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

252s Gastrointestinal (Noncolorectal) Cancer
4055 General Poster Session (Board #42F), Mon, 8:00 AM-12:00 PM
A randomized phase III multi-institutional study of TNFerade biologic with
5-FU and radiotherapy for locally advanced pancreatic cancer: Final results
Presenting Author: Aaron Tyler Wild, Department of Radiation Oncology
and Molecular Radiation Sciences, Johns Hopkins University School of
Medicine, Baltimore, MD
Background: TNFerade biologic (TNF) is a novel means of selective delivery
of TNF-� to tumor cells by gene transfer through intratumoral (IT) injection.
TNF is a replication deficient adenovirus vector containing TNF-� cDNA
ligated downstream from a radiation-inducible Egr-1 promoter, allowing
spatiotemporal constraint of TNF-� production to the radiation field. Herein
we report the final results of a multi-center, randomized, open-label,
controlled phase III trial of TNF with chemoradiotherapy for locally
advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with
locally advanced PDA were randomized 1:2 to standard of care (SOC;
5-FU/RT followed by GEM) versus TNF � SOC. RT dose was 50.4 Gy in 28
fractions. Concurrent 5-FU (200 mg/m2 /day IV) started on day 1 of RT each
wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or
endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was
given until progression or toxicity. Results: Of 277 pts, 187 were randomized
to TNF and 90 to SOC. Demographic/baseline characteristics were
similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs.
7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for
TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95%
CI, 7.6-11.2) for SOC (p�0.6). TNF delivery method did not affect OS (9.4
mos for PTA vs. 11.5 for EUS; p�0.7). Baseline CA19-9 � 1000 was
found to impart independent risk to TNF pts (HR�1.7; p�0.02). Subgroup
analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF
compared to SOC (10.9 vs. 9.0 mos, respectively; p�0.04). TNF resulted
in more grade 1-2 fever/chills (p�0.001) as well as grade 3 (p�0.001) and
4(p�0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/
chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity
rates. Conclusions: TNF � SOC did not prolong OS for locally advanced
PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and
CA19-9 � 1000. PTA and EUS injection achieved similar rates of efficacy
and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-�
(pyrexia/hypotension/chills) was common, but grade 3-4 was minimal.
4057 General Poster Session (Board #42H), Mon, 8:00 AM-12:00 PM
Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma
(PC) at Memorial Sloan-Kettering Cancer Center (MSKCC). Presenting
Author: Maeve A. Lowery, Memorial Sloan-Kettering Cancer Center,
New York, NY
Background: The PRODIGE/ACCORD trial recently established FFX as a
treatment option for good performance status (PS) pts with stage IV PC
(Conroy et al, NEJM 2011). We evaluated the activity and toxicity
associated with FFX therapy in pts with advanced PC treated at MSKCC
outside of a clinical trial. Methods: 80patients (pts) treated withFFX as
1st-line therapyat MSKCC between 07/1/10 and 12/30/11, were identified
from an institutional database (prior IRB approval). Records were reviewed
for demographic, treatment, toxcity, and response data. Results: 61 and 19
pts received FFX for stage IV and III PAC respectively. Demographics and
outcomes are summarized in the table. Median starting dose of FFX was
80% of that used in the PRODIGE/ACCORD trial. Median overall survival
(OS) was 12.5 months (mo) (95% CI 9.5–15.5) in pts treated with 1st line
FFX for stage IV PAC and 13.7 mo (95% CI 11.3–15.8) in pts with stage III
PAC. 68% of pts with stage IV PAC who discontinued FFX for disease
progression (PD) or toxicity received 2nd-line gemcitabine-based therapy.
Conclusions: We observed activity and acceptable toxicity in carefully
selected patients treated with FFX at 80% dose intensity and routine use of
growth factor support. Treatment with FFX resulted in median OS of � 1
year in pts with stage IV PAC and is an active front-line regimen.
1st line: Stage IV
N�61
1st line: Stage III
N�19
Age (yrs)
Sex
Male
64 (range 46-80)
-
33(54%)
58 (range 37-69)
-
11(58%)
Female
Primary tumor
28(46%)
-
8(42%)
-
Head
23(38%)
14(74%)
Body
21(34%)
2(10%)
Tail
Prophylactic growth factor
Median number of cycles
Dose reduction/discontinutation for toxicity
17(28%)
51(84%)
7
32(52%)
3(16%)
15(79%)
6
9(47%)
GI
11(18%)
4(21%)
Myelosupression
4(7%)
1(5%)
Neuropathy
9(15%)
1(5%)
Drug reaction
4(7%)
1(5%)
Other
Subsequent surgery/RT
Best response*
4(7%)
N/A
-
2(10%)
1(5%)/10(53%)
-
PR
21(40%)
4(21%)
SD
23(45%)
13(68%)
PD
8(15%)
2(11%)
* Evaluable pts N�52 (1 pt not yet staged, 3 pts� 2 cycles FFX due to toxicity/5 pts due to
non-treatment-related death).
4056 General Poster Session (Board #42G), Mon, 8:00 AM-12:00 PM
M402, a heparan sulfate mimetic and novel candidate for the treatment of
pancreatic cancer. Presenting Author: Birgit C. Schultes, Momenta Pharmaceuticals,
Cambridge, MA
Background: Recent advances in pancreatic cancer research implicate the
involvement of several heparin-binding growth factors (such as HGF,
HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions.
We have rationally designed a heparan sulfate mimetic, M402, which
has been previously shown to affect tumor progression and metastasis
through disruption of multiple pathways. We hypothesized that M402
could modulate tumor-stroma interactions and enhance the efficacy of
gemcitabine, and evaluated its efficacy in two preclinical models. Methods:
A genetically engineered mouse model (GEMM; KrasLSLG12D p53LSLR172H )
featuring spontaneous pancreatic tumor formation and metastasis assessed
M402’s effect on tumorigenesis and metastasis. The orthotopic
Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia,
a fibrotic response that hinders effective delivery of chemotherapeutics, via
inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate
cells. In both models, M402 was studied as monotherapy and with
gemcitabine. Results: In the GEMM, M402 significantly prolonged survival
in combination with gemcitabine while each monotherapy showed modest
efficacy. M402, alone and in combination, also reduced metastases and
local invasion and inhibited epithelial-to-mesenchymal transition. In the
Capan-2 model, gemcitabine was increasingly less effective as desmoplasia
progressed over time. The addition of M402 to gemcitabine increased
its efficacy with respect to primary tumor burden. Metastasis, invasion, and
surrounding fibrotic lesions appeared particularly impacted by the combination
treatment. M402 was also effective as monotherapy with dosedependency,
which correlated with reduced SHH signaling. Conclusions:
M402 can modulate tumor-stroma interactions involved in the metastatic
and desmoplastic pathways in two pancreatic cancer models supporting
the translation of these findings into a clinical study. A first-in-human study
is planned that will evaluate the safety, pharmacokinetics, efficacy, and
biomarker profiles of escalating M402 doses in combination with gemcitabine
in patients with metastatic pancreatic cancer.
4058 General Poster Session (Board #43A), Mon, 8:00 AM-12:00 PM
Benefits of platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma
(PC) associated with BRCA mutations: A translational case
series. Presenting Author: Olusola O. Faluyi, Princess Margaret Hospital,
Toronto, ON, Canada
Background: The prognosis of PC is poor with limited response to standard
chemotherapy. Prior randomized studies of cisplatin and gemcitabine in PC
demonstrated no additional benefit over gemcitabine alone. Preclinical
data and case reports suggest that BRCA mutant PC may have increased
sensitivity to Pt-chemo. Our case series characterizes the benefits of
Pt-chemo in germline BRCA mutant PC. Methods: Patients with PC and
germline BRCA mutations were identified using the Ontario Pancreatic
Cancer Study and Pharmacy databases. Review of clinical records provided
demographic, treatment and survival data. Radiology review assessed
responses to chemotherapy. RNA was extracted from tumor samples for
gene expression studies using a panel of DNA repair genes and Nanostring
technology. BRCA loss of heterozygosity (LOH) was also investigated.
Results: We identified 14 PC patients with BRCA mutations (8 BRCA2, 6
BRCA1). 11 of these had metastatic disease of which 5 received Pt-chemo.
Of the 5 treated with Pt-chemo, there were 3 partial responses (PR) and 2
complete responses (CR) using Recist criteria. For the remaining 6 not
treated with Pt-chemo, there was 1 PR with gemcitabine. Additionally, two
patients with locally advanced disease at diagnosis became resectable
following Pt-chemo. Overall survival was superior for patients receiving
Pt-chemo (33.0�25.6 vs 7.3�4.5 months; p�0.04). Gene expression
and LOH results will be presented. Conclusions: Responses and survival
associated with Pt-chemo observed in our case series of BRCA mutant PC
adds to existing data supporting the use of Pt-chemo in this subgroup.
Despite the low (2 to 5%) prevalence of BRCA mutations in PC, the benefits
gained from personalizing treatment using Pt-chemo supports BRCA
testing in selected patients.
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