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

266s Gastrointestinal (Noncolorectal) Cancer
4111 General Poster Session (Board #49F), Mon, 8:00 AM-12:00 PM
A phase II trial of gemcitabine, irinotecan, and panitumumab in advanced
cholangiocarcinoma, with correlative analysis of EGFR, KRAS, and BRAF:
An interim report. Presenting Author: Davendra Sohal, Abramson Cancer
Center at the University of Pennsylvania, Philadelphia, PA
Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy
approaches achieve modest results. The epidermal growth
factor receptor (EGFR) pathway appears to be associated with tumor stage,
prognosis and response to therapy. This trial was designed to evaluate the
tolerability and efficacy of the combination of panitumumab, a monoclonal
anti-EGFR antibody, with gemcitabine and irinotecan, in patients with
advanced cholangiocarcinoma. Molecular analysis of EGFR pathway genes
was planned as well. Methods: Patients with advanced (unresectable or
metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney
and bone marrow function were treated with panitumumab (9 mg/kg) on
day 1, and gemcitabine (1000 mg/m2 ) and irinotecan (100 mg/m2 ) on days
1 and 8 of a 21-day cycle. Tissue specimens were collected at diagnosis for
correlative molecular analyses. Primary objective is to evaluate the 5-month
progression-free survival (PFS) rate. Secondary objectives include overall
response rate (ORR), overall survival (OS) and toxicity of the combination.
Mutational analysis of EGFR (del 19; 858), KRAS (codons 12, 13) and
BRAF (V600E) was done on samples with adequate material for testing.
Results: There have been 26 (of planned 42) patients recruited to the study.
A median of 6 (0-30) cycles were administered. There were no treatment
related deaths. The most common gr 3 or higher toxicities were neutropenia
(10 pts, 38%), thrombocytopenia (10 pts, 38%), skin rash (10 pts, 38%)
and diarrhea (3 pts, 12%). During the study, there were 3 CR, 6 PR, 10 SD
(disease control rate of 90%), and 2 PD (by RECIST) in 21 evaluable pts.
Two pts went on to have surgical resection. Median OS is 12.7 months. Of
13 testable samples, no EGFR or BRAF mutations were identified; however,
there were 7 KRAS mutations. Retrospective analysis showed no difference
in OS by KRAS mutation status. Conclusions: Interim evaluation of this
ongoing study showed encouraging tolerability and efficacy of this regimen.
Several patients have KRAS mutations; there appears to be no association
with response, however. The pre-specified efficacy criteria to continue
enrollment were met.
4113 General Poster Session (Board #49H), Mon, 8:00 AM-12:00 PM
SWOG 0941: A phase II study of sorafenib and erlotinib in patients (pts)
with advanced gallbladder cancer or cholangiocarcinoma. Presenting
Author: Anthony B. El-Khoueiry, University of Southern California Norris
Comprehensive Cancer Center, Los Angeles, CA
Background: The treatment of pts with advanced biliary cancers represents
a therapeutic challenge. The vascular endothelial growth factor and
epidermal growth factor receptor pathways play an important role in biliary
carcinogenesis, as evidenced by their up-regulation and prognostic impact.
Methods: The primary objective was progression free survival (PFS) (improvement
in PFS from 4 to 8 months); secondary endpoints included overall
survival (OS), objective response rate, and toxicity. A two-stage design was
used; if 13 or more eligible pts of the 25 initially accrued were alive without
progression at 4 months, an additional 25 were to be accrued. Eligibility
criteria included no prior treatment for advanced or metastatic disease,
histologic diagnosis of gallbladder cancer or cholangiocarcinoma, presence
of measurable disease, Zubrod performance status 0-1, AST/ALT � 5
IULN, total bilirubin �1.5 IULN, adequate hematologic function. Pts were
treated with sorafenib 400 mg PO BID and erlotinib 100 mg PO q daily
continuously. Restaging scans were performed every 8 weeks. Results: 32
eligible pts were accrued. 30 pts were evaluable for response. 2 patients (7
%) had an unconfirmed partial response (95% CI:1%-23%), and 8 pts
(27%) had stable disease. Median PFS was 2 months (95% CI: 2-3
months). 22/32 patients progressed or died within 4 months of registration.
Median OS was 6 months (95% CI: 3 -7 months). The study failed to meet
its primary endpoint to proceed to the second stage of accrual. There were 3
deaths on study, 1 of which was possibly related to treatment. 19 patients
(59%) had grade 3 or 4 toxicities: AST/ALT (22%), bilirubin (16%),
alkaline phosphatase (16%), hypertension (16%), diarrhea (9%), hepatic
infection (6%). Conclusions: This multicenter study was the first to evaluate
the combination of sorafenib and erlotinib in pts with advanced biliary
cancers. Despite manageable toxicity, the study failed to meet its primary
endpoint. Correlative studies on collected tissue and blood are ongoing;
improved pt selection based on tumor biology and molecular markers is
necessary for future evaluation of targeted therapies in this disease.
4112 General Poster Session (Board #49G), Mon, 8:00 AM-12:00 PM
Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of
cediranib in advanced hepatocellular carcinoma (HCC): A phase II study
(CTEP 7147). Presenting Author: Andrew X. Zhu, Division of Hematology
and Oncology, Massachusetts General Hospital, Boston, MA
Background: Sorafenib remains the only approved systemic therapy in HCC.
We performed a phase II study of cediranib (AZD2171)—a more potent and
selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts).
Methods: Eligibility criteria included unresectable or metastatic measurable
HCC, ECOG PS �2, CLIP score �3, and adequate organ function.
Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The
primary endpoint was progression free survival (PFS). We also assessed
overall survival (OS) and response rates, steady-state PK of cediranib, and
blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the
targeted 17 pts required for the first stage of the planned study: ECOG
0/1/2�5/11/1, CLIP 1/2/3�6/4/7, Child A/B�14/3, BCLC C�17. Nine
pts had prior sorafenib. The best response was stable disease in five pts
(29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median
OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included
hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one
pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and
proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage
occurred in 1 pt each. Steady-state PK parameters (mean�SD) were, Cmin, 22�21 ng/mL; Cmax, 55�33 ng/mL; AUC�, 887�503 ng*h/mL. Plasma
levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2
decreased significantly after cediranib treatment (p�0.05). PFS was
inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and
OS was inversely correlated with baseline levels of sVEGFR1, Ang-2,
TNF-alpha and CD34�CD133� hematopoietic progenitor cells (p�0.05).
Conclusions: Cediranib at 30 mg daily is associated with high frequency of
grade 3 hypertension and shows preliminary evidence of antitumor activity
in advanced HCC pts. Exploratory studies confirmed potential PD and
response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in
HCC pts as in those with other tumor types and normal/near normal hepatic
function. This study was stopped by AstraZeneca after discontinuation of
cediranib development for unrelated factors.
4114 General Poster Session (Board #50A), Mon, 8:00 AM-12:00 PM
Multiparametric quantitative functional MRI for assessing early changes in
volumetric functional tumor burden in hepatocellular carcinoma treated by
intra-arterial therapies. Presenting Author: Vivek Gowdra Halappa, The
Johns Hopkins Hospital, Baltimore, MD
Background: Hepatocellular carcinoma (HCC) is the most common primary
malignant disease of the liver. Intra-arterial therapy (IAT) has been shown
to improve survival and is commonly used in unresectable HCC. Assessing
response to IAT as early as possible using objective criteria is paramount for
clinical care. The purpose of this study was to evaluate volumetric diffusion
weighted (DWI) and contrast Enhanced MR imaging (CE-MRI) changes for
assessing early treatment response to IAT in hepatocellular carcinoma.
Methods: This study included 177 lesions of HCC in 107 patients (85 Male,
mean age 64 years) with BCLC A (19) B (44) C (36) D (8) treated by IAT. All
patients had pre-IAT and 3-4 weeks follow up MRI with DWI and CE-MR.
Tumors were segmented using semi automated software to provide volumetric
functional analysis of DWI and CE- MRI as well as percent tumor
burden. Statistical analyses include paired t-test, Kaplan-Meier curves, log
rank test and multivariate analysis with cox model. Results: There was
significant increase in volumetric ADC and significant decrease in volumetric
arterial (AE) and venous (VE) enhancement after IAT. Patients with
tumor burden of � 10% had improved survival compared to patients with
high tumor burden of �10% (log rank p �.008 ) This survival benefit was
larger among patients with tumor burden of � 10% who demonstrated an
increase in volumetric ADC (�20%. Overall survival (OS) 33.5 mo) and
decrease in volumetric VE (�50% OS 35.2 mo) compared to patients with
high tumor burden �10% who no favorable response in ADC ( OS 14.1 mo)
or VE (OS 16.5 mo) (Log rank p � .001) . In multivariate analysis factors
associated with favorable prognosis were: increased ADC, (Hazard Ratio
(HR) � 0.44, 95% CI �0.24 - 0.80) decreased VE, (HR � 0.43, 95% CI �
0.22 - 0.84) and BCLC A and B (HR � 0.31, 95% CI �0.18 - 0.54).
Conclusions: Volumetric functional analysis of DWI and CE-MR are reliable
imaging biomarkers of treatment response and tumor necrosis were able to
differentiate responders and non responders. Early assessment of treatment
response by volumetric functional MRI predicts prognosis in patients
undergoing IAT in HCC.
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