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

244s Gastrointestinal (Noncolorectal) Cancer
4021 Poster Discussion Session (Board #13), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I/II study of preoperative (pre-op) short course chemoradiation (CRT)
with proton beam therapy (PBT) and capecitabine (cape) followed by early
surgery for resectable pancreatic ductal adenocarcinoma (PDAC) of the
head. Presenting Author: Theodore S. Hong, Massachusetts General
Hospital, Boston, MA
Background: Standard adjuvant 6 week CRT may delay and reduce
tolerability of adjuvant gemcitabine-based chemotherapy. We explore the
safety and efficacy of a one-week course of pre-op CRT with PBT and cape
followed by early pancreaticoduodenectomy (PD). Methods: Patients with
radiographically resectable, biopsy-proven PDAC of the head were enrolled
from May 2007-December 2010 on this prospective, NCI-sponsored
clinical trial. Eligibility included no CT involvement of SMA or celiac artery;
No metastatic disease. Dose level 1 consisted of PBT delivered 3 Gy x 10.
Pts in subsequent dose levels received 5 Gy x5inprogressively shortened
schedules: level 2 (wk1MWF,wk2TTh), level 3 (wk1MTThF,wk2M),
level 4 (wk 1 M-F). PBT was targeted at pancreatic mass with elective nodal
coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. Surgery was
performed 1-6 wks after completion of cape. Patients were recommended
to receive 6 mo of gemcitabine after surgery. Genotyping of 15 genes
(including KRAS, PIK3CA, BRAF, NRAS, TP53, IDH1) was performed.
Results: 50 pts were enrolled on study. 48 patients are eligible for this
analysis. 3 pts were treated at each of dose levels 1-3. 6 pts were at dose
level 4, which was selected as MTD. No DLTs were observed. 35 patients
were treated in the phase II portion at the MTD. Gr 3 toxicity was noted in 2
pts (chest wall pain-1, colitis-1). 38 pts underwent PD. Reasons for no PD
were: metastatic disease-9, unresectable tumor-1. Mean post-op length of
stay was 7 days (range 5-47). 6/38 (16%) resected pts had positive
margins. 28/38 (74%) had positive nodes. Median follow up is 21 months
among the 19 patients still alive. 4/48 (8%) local failures in ALL patients.
mOS and mPFS are 18 and 10 months respectively for ALL patients and 27
and 14 months for RESECTED patients. Of 28 patients with genotype data
available, 22 (79%) had KRAS mutations. 10/22 KRAS mt and 4/6 KRAS
wt pts are alive. Conclusions: Pre-op CRT with 1 wk of PBT and capecitabine
followed by early surgery is well tolerated and associated with favorable
local control. Complete genotype and DPC4 data will be presented at the
meeting.
4023 Poster Discussion Session (Board #15), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Correlation of hand-foot skin reaction (HFS) with treatment efficacy in
pancreatic cancer (PC) patients (pts) treated with gemcitabine/capecitabine
plus erlotinib: A subgroup analysis from the AIO-PK0104 randomized,
cross-over phase III trial in advanced PC. Presenting Author: Michael
Haas, Department of Hematology and Oncology, Klinikum Grosshadern and
Comprehensive Cancer Center, LMU Munich, Munich, Germany
Background: AIO-PK 0104 investigated the efficacy and safety of gemcitabine/erlotinib
(G/E) followed by capecitabine (C) vs. C/E followed by G.
The present subgroup analysis evaluated the correlation between Cassociated
skin toxicity and outcome parameters in PC. Methods: Within
this multicenter phase III trial, pts with confirmed advanced PC were
randomly assigned to 1st-line treatment with either C (2,000 mg/m2 /d,
d1-14 q d21) plus E (150 mg/d, arm A) or G (1,000 mg/m2 over 30 min
weekly x 7, then d1, 8, 15 q d28) plus E (150 mg/d, arm B). A cross-over to
either G (arm A) or C (arm B) was performed after treatment failure (e. g.
disease progression or unacceptable toxicity). Time to treatment failure
after 1st- and 2nd -line therapy (TTF2) was the primary study endpoint.
Treatment-related skin toxicity was evaluated separately for each treatment
arm/each regimen based on NCI-CTCv2. Results: Of 279 eligible pts, 47
had locally advanced, 232 had metastatic disease and 141 pts received
second-line chemotherapy. For the present subgroup analysis data on skin
toxicity were available from 255 pts. For the 73 pts (29%) with a HFS (any
grade documented at any time during the treatment strategy), TTF2 and OS
both were significantly prolonged compared to pts without HFS (7.4 vs 4.0
months, p�0.001 and 9.7 vs 5.5 months, p�0.002, respectively).
Considering HFS during 1st-line treatment in 123 pts within the CE arm,
these results could be confirmed for the 47 pts (38%) with a documented
HFS of any grade (TTF2: 7.6 vs. 3.2 months, p�0.001; OS: 10.2 vs. 4.4
months, p�0.001). In pts receiving 1st-line treatment with G/E (n�132)
no difference in outcome was observed for pts with (n�13) or without
(n�119) HFS of any grade (TTF2: 5.7 vs. 4.2 months, p�0.375; OS: 8.4
vs. 6.6 months, p�0.505). Conclusions: The current subgroup analysis of
AIO-PK0104 supports the assumption of a correlation between HFS in PC
pts treated with capecitabine or capecitabine/erlotinib and efficacy endpoints
like TTF2 and OS. A capecitabin-associated HFS thus might be
predictive for efficacy in patients with advanced PC.
4022 Poster Discussion Session (Board #14), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P)
or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with
metastatic pancreatic cancer (PC): Interim analysis of a University of
Chicago phase II consortium study. Presenting Author: Daniel Virgil
Thomas Catenacci, University of Chicago, Chicago, IL
Background: Sonic Hh (SHh), the ligand for the Hh pathway, is overexpressed
in �80% of PC. V, a small molecule antagonist of the Hh
signaling pathway, has activity in preclinical PC models. Methods: We
conducted a multi-center, placebo-controlled, phase IB/randomized phase
II trial of GV or GP. Eligible pts, KPS 80-100, had previously untreated
metastatic PC, or had completed adjuvant therapy � 6 months (mo) prior.
Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh
serum levels; serial contrast perfusion CT imaging. To allow for early
stopping due to lack of efficacy, a planned interim analysis was performed
after approximately 50% of the expected number of PFS events occurred.
The protocol stipulated that the trial would be terminated if the probability
of rejecting the null hypothesis were the trial to continue (conditional
power) was �10%. All pts received G 1000mg/m2 over 30 minutes, days
(D) 1, 8, 15, Q28D. Pts, stratified by KPS (80 v 90/100), and disease
status (newly-diagnosed/recurrent), were randomized to V (150 mg PO
daily) or P. For pts on P, cross-over was allowed at progression. Results: 70
evaluable pts (V/P 35/35) enrolled at 12 sites 2/10-6/11. Pt characteristics:
median age 63/63 (range 49-79/48-82); KPS 80: 8/8; 90: 12/14;
100: 15/13. Grade 3/4 toxicity (%pts): neutropenia 20/26; hyponatremia
3/11; fatigue 9/6; hyperglycemia 14/6; elevated alkaline phosphatase
9/11. Response (%): complete 0/3, partial 0/11, stable disease 49/31.
Median PFS: 3.7/2.4 mo (95% CI: 2.4-4.6/1.9-3.7; adjusted HR 0.92
[0.52-1.64]). Upon progression/unblinding, 23 GP pts crossed over to GV.
Median overall survival (OS): 6.3/5.4 mo (95% CI:4.9-7.8/4.2-8.0, adjusted
HR 0.97, [0.47-2.01]). 1-year survival (%): 24/24. Laboratory and
radiological correlatives will be presented. Conclusions: GV has an acceptable
toxicity profile. This trial did not meet criteria for futility at this interim
analysis. The study is expected to complete accrual of 112 pts in February
2012. The final analysis will be reported after 90 events. Funded by NCI
N01-CM-62201.
4026 Poster Discussion Session (Board #18), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Ethnic gene profile of genes involved in angiogenesis to predict regional
bevacizumab efficacy difference in gastric cancer. Presenting Author:
Takeru Wakatsuki, University of Southern California Norris Comprehensive
Cancer Center, Los Angeles, CA
Background: AVAGAST showed regional bevacizumab (Bev) efficacy difference
(RBED), namely, Asian (Asi) patients (pts) with gastric cancer (GC)
had no benefit whereas European and Pan-American patients had more
benefit from Bev. Recently, germline gene polymorphisms in angiogenesis
have been recognized as predictive marker for Bev efficacy. Allele frequency
(AF) in gene polymorphisms may vary depending on ethnicity. We
tested the hypothesis whether angiogenic pathway gene polymorphisms
may have different AF among Asi, Caucasian (Cau), and Hispanic (Hisp) in
GC and this disparity may explain RBED. Methods: Three-hundred pts
[Japanese (Jap), Cau, and Hisp, 100 from each race] with histopathologically
confirmed GC were collected from Japan, USA, Austria, and Italy
between 1991 and 2011. These pts were divided into 2 groups as training
set (n�50) and validation set (n�50) in each race. Seven functional gene
polymorphisms previously reported as predictive marker were selected. All
samples were analyzed using PCR-based direct DNA- sequencing. Fisher’s
exact test was used to compare the distribution of AF among races. Results:
Significant disparate distributions in favorable AF for Bev were shown
among races in Table. Jap GC pts had significant lower AF of 5 predictive
gene polymorphisms in training set, and among these 5, three predictive
gene polymorphisms were also validated. Conclusions: Our preliminary
results showed significant disparate AF distributions in predictive gene
polymorphisms for Bev, and these disparities may explain RBED in
AVAGAST. Further investigation is warranted to elucidate RBED.
The favorable allele frequencies for bevacizumab.
Training set Validation set
Cau (%) Hisp (%) Jap (%) P value Cau (%) Hisp (%) Jap (%) P value
VEGFR2 rs12505758 T/C 84.0 85.0 68.8 0.009 87.0 83.3 64.3 0.004
VEGFR1 rs9582036 C/A 79.0 86.0 82.7 0.660 75.0 80.0 83.0 0.740
VEGF-A rs699946 A/G 78.0 60.2 49.0 0.001 78.0 76.0 58.0 0.021
VEGFR2 rs11133360 C/T 55.1 43.8 70.8 0.002 60.0 35.9 68.0 �0.001
VEGF-A rs833061 C/T 52.0 35.0 29.6 0.020 50.0 40.0 33.0 0.200
VEGF-A rs699947 A/C 51.0 34.0 27.6 0.013 51.0 36.0 29.0 0.026
VEGF-A rs1570366 A/G 39.0 17.0 14.6 0.001 37.0 22.0 20.4 0.130
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