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

9544 Poster Discussion Session (Board #24), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
The application of radiotherapy to the pediatric preclinical testing program:
Results of a pilot study. Presenting Author: Christopher E. Pelloski, The
Ohio State University Arthur G. James Comprehensive Cancer Center and
Richard L. Solove Research Institute, Columbus, OH
Background: The Pediatric Preclinical Testing Program (PPTP) has been
successfully utilized to determine the efficacy of novel agents by testing via
its mouse-flank in vivo model. We report on the feasibility and biologic
outcomes of a pilot study using rhabdomyosarcoma (RMS) xenograft lines
treated with radiotherapy (RT) alone and concurrently with the mTOR
tyrosine kinase inhibitor, AZD8055, using the PPTP model. Methods: We
developed a mouse flank irradiation device for daily delivery of RT in
clinically relevant doses (2 Gy per fraction up to 40 Gy).Two RMS xenograft
lines of the PPTP, Rh30 (alveolar) and Rh18 (embryonal), were implanted
into SCID mice, grown to appropriate volumes and were subjected to
fractionated RT. In a second study, daily co-administration of AZD8055
(5-20 mg/Kg, gavage) with RT was performed. Cure rates (durable complete
response �12 weeks post-treatment) and RT dose densities (given dose /
initial xenograft volume, Gy/cc) were compared between groups. Results:
With RT alone at mean dose-densities of 59-60 Gy/cc, cure was achieved in
only 4/18 (22%) of the Rh30-bearing mice and 9/12 (75%) of the
Rh18-bearing mice (p�0.006). Profiling data revealed higher levels of
Fanconi anemia pathway gene expression in Rh30 compared to the more
sensitive Rh18. Since recent data showed conditional knockout of mTOR
resulted in the loss of FANCD2 gene expression, we postulated that
blockade of TORC1/TORC2 with AZD8055 would reduce FANCD2 and
increase the RT-sensitivity of Rh30. The addition of AZD8055 to RT
resulted in a selective sensitization of the Rh30 line. With a mean RT
dose-density of 27 Gy/cc, the cure rate in Rh30-bearing mice improved to
11/15 (73%). For the Rh18 group, the cure rate was 7/15 (46%) at a mean
dose density of 44 Gy/cc. Western blot analysis showed the coadministration
of AZD8055 abrogated the brisk increase in mTOR signaling
and FANCD2 expression after the first several 2 Gy fractions of RT; most
strikingly in Rh30. Conclusions: This study demonstrates the feasibility of
applying RT to the PPTP model. It recapitulated the expected clinical
radiobiology and demonstrated its utility in preclinical testing and the
discovery of novel mechanisms of RT resistance in pediatric tumors.
9546 General Poster Session (Board #40A), Sun, 8:00 AM-12:00 PM
Trends in body mass index (BMI) during and after treatment for standard
risk (SR) acute lymphoblastic leukemia (ALL): A report from the Children’s
Oncology Group (COG). Presenting Author: Susan Joy Lindemulder, OHSU,
Portland, OR
Background: Obesity is a potential complication in children treated for ALL.
Limited data exist regarding timing of BMI changes and risk in long-term
survivors of ALL treated without cranial radiation (CRT). This study
describes temporal trends in BMI during and after therapy for SR-ALL and
identifies associated factors. Methods: We conducted a retrospective cohort
study of children with SR-ALL enrolled on two sequential clinical trials
between 1993 and 2000 and on the COG ALTE02C2 follow-up study.
Therapy included prednisone or dexamethasone during induction, the
same steroid in maintenance phases, and no CRT. Standing height and
weight was ascertained at diagnosis (dx), start of consolidation, start of
maintenance, start of the last cycle of maintenance, and at least one year
off therapy. Age and gender-specific BMI percentiles (BMI%) were calculated
using 2000 CDC growth charts for patients 2-20 years. Results: The
269 subjects were a median of 3.5 years at dx, 46.7% female, 82.3%
white, and a median of 9.1 years since dx at the last timepoint. The BMI%
was associated with elapsed time since dx: BMI% increased between dx
and consolidation (50.9%-68.3%, p � 0.0001), remained stably elevated
until the end of maintenance, and then decreased somewhat from the end
of maintenance to the last timepoint (74.1%-70.6%, p � 0.03). After
therapy, 18.1% of survivors were overweight (BMI% 85-95) and 20.9%
were obese (BMI% � 95). By unadjusted linear regression, higher dx BMI%
was positively associated with BMI% post-therapy (p � 0.0001). There was
an interaction with steroid and dx BMI% such that the association between
dx BMI% and post therapy BMI% was significantly greater for the
dexamethasone group than the prednisone group (p � 0.01). There was no
association with age at dx, gender, or race. Conclusions: In this retrospective
study of SR-ALL survivors treated without CRT, we found that BMI%
increased significantly in the month after dx and remained substantially
elevated even several years after the end of therapy. Dx BMI% was highly
associated with off-therapy BMI%, particularly in patients who had
received dexamethasone rather than prednisone.
Pediatric Oncology
617s
9545 Poster Discussion Session (Board #25), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Ipilimumab: First results of a phase I trial in pediatric patients with
advanced solid tumors. Presenting Author: Melinda S. Merchant, National
Cancer Institute, Bethesda, MD
Background: Ipilimumab is a fully-human IgG1 monoclonal anti-CTLA-4
antibody which has been approved by the FDA for adult patients with
metastatic melanoma . Although the approved dose is 3mg/kg every 21
days, the dose of 10mg/kg IV every 21 days for 4 doses in combination with
chemotherapy was well tolerated in a phase III trial enrolling adult patients
with melanoma. Methods: This pediatric phase I, dose escalation study
examined the safety, tolerability, pharmacokinetics, and immunogenicity
of ipilimumab administered to patients �21yo with recurrent or progressive
solid tumors. Ipilimumab was administered at 1, 3, 5, and 10mg/kg IV
in a standard 3 � 3 design with 4 doses of induction therapy q3 weeks
followed by maintenance q3 months until disease progression or unacceptable
toxicity. Tumors were measured after 6 weeks, 12 weeks, and then
every 3 months. Results: Twenty one patients (melanoma n�6, osteosarcoma
n�6, soft tissue sarcomas n�7, neuroblastoma, and renal cell
carcinoma) received a total of 57 doses of Ipilimumab to date. One of 6
patients treated at 5mg/kg developed a dose-limiting grade 3 pancreatitis.
.At the highest dose level of 10mg/kg, two of three patients under 12yo
developed DLT: grade 3 colitis and concurrent norovirus in one patient, and
self-resolving grade 3 transaminitis in a second patient. Three of three
patients between the ages of 12 and 21yo tolerated the 10mg/kg dosing
schedule without DLT. Across all dose levels, grade 2 or 3 adverse events
included colitis (n�1), transaminitis (n�3), pancreatitis (n�1), autoimmune
thyroiditis (n�2), and hypophysitis (n�1) observed between C1D8
and C4D21. A single grade 1 rash was observed. Stable disease was the
best response in 5 patients with a duration of 3 to 18 months. Conclusions:
Ipilimumab can be safely administered to pediatric patients. Adolescents
are able to tolerate the highest dose of 10mg/kg. Younger children (�12yo)
had 2 DLTs in 3 patients at 10 mg/kg . Expansion of the 10 mg/kg cohort for
adolescents and of the 5 mg/kg dose for the �12yo for further safety and
pharmacokinetic information is underway. The spectrum of adverse events
appears similar to those described in the adult trials, although there were
no grade 2 or higher incidents of rash.
9547 General Poster Session (Board #40B), Sun, 8:00 AM-12:00 PM
Pharmacokinetics (PK) of bendamustine in pediatric patients with relapsed/
refractory acute leukemia. Presenting Author: Mona Darwish, Teva Pharmaceutical
Industries Ltd., Frazer, PA
Background: The PK profile of bendamustine in adult patients is well
characterized. The objective of this analysis was to describe the pediatric
PK profile of bendamustine relative to the adult PK profile and correlate the
systemic exposure of bendamustine to efficacy and safety parameters.
Methods: Samples were obtained after a single dose from patients aged
1-19 years with relapsed/refractory acute leukemia who were enrolled in an
open-label, nonrandomized study of bendamustine (90–120 mg/m2 ,
infused over 60 minutes). Samples were obtained prior to bendamustine
infusion and preselected time points through 24 hours after start of
infusion on day 1. Population PK modeling was performed using plasma
concentration data from these patients. PK data from adults were used for
comparison. Results: Systemic exposure of pediatric patients to bendamustine
was similar to that obtained previously in adult patients. Mean Cmax was 6806 ng/mL and mean AUC0-24 was 8240 ng*hr/mL in pediatric
patients, compared with a mean Cmax of 5746 ng/mL and AUC0-24 of 7121
ng*hr/mL in adults. Similarity in exposure despite the large range of body
surface area across the pediatric and adult populations confirms appropriateness
of the body surface area–based dosing scheme. In pediatric
patients, age, race, sex, or disease state had no statistically significant
effect on systemic exposure to bendamustine. No changes in systemic
exposure to bendamustine in the presence of a CYP1A2 inhibitor/inducer
were observed. Differences in PK were not observed in pediatric patients
with mild renal impairment as compared with patients with normal renal
function. Exposure in 2 pediatric patients with moderate hepatic dysfunction
appeared to be higher. No clear exposure-response relationship was
observed. Infection was the only adverse event for which the probability of
occurrence increased with increase in exposure to bendamustine.
Conclusions: The PK profile of bendamustine in pediatric patients was
similar to the known PK profile in adults, demonstrating that exposures
reflective of the therapeutic range in adults were attained following
administration of 120 mg/m2 to pediatric patients. Support: Teva Pharmaceutical
Industries Ltd., Frazer, PA.
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