Annual Meeting Proceedings Part 1 - American Society of Clinical ...

616s Pediatric Oncology
9540 Poster Discussion Session (Board #20), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Phase I trial of temsirolimus (TEM), irinotecan (IRN), and temozolomide
(TMZ) in children with refractory solid tumors: A Children’s Oncology
Group study. Presenting Author: Rochelle Bagatell, The Children’s Hospital
of Philadelphia, Philadelphia, PA
Background: Inhibitors of mTOR have demonstrated activity in preclinical
pediatric solid tumor models. A phase I trial to define the dose limiting
toxicities (DLTs) associated with the mTOR inhibitor TEM in combination
with IRN and TMZ was conducted in patients (pts) with refractory solid
tumors. Methods: Escalating doses of TEM were administered intravenously
on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50
mg/m2 /dose) was administered orally on d1-5. TMZ (100 mg/m2 /dose) was
administered orally on d1-5. When the maximum planned dose of TEM was
reached (35 mg/m2 /dose), IRN was escalated stepwise from 50 to 90
mg/m2 /dose. Pts were enrolled on 6 dose levels using the rolling-six design.
Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were
enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma
(4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other
(8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered.
Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose
level 3 (TEM 25 mg/m2 , IRN 50 mg/m2 , TMZ 100 mg/m2 ); both pts were on
chronic corticosteroids. The protocol was amended to preclude chronic
systemic steroid use and modify hyperlipidemia management. Doselimiting
hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT
(elevated GGT) was observed in 1 pt treated with TEM 35 mg/m2 , IRN 65
mg/m2 , TMZ 100 mg/m2 . DLT has not been observed in 4 of the first 6 pts
treated at the highest planned dose level (TEM 35 mg/m2 , IRN 90 mg/m2 ,
TMZ 100 mg/m2 ). Additional �Grade 3 regimen-related toxicities occurring
in �1 evaluable pt include neutropenia (12), lymphopenia (10),
leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5),
hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases
(2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1
pt had a confirmed partial response and 4 have remained on protocol
therapy for �1 year. Conclusions: The combination of TEM (35 mg/m2 /
dose) d 1 and 8, IRN (90 mg/m2 /dose) d 1-5, and TMZ (100 mg/m2 /dose) d
1-5 of a 21-d cycle appears to be well tolerated in children with refractory
solid tumors.
9542 Poster Discussion Session (Board #22), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for
72 hours every 21 days via intravenous infusion in children and adolescents
with relapsed and refractory solid tumours. Presenting Author: Darren
R Hargrave, Great Ormond Street Hospital, London, United Kingdom
Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B,
JAK & ABL kinases. Aurora kinases are potential therapeutic targets in
paediatric solid cancers. Methods: A phase I dose escalation study was
performed using a 72 hour intravenous infusion repeated 3 weekly using a
rolling 6 design for patients aged �2to�19 years with relapsed/ refractory
solid tumours. Results: Eighteen patients treated with a median age of 10
(range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2 /day.
The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3
neuroblastomas, 3 sarcomas & 3 others. There has been only one dose
limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2 /day. The
majority of adverse events (AEs) have been grade 1/2 & considered
unrelated/ unlikely related to study drug. Two patients have experienced
Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3
haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m 2 /day &
Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count
and aspartate transaminase in a patient treated at 11.5 mg/m2 /day.
Pharmacokinetics of AT9283 in this population are largely in keeping with
those seen in adult patients at similar doses (Arkenau et al., 2011)
although there may be greater variability. Pharmacodynamic evidence of
aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation
in normal skin biopsies pre & post infusion, has been documented at
all dose levels tested. Stable disease (up to 6 cycles) has been observed in
3 patients. Conclusions: This paediatric phase I study has demonstrated
AT9283 administered as a 72 hour continuous infusion can be given at a
dose level of 11.5 mg/m2 /day which is higher than the maximum tolerated
dose observed in adult patients (9 mg/m2 /day) with advanced solid
tumours. Myelosuppresion is the main toxicity but the regimen is well
tolerated with preliminary anticancer activity seen in heavily pre-treated
paediatric patients.
Dose level mg/m2 /day
(N) Cmax (ng/mL) AUC (ng/mL.hr) Half life (hr) Tmax (hr)
7(3) 14.4 698 5.4 56
9(3) 32.0 1818 4.7 56
11.5(6) 39.4 2081 5.1 56
9541 Poster Discussion Session (Board #21), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
A phase I trial of IMC A12 and temsirolimus in children with refractory solid
tumors: A Children’s Oncology Group study. Presenting Author: Maryam
Fouladi, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Background: IMC-A12, a fully recombinant IgG1 monoclonal antibody that
targets the human IGF-IR and inhibits downstream signaling of MAPK and
PI3K/AKT, and temsirolimus, an mTOR inhibitor, have demonstrated
preclinical single agent, antitumor activity against many pediatric tumors.
A phase I and pharmacokinetic (PK) trial evaluating the combination of
these agents was conducted in children with refractory solid and CNS
tumors. Methods: Using a modified 3�3 design, IMC-A12 and temsirolimus
were administered intravenously once every 7 days in 28 day cycles.
Serial PK studies were obtained on day 1, cycle 1 and trough samples were
obtained on days 15 and 28. Biology studies included assessment of IGFR
and insulin receptor expression and phosphorylation in archival tumor
samples and phosphorylation of IGFR and mTOR downstream targets in
peripheral blood mononuclear cells (PBMC) pre and post therapy. Results:
Thirty-nine patients [20 male, median age 11.8 years (range 1-21.5)] with
rhabdomyosarcoma (n�10), osteosarcoma (n�6), Ewings sarcoma (n�5),
astrocytoma (n�5), or other tumors (n�13) were enrolled; 33 were
evaluable for toxicity. At dose level 1 [IMC-A12 (6 mg/kg); temsirolimus
(15 mg/m2 )], 2 DLTs (grade 3 hypercholestrolemia, mucositis) occurred
among 6 evaluable patients. Six more patients were accrued and 3
additional DLTs were observed (grade 3 ALT, fatigue and prolonged
thrombocytopenia � 14 days). At dose level 0 [IMC-A12 (6 mg/kg);
temsirolimus (10 mg/m2 )], dose-limiting mucositis occured in 2/6 patients.
At dose level -1 [IMC-A12, (4 mg/kg) and temsirolimus at (8
mg/m2 )], 0 of 3 patients experienced a DLT. At an intermediate dose level
[IMC-A12 (6 mg/kg) and temsirolimus (8 mg/m2 )], 1 of 6 patients
experienced mucositis; among an expanded PK cohort for children �12
years, none of 6 patients experienced a DLT. Target inhibition (decreased
S6K1 and PAkt) in PBMCS were noted at all dose levels. At 8 mg/m2 , the
median sirolimus AUC was 225 �g/ml · h (159-226), and median temsirolimus
AUC was 3340 �g/ml · h (1894-4387), and median Cmax 1176
�g/ml (480-2231). Conclusions: The recommended pediatric phase II
doses for the combination of IMC-A12 and temsorolimus are 6 mg/kg and 8
mg/m2 , respectively.
9543 Poster Discussion Session (Board #23), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Pharmacokinetic (PK) and pharmacodynamics (PD) properties of SC-PEG
e. coli L-asparaginase (EZN-2285) in the treatment of patients with acute
lymphoblastic leukemia (ALL): Results from Children’s Oncology Group
(COG) study AALL07P4. Presenting Author: Anne L. Angiolillo, Children’s
National Medical Center, Washington, DC
Background: Asparaginase is a critical therapeutic agent in the treatment of
childhood ALL, and pegaspargase (Oncospar, ONC) is now the preferred
product in COG frontline ALL trials. EZN-2285 replaces the succinimidyl
succinate linker in ONC with a succinimidyl carbamate linker creating a
more stable molecule. AALL07P4 was designed to determine the PK
comparability of EZN-2285 to ONC when given intravenously in newly
diagnosed patients with NCI high-risk (HR) B-precursor ALL. Methods: 162
eligible patients were randomized to receive EZN-2285 at 2100 (LD,
n�66) or 2500 (HD, n�42) IU/m 2 vs. 2500 IU/m2 of ONC (n�51) in a 2:1
manner based on the prednisone/Capizzi methotrexate arm of COG
AALL0232. All groups were similar demographically with the exception of
number of patients over the age of 16 years were 6, 5, and 19 in the ONC,
HD and LD, respectively. Results: PK, PD and targeted AEs (Gr 3-5) after
the first doses of study drug are presented in the table below. Adverse
events in induction were not significantly different between arms with the
exception of a higher incidence of hyperglycemia (p�0.042). Conclusions:
Based on Cmax , AUC0-25d , and asparaginase activity 25 days post drug,
EZN-2285 2500 IU/m2 appears to have an improved PK/PD profile
compared to pegaspargase 2500 IU/m2 and a comparable toxicity profile in
children with HR ALL.
PK/PD (mean�SD) and AEs post induction dose.
Pegaspargase
2500 IU/m 2 (n�43)
EZN-2285
2500 IU/m 2 (n�40)
EZN-2285
2100 IU/m 2 (n�62)
Cmax (mIU/mL) 1,647�474 1,655�366 1,291�379
t½ (hrs) 127�51 322�118 305�98
AUC0-25d (mIU*hr/mL) 359,781�80,309 470,742�123,584 369,998�122,013
AUC0-inf (mIU*hr/mL) 387,015�85,753 574,091�158,574 454,394�144,348
Asparaginase activity (mIU/mL) 25 D
post drug
72.8�47.9 339.6�126.8 271.6�118.2
Asparaginase activity >100/>400 mIU/mL 25 D
post drug (%)
67/0 98/28 94/14
Plasma asparagine depletion 25/42 D
post drug (%)
88/8 92/72.4 93/75
Safety population (n�54) (n�42) (n�69)
Allergy (%) 7 2 1
Coagulopathy (%) 0 7 3
Hyperbilirubinemia (%) 7 12 9
Hyperglycemia (%) 15 26 35
Hyperlipidemia (%) 6 5 1
Pancreatitis (%) 4 5 6
Thrombosis (%) 0 0 6
CNS (%) 0 0 1
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