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

4051 General Poster Session (Board #42B), Mon, 8:00 AM-12:00 PM
Updated survival analysis of preoperative gemcitabine (gem) plus bevacizumab
(bev)-based chemoradiation for resectable pancreatic adenocarcinoma.
Presenting Author: Rachna T. Shroff, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: Preop therapy for resectable pancreatic cancer (PC) maximizes
access to multimodality therapy and increases the R0 resection rate. Based
on our phase I chemoradiation (chemoRT) trial in PC patients, we
hypothesized that the addition of bev to gem-based chemoRT in pts with
resectable PC may allow more pts to undergo pancreaticoduodenectomy
(PD), improve the rate of R0 resections, and prolong overall survival.
Methods: Pts with biopsy proven, stage I/II adenocarcinoma of the pancreatic
head or uncinate process received 6 weekly infusions of gem (400
mg/m2 ) and 3 infusions of bev (10 mg/kg, every 2 wks) with concomitant
RT, 50.4 Gy at 1.8 Gy/fr. Pts were restaged 4-6 wks after the last dose of
radiation. Those without disease progression and with good PS underwent
surgery. Pts with adequate recovery received bev (10 mg/kg) every 2 weeks
for 3 mo starting ~ 6 wks after surgery. Results: This study enrolled 11 of a
planned 31 pts but was terminated early due to unforeseen postop
complications. Median age is 64 yrs; all pts had ECOG-PS 0-1. Median
CA19-9 was 52. Median follow-up from surgery was 41 mths. All completed
chemoRT; 10 underwent restaging and 1 pt died from cardiac arrest
before restaging. 9 pts (90 %) went to surgery and underwent a successful
R0 PD. Pathologic PR rate (�50 % tumor kill) was 56 %. As we have
previously reported, preop grade 3-4 toxicities were infrequent and major
postop complications occurred in 5 of the 9 pts (56%) who underwent PD.
Median overall survival (OS) was 30.1 mths (range: 2.6 - 63.9) for the
entire cohort. Of the 9 resected pts, median OS was 45.5 mths with 5 of 11
pts (45%) achieving survival longer than best historical control (median
58.2 mths). Conclusions: The addition of bev to our prior backbone of
gem-based preoperative chemoRT led to a higher resection rate (90%) than
our previous protocols. Updated survival results of this study are promising.
Taken together, these results may prompt further investigation of this
regimen with modifications in the timing of bev delivery.
4053 General Poster Session (Board #42D), Mon, 8:00 AM-12:00 PM
International experts’ panel for the development of guidelines for the
definition of time to event endpoints in clinical trials (DATECAN project):
Results for pancreatic cancer. Presenting Author: Franck Bonnetain,
Biostatistics and Epidemiology Unit, Centre Georges François Leclerc,
Dijon, France and EA4184, College of Medicine, Dijon, France
Background: Variability in the definition of survival endpoints in oncology
trials was identified (Mathoulin et al.JCO 2008). Lack of a formal
consensus could cause this, which limits inter-trial comparisons. The
DATECAN project aimed at obtaining a formal consensus recommendation
for defining survival endpoints for randomized clinical trials (RCTs) in the
following cancer sites: pancreas, sarcoma/GISTs, breast, colorectal, gastric/
œsophagus, head and neck, kidney-bladder. We report results for pancreatic
cancer. Methods: Based on a literature review of RCTs (2006-2009),
we identified survival endpoints and events currently used. A 2-round
modified Delphi method using RAND scoring (range:1-9) was used to reach
consensus. Academic research groups were contacted for participation in
order to select clinicians and methodologists for Pilot and Scoring groups
(�30 experts/localization). Results: The Pilot group identified 14 endpoints
that needed definition through consensus, such as progression free survival
(PFS), time-to-treatment failure, time to quality of life deterioration.
Endpoint definitions were seeked by disease setting (detectable disease vs
not). Amongst the 52 European experts contacted, 33 and 30 participated
to the 1st and 2nd round respectively. The experts scored a total of 204
events; a consensus was reached for 25 (12%) at the 1st round and 156
(76%) at the 2nd round. As example PFS was defined as time interval
between the date of randomization, and the day of first local, regional
progression or occurrence of distant metastases (including liver or non liver
metastases) or occurrence of 2nd pancreatic cancer or death (all causes),
whichever occurs first. The consensus was finalized during a face-to-face
meeting organized during the ESMO 2011 congress and general rules were
proposed for final ratification. Conclusions: Based on this consensus, an
European charter is being finalized and proposed for endorsement to all
academic groups in order to harmonize results and to allow formal
comparisons of pancreatic RCTs. The impact of these definitions on trial
results will be also investigated in a further project.
Gastrointestinal (Noncolorectal) Cancer
251s
4052 General Poster Session (Board #42C), Mon, 8:00 AM-12:00 PM
A phase IB study of erlotinib in combination with gemcitabine and
nab-paclitaxel in patients with previously untreated advanced pancreatic
cancer: An Academic GI Cancer Consortium (AGICC) study. Presenting
Author: Lawrence P. Leichman, Comprehensive Cancer Center at Desert
Regional Medical Center, Palm Springs, CA
Background: The combination of gemcitabine (gem) and nab-paclitaxel
(nab) has demonstrated promising activity in advanced pancreatic cancer.
Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase
IB study to evaluate the safety of the three drug combination and obtain
preliminary evidence of efficacy. Methods: Patients (pts) with previously
untreated locally advanced (la) or metastatic (met) pancreatic cancer with
ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily
erl days 1-28 Q28 days. Standard 3�3 design was used with dose levels
(DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000,
75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was
defined as �grade (gr) 3 non-hematologic, febrile neutropenia, �gr 3
thrombocytopenia, or missing �2 doses gem, nab or �5 doses erl within
first cycle (C). Results: Nineteen pts were enrolled and completed a total of
62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA
(15/2/2), median age 63 (range 54-78), ECOG PS 1�11, met/la (12/7). In
DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/
sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the
next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1
other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2
DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3
pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis).
Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4
toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each),
and hypotension (2). Of 13 pts evaluable for response, 6 had partial
response (46%), 5 stable disease (38%), and 2 progressive disease (15%)
as best response. Median PFS and OS of entire cohort were 5.3 and 9.3
months respectively. Conclusions: The combination of erlotinib with gemcitabine
and nab-paclitaxel is not tolerable at standard single agent dosing of
all drugs. However, significant clinical activity was noted, even at DL -3.
Further study of the combination will need to incorporate reduced dosing.
4054 General Poster Session (Board #42E), Mon, 8:00 AM-12:00 PM
Tumor IGF-1 expression as a predictive biomarker for IGF1R-directed
therapy in advanced pancreatic cancer (APC). Presenting Author: Milind M.
Javle, University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: IGF-1 up-regulates PC proliferation and invasiveness through
activation of PI3K/Akt signaling pathway and down-regulates PTEN. We
investigated IGF-1 expression in tissue and blood as potential predictive
markers in phase II study of IGF1R-directed monoclonal antibody, MK-
0646 in APC. Prior phase I established the MTD of MK0646 at 5 mg/kg
with gemcitabine (G) and erlotinib (E) and 10 mg/kg with G alone. Methods:
Patients (pts) with stage IV, previously untreated APC, ECOG PS 0-1,
adequate hematologic and organ function were enrolled. Arm A: G 1,000
mg/m2 over 100 min, weekly x 3, MK-0646 weekly x 4; Arm B: G 1000
mg/m2 and MK-0646 � E 100 mg daily. Arm C (control) was G 1,000
mg/m2 � E 100 mg. Cycles were repeated every 4 weeks. Pts were equally
randomized in the 3 arms. Primary study objective was progression-free
survival (PFS). Pre-treatment peripheral blood samples were measured for
IGF-1 level by ELISA; archival core biopsies were analyzed for IGF-1 mRNA
expression. RNA extraction from FFPE samples used Roche Transcriptor
First Strand cDNA Synthesis Kit. TaqMan PreAmp technique was used to
amplify target cDNA prior to TaqMan RT-PCR analysis. Cox proportional
hazards model for PFS analyzed the interaction between tissue IGF-1
expression and treatment. Results: 50 pts were enrolled (A�15,
B�16,C�16 pts, 3 ineligible). Median PFS of arms A, B and C were 5.5
months (95% CI: 3.9 – NA), 3.0 months (95% CI:1.8 – 5.6) and 2.0
months (95% CI: 1.8 – NA), respectively (log-rank test; p � 0.17). Median
OS of A was 11.3 months (95% CI: 8.9 – NA), B 8.9 months (95% CI: 5.3 –
NA) and C 5.7 months (95% CI: 2.0 – NA) (log-rank test; p � 0.44). 35
archival core biopsies were analyzed, 21 had adequate tissue for analysis.
Using a Multivariable Cox proportional hazards model for PFS, where IGF-1
was dichotomized at the median, there was a 76% reduction in the risk of
disease progression or death in arm A as compared with the control (arm C)
at high IGF-1 level (p � 0.16). When IGF-1 was fitted as a continuous
variable, this reduction was 96% (p � 0.08). There was no correlation
between tissue and serum IGF-1. Conclusions: Tissue expression of IGF-1
level may represent a promising predictive biomarker for IGF1R-directed
therapy in APC.
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