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

250s Gastrointestinal (Noncolorectal) Cancer
4047 General Poster Session (Board #41F), Mon, 8:00 AM-12:00 PM
Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in
pancreatic neuroendocrine tumor (PNET): Results of a planned interim
efficacy analysis. Presenting Author: Timothy J. Hobday, Mayo Clinic,
Rochester, MN
Background: PNET has long had few effective therapies other than chemotherapy.
Recent placebo-controlled phase III trials of the mTOR inhibitor
everolimus and the VEGF/ PDGF receptor inhibitor sunitinib noted improved
progression-free survival (PFS). However, objective response rates
(RR) with these agents are still �10%. Preclinical studies suggest
enhanced anti-tumor effects with combined mTOR and VEGF targeted
therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM
(25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV
q 2 weeks) in patients (pts) with well or moderately differentiated PNET
and progressive disease by RECIST within 7 months of study entry.
Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50
patients, with interim analysis for futility after the first 25 evaluable pts. Pts
had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate
hematologic and organ function. Continued octreotide was allowed, but not
required. Prior interferon, embolization, and � 2 chemotherapy regimens
were allowed. Results: Confirmed PR was documented in 13 of the first 25
(52%) evaluable patients. 21 of 25 (84%) patients were progression-free
at 6 months. Both endpoints exceeded the protocol-defined criteria to
continue enrollment. For 36 evaluable patients, the most common grade
3-4 adverse events attributed to therapy were hypertension (14%), leukopenia
(11%), lymphopenia (11%), hyperglycemia (11%), mucositis (8%),
hypokalemia (8%), and fatigue (8%). Conclusions: The combination of
TEM/BEV has substantial activity in a multi-center phase II trial with RR of
52%, well in excess of single targeted agents in PNET. 6-month PFS was a
notable 84% in a population of patients with RECIST criteria progression
within 7 months of study entry. Accrual is ongoing.
4049 General Poster Session (Board #41H), Mon, 8:00 AM-12:00 PM
Addition of algenpantucel-L immunotherapy to standard of care (SOC)
adjuvant therapy for pancreatic cancer. Presenting Author: Jeffrey M
Hardacre, University Hospitals Case Medical Center, Cleveland, OH
Background: Resected pancreatic cancer carries a one year survival rate of
~65%. Algenpantucel (HyperAcute-Pancreas, HAPa) exploits the hyperacute
rejection mechanism of xenotransplantation by administering genetically
modified, irradiated, allogeneic tumor cells expressing aGal moieties
on their surface. We propose that addition of algenpantucel-L to SOC
adjuvant therapy may improve survival for patients with resected pancreatic
cancer. Methods: Open-label, dose-finding, Phase 2 study (16 sites)
evaluating HAPa (100/300 M cells / dose) � SOC (RTOG-9704: Gemcitabine
� 5-FU-XRT) for resected pancreatic cancer patients. Primary
endpoint: 1-year disease-free survival (DFS). Secondary Endpoints: overall
survival (OS), toxicity and immunologic analysis. Results: : 70 patients,
median age 62 years, 47% female, 81% lymph node positive, median
tumor size 3.2 cm, and 17% post-operative CA 19-9 � 180 received SOC
� HAPa. 1-year DFS of 63% and OS of 86% compares favorably to
historical controls (~45%% and 65%, respectively) for this high risk
population. Subgroup analysis of patients receiving 300M cells /dose
shows a higher 12-month DFS compared to 100M cells/dose, 81% vs. 52%
(p � 0.02). Likewise, patients receiving 300M cells/dose tended to better
1-year survival compared to a 100M cells/dose, 96% vs. 80% (p � 0.053).
Forty-four (63%) developed strong (G1-G3) skin reactions at the injection
sites including many long term survival patients with periodic skin flares at
injection sites far beyond their last vaccination. In 13/45 (29%) tested
patients, an increase of �30% in anti-mesothelin Ab titer was seen after
immunization. Thirty-nine (56%) presented with eosinophilia (range: 5-
45%), including one patient with persistent eosinophilia and stable lung
metastasis for over 2 years. Conclusions: Addition of HAPa to standard
adjuvant therapy for resected pancreatic cancer shows promising immunological
activation and may improve survival. A multi-institutional, phase 3
study is currently underway.
4048 General Poster Session (Board #41G), Mon, 8:00 AM-12:00 PM
A phase I study of nab-paclitaxel (A), gemcitabine (GEM), and capecitabine
(X) in patients with metastatic pancreatic adenocarcinoma (MPA). Presenting
Author: Thach-Giao Truong, University of California, San Francisco
Comprehensive Cancer Center, San Francisco, CA
Background: GEM-based doublets, such as GEM � capecitabine (X), may
be beneficial in select pts with MPA. Given preclinical evidence of synergy
when a taxane is added to GEM � X, as well as recent phase I/II study
results showing substantial activity with GEM � nab-paclitaxel (A) (ORR of
48%, median OS � 12 mos at MTD), we conducted a phase I study
evaluating the 3-drug combination of A, GEM, and X (AGX) given biweekly
in pts with MPA. Methods: Pts with previously untreated MPA and ECOG PS
0-1 were eligible. A (100-150 mg/m2 ) and GEM (750-1000 mg/m2 at 10
mg/m2 /min) were both administered on day 4, and X (500-1000 mg/m2 bid) on days 1-7, of each 14-day cycle. A 3�3 dose escalation design was
used, with expanded cohort at MTD. Primary objective was to establish
MTD of this regimen; secondary objectives include safety and preliminary
assessment of efficacy. DLT definitions: gr 3-4 ANC or neutropenic fever; gr
4 plts; gr 2-4 hand-foot syndrome (HFS), neuropathy or diarrhea; or other gr
3-4 non-heme toxicity. Results: Fifteen patients were enrolled across two
dose levels (age range, 45-74 y). Final MTD was established at dose level 0,
consisting of A 100 mg/m2, GEM 750 mg/m2, and X 750 mg/m2 bid. At
dose level 1, two of 4 pts experienced DLTs (gr 3 LFT elevation, gr 3 ANC).
For the entire study cohort, 10 pts (67%) experienced at least one gr 3-4
AE, including LFTs (20%), N/V (13%), and fatigue (7%). Gr 3-4 heme
toxicity was uncommon. Other notable AEs (any grade): fatigue (87%),
rash/HFS (67%), N/V (53%), diarrhea (40%), neuropathy (33%). Median #
cycles received � 4 (range, 2-16). 73% of pts d/c’ed study treatment due
to disease progression. Best response for the entire cohort (n�14 evaluable
pts): 2 PR, 8 SD, 4 PD (disease control rate � 71%). Of 12 pts with
elevated CA19-9 at baseline, 5 (42%) had �50% biomarker decline.
Conclusions: Recognizing the limits of cross-study comparisons and small
sample size, these results do not match those reported at MTD in the phase
I/II trial of GEM (1000 mg/m2) � A (125 mg/m2 ). The modest activity seen
with this AGX regimen may have resulted from suboptimal dosing, and
suggests that dose intensity may be an important factor when trying to
incorporate nab-paclitaxel into multidrug regimens.
4050 General Poster Session (Board #42A), Mon, 8:00 AM-12:00 PM
A phase I/II study of the MEK inhibitor BAY 86-9766 (BAY) in combination
with gemcitabine (GEM) in patients with nonresectable, locally advanced or
metastatic pancreatic cancer (PC): Phase I dose-escalation results. Presenting
Author: Jean-Luc Van Laethem, Hôpital Universitaire Erasme, Brussels,
Belgium
Background: Targeting the RAS–RAF–MEK–ERK pathway may be useful in
the treatment of PC, as 75–90% of PCs have KRAS mutation. BAY is an
orally bioavailable, potent, allosteric MEK 1/2 inhibitor that showed
single-agent activity, and synergistic activity with GEM, in ectopic, orthotopic,
syngenic and patient-derived xenograft PC models. Methods: The
phase I part aimed to determine the maximum tolerated dose (MTD) of BAY
in combination with GEM, and the pharmacokinetics of BAY and GEM.
3�3 study design was used. After informed consent, eligible patients with
advanced PC received GEM 1000 mg/m2 (30-min, once-weekly IV infusion
for 7 out of 8 weeks in cycle 1 [C1], and 3 out of 4 weeks in subsequent
cycles) and oral BAY 30 mg BID (dose level 1 [DL1]) or 50 mg BID (DL2).
No escalation beyond DL2 was planned. MTD was the highest dose at which
maximum 1 out of 6 evaluable patients displayed dose-limiting toxicities
(DLT) during C1. Results: As of 6 Jan 2012, 17 patients were enrolled and
treated (10 at DL1, 7 at DL2). DL1 cohort has completed; DL2 evaluation
is ongoing. At DL1, DLTs occurred in 1/6 evaluable patients: a patient with
extensive liver metastasis developed chemotherapy-associated steatohepatitis
(CASH) and died of hepatic failure. Rare CASH cases have been
reported to be associated with GEM alone, but co-involvement of BAY
currently cannot be ruled out. To date, 3 patients have completed C1 at
DL2 without DLTs. DL2 completion is expected in March 2012. BAY�GEM
showed a manageable tolerability profile. The most frequent treatmentrelated
grade 3–4 adverse event (AE) at any DL was neutropenia (n�6).
The most frequent clinically relevant BAY-related AE was acneiform rash
(n�11), which was mostly grade 1–2 (one case grade 3) and manageable.
BAY�GEM showed evidence of clinical efficacy: partial responses were
seen in 4/10 patients at DL1 and 1/3 patients at DL2. No pharmacokinetic
interaction between BAY and GEM was seen at DL1. Conclusions: In
patients with advanced PC, BAY 30 mg BID in combination with GEM had a
manageable safety profile, with acneiform rash as the clinically most
relevant toxicity attributable to BAY.
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