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

10028 Poster Discussion Session (Board #20), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I study of doxorubicin (D) plus anti-insulin-like growth factor 1 receptor
(IGF-1R) antibody cixutumumab (IMC-A12) in advanced soft tissue sarcoma
(STS). Presenting Author: Rashmi Chugh, University of Michigan, Ann Arbor, MI
Background: IGF1R is overexpressed in many STS, but its exact role in the biology
of the disease is unclear. Anti-IGF1R antibody cixutumumab (C) has shown
acceptable toxicity in a single-agent phase 2 study of STS. Here we performed a
dose escalation study of C with D in STS. Methods: Eligible pts had advanced
STS, ECOG �2, age�16, �1 prior chemotherapy, fasting glucose�120 mg/dL
and acceptable organ function. C was administered IV over 60 min on D1,8,15 at
one of three dose levels and D as a 48 hr infusion on D1 of a 21-day cycle. After 6
cycles of combination rx, pts with SD or better continued on single agent C. The
Time-to-Event Continual Reassessment Method (TITE-CRM) was used to estimate
the probability of DLT at each dose level and to assign patients to the dose
with the estimated probability of DLT closest to but not exceeding 30%. Results:
30 pts with STS were enrolled between 9/08-1/12. Median age was 64 (range
29-80); 17M/13 F, 7 pts received prior chemo. One pt withdrew prior to rx; 5 pts
are on active rx. Reasons for discontinuation were: progression (18), toxicity (3),
death (1), pt decision (2). DLTs observed were hyperglycemia and mucositis.
Grade 3 decrease in cardiac left ventricular ejection fraction was observed in 2
pts at dose level 2 after 4 or more cycles. Common G1/2 nonhematologic AEs:
nausea (73%), fatigue (68%), pain (59%), diarrhea (41%), constipation (36%),
hyperglycemia (32%), mucositis (32%), nail changes (27%), weight loss (27%).
Gr3/4 toxicities in �10%: hyperglycemia (18%), lymphopenia (18%), anemia
(14%), neutropenia (14%), thrombocytopenia (14%). Median PFS was 5.3
months, 95% CI 2.7 -7.9 months. Four of 22 pts (18%) evaluable for response
achieved a PR. Conclusions: C and D is tolerable and the recommended phase II
dosing is dose level 3. The potential of cardiotoxicity should be monitored and
assessed further in ongoing studies of this regimen.
Dose
level
1: C: 1 mg/kg
D: 75 mg/m2 2: C: 3 mg/kg
D: 75 mg/m2 3: C: 6 mg/kg
D: 75 mg/m2 Pts enrolled
(evaluable)
DLTs
observed
TITE-CRM estimates
Probability of DLT 95% Credible interval
Objective
responses
4 (4) 0 4.7 1.1 – 14.7 1
13 (13) 2 6.5 1.6 – 18.4 2
13 (10) 0 9.7 4.8 – 24.3 1
10030 Poster Discussion Session (Board #22), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Efficacy of a phosphoinositol 3 kinase (PI3K) inhibitor in gastrointestinal
stromal tumor (GIST) models. Presenting Author: Thomas Van Looy,
Laboratory of Experimental Oncology and Department of General Medical
Oncology, KU Leuven and University Hospitals, Leuven, Belgium
Background: PI3K signaling is crucial for GIST proliferation and survival.
We assessed the efficacy of the PI3K inhibitor NVP-BEZ235 (BEZ), alone
or in combination with imatinib (IM), in GIST xenografts. Methods: Nude
mice were grafted bilaterally with human GIST, carrying either KIT exon 9
(GIST-BOE, dose-dependent IM resistant) or exon 11 (GIST-DFR, IM
sensitive) mutations. Animals, randomized into four groups (n�8/group)
were dosed orally for 2 weeks with either vehicle, IM (50mg/kg/bid), BEZ
(10mg/kg/qd), or IM�BEZ. Treatment efficacy was assessed by tumor
volume, histopathology and Western immunoblotting. Moreover tumor
regrowth was evaluated for 3 weeks after treatment cessation. Results: As a
single agent IM and BEZ stabilized tumor growth of both GIST-BOE and
DFR. Moderate to significant tumor regression was observed in GIST-BOE
under BEZ (by 27%), and IM�BEZ (66%), and also in GIST-DFR under IM
(75%) and IM�BEZ (75%). In GIST-BOE significant reduction in mitotic
index was observed under BEZ (8.5 fold) and IM�BEZ (8.5 fold) as
compared to control. In GIST-DFR mitotic activity was virtually absent
under all regimens. Apoptotic activity increased significantly after treatment
with IM (5.5 fold) and IM�BEZ (14.0 fold) in GIST-DFR, whereas it
was almost unaffected by BEZ as single agent, as well as in all treatment
groups in GIST-BOE. By Western, PI3K signaling was incompletely inhibited
in all groups in GIST-DFR, and after BEZ in GIST-BOE. Complete
inhibition of PI3K signaling was observed only after combination treatment.
After treatment cessation long-lasting growth-inhibition was observed
in IM�BEZ treated GIST-DFR. Moreover, mitotic index after BEZ
and BEZ�IM in GIST-DFR was lower than in control even after treatment
withdrawal. Conclusions: BEZ shows significant efficacy in GIST xenografts.
Furthermore, combination with IM shows synergistic and long-lasting
effects even after treatment withdrawal, which is not the case with drugs
routinely used for GIST treatment.
Sarcoma
637s
10029 Poster Discussion Session (Board #21), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Immunohistochemical identification of SDHA-mutant gastrointestinal stromal
tumors (GISTs). Presenting Author: Andrew J. Wagner, Dana-Farber
Cancer Institute, Boston, MA
Background: GISTs are most commonly driven by activating mutations in
KIT or PDGFRA. However, 15% of GISTs in adults and �90% in children
lack such mutations. A subset of KIT/PDGFRA wild-type GISTs shows
distinctive morphologic and clinical features and loss of expression of
succinate dehydrogenase (SDH) B. Only a fraction of SDHB-deficient
GISTs carry loss-of-function mutations in SDHB or SDHC. Due to the
complexity of its locus and the presence of several pseudogenes, SDHA is
rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of
expression of SDHA and SDHB in paraganglionomas. We sought to
determine whether SDHA IHC could identify GISTs with SDHA mutations.
Methods: Tumors (n�11) with features of SDH-deficient GIST (gastric
origin, epithelioid morphology, multinodular/plexiform architecture) were
selected from pathology archives under an IRB-approved protocol. Expression
of SDHA and SDHB was determined on tumor sections by IHC.
Genomic DNA was isolated from SDHA-negative tumors and amplified
using primers specific to introns flanking each of the 15 SDHA exons.
Amplicons were bidirectionally sequenced and compared to genomic
repository data. Exons with somatic mutations were also examined in DNA
from corresponding normal tissue to determine germline status. Results: All
tumors (100%) were deficient for SDHB expression by IHC. Four of 11
(36%) SDHB-deficient GISTs also lacked expression of SDHA. SDHA
expression was intact in the 7 remaining tumors, including 3 with known
SDHB (n�2) or SDHC (n�1) mutations. Nonsense mutations in SDHA
were identified in all 4 SDHA-deficient tumors, caused by a single base pair
(bp) substitution (n�3) or a single bp deletion (n�1), and heterozygous
mutations were also found in DNA from normal tissue of all 4 patients.
Somatic loss of the 2nd allele has thus far been found in 3 of 4 tumors; 2 by
loss of heterozygosity and 1 by a 13-bp deletion. Further analysis of the 4th specimen is ongoing. Conclusions: SDHA mutations are a common cause of
SDH-deficient GISTs and result in combined loss of expression of both
SDHA and SDHB. Loss of SDHA expression by IHC reliably predicts SDHA
mutations and can be used to select cases for SDHA genetic testing.
10031 Poster Discussion Session (Board #23), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Neoadjuvant treatment of locally advanced GIST: Results of APOLLON, a
prospective, open label phase II study in KIT- or PDGFRA-positive tumors.
Presenting Author: Peter Hohenberger, Department of Surgery, Mannheim
University Medical Center, Mannheim, Germany
Background: Imatinib may significantly downstage the metastatic GIST.
This prospective, phase II, open-label trial of neoadjuvant imatinib evaluated
the overall tumor response and progression rate of disease in locally
advanced, non-metastic patients. Methods: Inclusion criteria were: KIT
(n�39) or PDFRA (n�6) positive GIST, proven by biopsy and IHC. Tumors
had to be locally advanced, potentially resectable, M0. Patients received
400 mg of imatinib daily (KIT exon 9 mutations: twice daily) for 6 months,
in the absence of disease progression or unacceptable toxicity. At two
months 18F-FDG-PET examination was performed to assess response in
paralle to CT imaging. Adjuvant treatment postoperatively was not part of
the study protocol (CST1571-BDE43, NCT00112632). Median follow-up
is 36 months in 39 patients. Results: From 7/2005 to 10/ 2009, 41
patients (16f, 25 m, mean age 54 yrs) were recruited to the trial with an
average tumor size of 10.8 cm. One patient died from myocardial infarction
3 weeks after start of treatment, all other patients completed the protocol.
In two patients dose reduction/interruption due to toxicity was required.
34/41 patients underwent resection of the tumor after a median of 200 d
(range 57-394), while two patients had to be operated early due to disease
progression. R0 resections were performed in 30/34 patients, two patients
showed M1 disease at resection. Five patients showed developed progression
postop., resulting in a PFS rate at 3 years of 85.2%. No patient has
died so far from the disease. Conclusions: Neoadjuvant treatment with
imatinib for six months is a safe treatment in patients with locally advanced
disease. The extent of the operation can be significantly downsized after
pretreatment. Despite the fact that no adjuvant treatment was foreseen, the
progression-free rate at 3 years postoperatively is promising.
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