of
three evaluable patients were treated at each dose level. If one of three patients
at a given dose level experienced a DLT, up to three more were accrued at the
same dose level. If ⱖ two patients experienced DLT, then the MTD was
exceeded and three more patients were treated at the next lower dose level. The
MTD was defined as the dose level at which at most one patient experienced
DLT with at least two of three to six patients experiencing a DLT at the next
higher level. If observed DLTs were different classes of adverse effects, then
expansion of the cohort to 12 patients was considered if the following conditions were met: one of the DLTs did not appear to be dose related; the toxicity
was readily reversible; the study chair, statistician, Children’s Oncology Group
Developmental Therapeutics Chair, and investigational new drug sponsor all
agreed that cohort expansion was acceptable. If fewer than one third of patients
in the expanded cohort experienced DLT at the dose, further dose escalation
could proceed.
In part B, six patients with recurrent or refractory leukemia received
vorinostat at the solid tumor MTD to assess its tolerability.
To study the pharmacokinetics of an oral suspension formulation in part
D, 12 patients with recurrent or refractory solid tumors (six patients ⬍ 12
years, six ⬎ 12 years) were enrolled. The suspension was administered on day
1 of course 1 at the solid tumor MTD; after day 1, patients could continue their
course using either capsules or suspension.
Toxicities were graded according to the Common Terminology Criteria
for Adverse Events version 3.0. Hematologic DLT was defined as grade 4
neutropenia or thrombocytopenia (children with leukemia were not considered evaluable for hematologic toxicity). Nonhematologic DLT was defined as
grade 3 or 4 nonhematologicatoxicity with the specific exclusion of: grade 3
nausea and vomiting of fewer than 5 days duration responsive to antiemetic
therapy, grade 3 transaminase elevations that met eligibility criteria within 7
days of interruption and did not recur on rechallenge with study drug, grade 3
fever or infection fewer than 5 days, any grade 2 nonhematologic toxicity that
persisted for ⱖ 7 days and was considered sufficiently medically significant or
sufficiently intolerable by patients that it required treatment interruption,
grade 2 allergic reactions that necessitated discontinuation of study drug, or
any adverse event requiring interruption of study drug for longer than 7 days
or which recurred on drug rechallenge. Before opening part D of the study, the
protocol was amended to exclude grade 3 hypokalemia, hypophosphatemia,
hypocalcemia, and hypomagnesemia responsive to oral supplementation
from the definition of DLT.
Pretreatment evaluations included a history, physical examination and
CBC, electrolytes, renal and liver function tests, serum protein and albumin,
triglycerides (part C only). CBCs were obtained twice weekly during the first
course and weekly thereafter. History, physical examinations, and laboratory
studies were obtained weekly in course 1 and before each subsequent course.
Disease evaluations were obtained at baseline, at the end of course 1 and after
every other course. Tumor response was reported using the Response Evaluation Criteria in Solid Tumors (RECIST).23
Pharmacokinetics Studies
Participation in pharmacokinetic studies in parts A, B, and C was voluntary24 whereas all subjects enrolled in part D had to agree to participate in
pharmacokinetics studies before enrollment. Blood samples (2 mL) were
collected in heparinized tubes before the vorinostat dose, and at 0.25, 0.5, 1,
1.5, 2, 4, 6, 8, and 24 (⫾ 2) hours after the first dose. The plasma concentrations
of vorinostat and its metabolite, 4-anilio-4-oxobutanoic, acid were determined using a previously described validated liquid chromatography, tandem
mass spectrometry method.25 The lower limit of quantitation was 2 ng/mL for
vorinostat and 10 ng/mL for 4-anilio-4-oxobutanoic acid. The within-day and
between-day precision (coefficient of variation) values and accuracy values for
both analytes met standard assay validation criteria.26
Pharmacokinetic parameters for vorinostat and 4-anilio-4-oxobutanoic
acid were calculated using noncompartmental methods. For each patient, the
maximum concentration and time to maximum concentration were the observed values. The area under the plasma concentration-time curve (AUC03t
where t was the last measured time point) was calculated by the trapezoidal rule.
Biologic Assays
PBMC protein lysates were isolated as described previously27 from patients’ whole blood drawn before, and at 1, 6, and 24 hours (⫾ 2 hours) after
the first vorinostat. Ten to 25 micrograms of each lysate was analyzed by
Western blotting using a purified rabbit polyclonal antiacetyl-H3 antibody
Table 2. Summary of Dose-Limiting Toxicities
No.
Entered
No.
Evaluable
No. With
DLT
Vorinostat 180 mg/m2
Vorinostat 230 mg/m2
10
6
6
6
1
1
Vorinostat 300 mg/m2
14
12
4
Part B
Vorinostat 230 mg/m2
6
5
2
Part C
Vorinostat 180 mg/m2 daily, cis retinoic
acid 80 mg/m2/dose bid
7
6
2
Vorinostat 180 mg/m2 4 times per week,
cis retinoic acid 80 mg/m2/dose bid
Vorinostat 230 mg/m2
7
6
0
13
12
4
Stratum
Part A
Part D suspension
www.jco.org
Dose Level
DLT Type (No.)
Thrombosis (1)
Hypokalemia (1)
Hypokalemia (1)
Platelets (2)
Neutropenia (1)
AST (1)
Hyperbilirubinemia (1)
GGT (1)
Hypokalemia (1)
Platelets (2)
Neutropenia (1)
Anorexia (1)
Hypertriglyceiremia (1)
Hypophosphatemia (1)
ALT (1)
Platelets (3)
Hyponatremia (1)
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3625
Fouladi et al
RESULTS
Of the 64 patients enrolled on study, one patient was ineligible
(only 1 month had elapsed since stem-cell transplant) and 10 were
not fully evaluable for toxicity: five never received vorinostat, four
experienced disease progression during course 1, one patient received a single dose of vorinostat but no 13cRA, developed thrombocytopenia and was taken off therapy due to parental withdrawal
of consent. Patients received a median of two courses (range, 1 to
12) of therapy (Table 1).
Toxicity
Table 2 summarizes the DLTs observed. In part A, at 180 mg/m2,
one patient on oral contraceptives who had a vascular anomaly
developed a deep vein thrombosis of the iliac vein. No DLTs
occurred at 230 mg/m2/d dose level (n ⫽ 3). At 300 mg/m2/d
dose-limiting hypokalemia (n ⫽ 1) and thrombocytopenia (n ⫽ 1)
occurred in two of six patients. Since these adverse events were of
different classes, the cohort was expanded to six additional evaluable patients. In this expanded cohort, one patient each had doselimiting neutropenia and thrombocytopenia thereby exceeding the
MTD. Three additional patients were subsequently enrolled at the
230 mg/m2; only one experienced a DLT of grade 3 hypokalemia,
defining 230 mg/m2/d as the MTD and recommended phase II
dose for children with solid tumors. Two of the first five patients
with relapsed or refractory leukemia receiving vorinostat at 230
mg/m2/d experienced DLTs: elevated AST (n ⫽ 1), hyperbilirubinemia (n ⫽ 1), elevated gamma-glutamyl transferase (n ⫽ 1),
and hypokalemia (n ⫽ 1). The solid tumor MTD thus did not
appear tolerable in children with refractory leukemia; no other
dose finding was attempted in this population.
For the combination of vorinostat with 13cRA, two of the six
patients treated at the starting dose of vorinostat 180 mg/m2/dose and
13cRA 80 mg/m2/dose twice per day for 14 days every 28 days,
developed DLT. DLTs in one patient included anorexia and
thrombocytopenia and in the other patient included thrombocytopenia, neutropenia, hypertriglyceridemia, and hypophosphatemia.
When the vorinostat dosage was de-escalated to 180 mg/m2/d four
times per week, none of the six patients experienced DLTs.
In part D, of 13 patients who agreed to participate in pharmacokinetic studies, 12 had adequate samples for analysis. Six received the suspension throughout the first course and six received
it as a single dose before changing to the capsule formulation. Four
(two who received suspension throughout) experienced grade 3 or
4 toxicities: increased ALT (n ⫽ 1), thrombocytopenia (n ⫽ 3), and
hyponatremia (n ⫽ 1).
Table 3 summarizes non– dose-limiting hematologic toxicities
ⱖ grade 2 at least possibly attributable to vorinostat in 24 evaluable
patients in part A and 13 evaluable patients in part C, respectively.
Appendix Table A1 (online only) summarizes all non– dose-limiting,
A
Vorinostat AUC (mg/mL/hr)
(Upstate Biotechnology, Lake Placid, NY) and chemiluminescence. The level
of acetyl-H3 in each sample was determined relative to the expression of the
housekeeping gene HPRT (Abcam, Cambridge, MA).
10,000
5,000
0
180
Course 1 by Grade
(total, 24 courses)
Courses 2 to 8 by Grade
(total, 31 courses)
Toxicity Type
1
2
3
4
Part A
Hemoglobin
Leukopenia
Lymphopenia
Neutropenia
Platelets
5
7
3
2
8
4
5
2
4
3
3
3
4
4
1
Course 1 by Grade
(total, 12 courses)
Part C
Hemoglobin
Leukopenia
Lymphopenia
Neutropenia
Platelets
3626
1
2
2
2
3
3
3
2
2
4
3
1
2
4
6
3
1
7
5
3
1
5
3
4
2
1
2
1
1
Courses 2 to 12 by
Grade (total, 26 courses)
4
2
3
1
1
1
2
4
2
2
3
1
2
3
1
1
3
4
230
300
230
2
Vorinostat Dosage (mg/m )
B
Vorinostat AUC (mg/mL/hr)
Table 3. Non–Dose-Limiting Hematologic Toxicities (ⱖ grade 2),
Independent of Frequency and Attribution, Observed in Evaluable Patients
Enrolled on Part A (24 evaluable patients) and Part C (12 evaluable)
10,000
5,000
0
100
150
200
250
300
350
2
Actual Vorinostat Dosage (mg/m )
2
Fig 1. Vorinostat area under the curve (AUC) 03⬁ does not increase with (A)
vorinostat dosage level or (B) actual dosage (mg/m2/d). Patients in parts A, B, or
C (blue circle) on the dosage level were combined. Gold box represents
vorinostat AUC of patients in part D (suspension). Horizontal line represents
median for each group.
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JOURNAL OF CLINICAL ONCOLOGY
Pediatric Phase I Trial of Vorinostat
nonhematologic toxicities that were at least possibly attributable to
vorinostat in parts A and C. Similar Tables for parts B and D are
included as Appendix Tables A2-A4 (online only).
Responses
No objective responses were observed to single-agent vorinostat.
Prolonged stable disease (median, 4; range, 4 to 8 cycles) was observed
in five patients (one each with osteosarcoma, spindle cell sarcoma,
diffuse intrinsic pontine glioma, low-grade glioma, and synovial cell
sarcoma). One patient with neuroblastoma treated with the combination of vorinostat and 13cRA experienced a complete response and
completed 12 courses of therapy. The patient had evaluable disease
detected by iodine-123 metaiodobenzylguanidine at study entry and
after course 9 had no abnormal radiotracer uptake. Two additional
A
patients (medulloblastoma, pineoblastoma) treated with the combination had stable disease for 5 and 7 courses, respectively.
Pharmacokinetics
After the first vorinostat dose on course 1, pharmacokinetic studies were obtained in 21 subjects after administration of the capsule
formulation and from 11 subjects after administration of the suspension formulation (Appendix Table A5, online only). Wide interpatient
variation in drug disposition was noted such that there did not appear
to be a clear relationship between dose and drug exposure (Fig 1).
Similarly, no relationship was noted between drug exposure, toxicity,
or prolonged stabilization. After administration of the capsule formulation, the median apparent oral vorinostat clearance was 171 L/h/m2
Time post dose (hour)
0
1
6
24
Vorinostat data
Acetyl-H3
Dose: 180 mg/m2 Part A
Peak AUC 476 ng h/mL
HPRT
Acetyl-H3
Dose: 230 mg/m2 Part A
Peak AUC 1,387 ng h/mL
HPRT
Acetyl-H3
Dose: 300 mg/m2 Part A
Peak AUC 1,520 ng h/mL
HPRT
Acetyl-H3
Dose: 230 mg/m2 Part D
Peak AUC 3,739 ng h/mL
HPRT
Fig 2. (A) Western blot analysis of
acetyl-H3 (and HPRT loading control) in peripheral blood mononuclear cells (PBMC)
isolated from trial patients. (B) Graph reporting the fold induction of acetyl-H3 (relative
to pretreatment levels) at 1, 6, and 24 hours
post-treatment in PBMC isolated from 27
trial patients. AUC, area under the curve.
Group A
1,000
180
230
Group B
300
230
Group C
Group D
180
230
100
10
1
1 hr
6 hr
24 hr
0.1
0.01
N
A
N
A
47
6
81
1, 6
38
1, 7
94
1, 7
52
1, 0
79
2, 1
14
1, 1
47
3, 5
03
3, 6
78
5, 7
80
9, 9
00
8
N
1, A
33
3, 7
09
3, 4
50
7, 5
47
1, 0
18
1, 5
54
1, 7
93
2, 3
59
2, 1
64
2, 1
97
2, 9
99
3, 3
73
9
Fold Increase in Acetyl-H3 Expression by PBMC
B
Vorinostat AUC/24 Hours Range (ng/mL/hr)
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3627
Fouladi et al
(range, 102 to 263 L/h/m2) with a median vorinostat half-life of 2.4
hours (range, 1.1 to 8.0 hours).
Histone Acetylation
One hundred five adequate PBMC samples were obtained from
27 patients. Patients receiving 180 mg/m2/d of vorinostat capsules
alone or 180 mg/m2/d in combination with 13cRA showed little evidence of acetyl-H3 accumulation in PBMC (Figs 2A and Fig 2B). In
contrast, patients receiving 300 mg/m2/d of vorinostat capsules alone
demonstrated significant induction of acetyl-H3 in PBMC at 1, 6, and
24 hours after dose (group A, P ⬍ .05; Figs 2A and Fig 2B). Wide
interpatient variability in PBMC acetyl-H3 accumulation was observed among patients receiving the intermediate dose of 230 mg/
m2/d vorinostat either as capsules or suspension (parts B and D). A
significant induction of PBMC acetyl-H3 accumulation was observed
at 6 hours after dose among patients in part D (P ⬍ .01) and in two
patients in part B, suggesting 230 mg/m2/d may produce a more
transient inhibition of HDAC relative to 300 mg/m2.
DISCUSSION
This pediatric phase I trial established the MTD of vorinostat as 230
mg/m2/d administered orally in patients with recurrent or refractory
solid tumors. Patients with refractory leukemia did not appear to
tolerate this dose due to liver dysfunction. The combination of
vorinostat with standard neuroblastoma dosing of 13cRA (80 mg/
m2/dose twice per day, days 1 through 14) required a reduced dose/
schedule of vorinostat (180 mg/m2/dose 4 times per week). Our
single-agent DLTs for vorinostat (ie, neutropenia, thrombocytopenia,
and hypokalemia) were similar to those observed in adult studies.
Frequent adverse events included nausea, vomiting, anorexia, increased transaminases, and hyperbilirubinemia. The vorinostat suspension was generally tolerable at the MTD of 230 mg/m2 in patients
with solid tumor, with four of 12 patients experiencing toxicities that
required dose modifications during course 1. A detailed toxicity comparison between formulations was not possible as six of these 12
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The disposition of vorinostat in children was similar to that
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(1.5 hours in adults28-30). Although in adults, the maximum plasma
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Accumulation of acetyl H3 histones in PBMCs was detected in
patients receiving the highest vorinostat dosages and particularly in
patients treated with 300 mg/m2/dose in whom accumulation of
acetyl-H3 persisted for 24 hours. Evidence of more transient (6 hours)
PBMC acetyl H3 accumulation was observed in patients receiving 230
mg/m2/dose. No significant accumulation was seen at the 180 mg/
m2/d dosage. Acetyl-H3 accumulation did not appear to correlate with
drug exposure as measured by the AUC.
Overall, vorinostat drug disposition and tolerance in children
was similar to that observed in adult patients. Additional studies will
be needed to understand the basis for the wide interpatient variation in
drug disposition that was observed. Future trials include the combination of 13cRA and vorinostat in children with neuroblastoma or
select CNS malignancies.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
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