- Email: [email protected]
Randomized Phase II Trial of Gemcitabine Plus S-1 Combination Therapy Versus S-1 in Advanced Biliary Tract Cancer: Results of the Japan Clinical Oncology Group Study (JCOG0805)
Annals of Oncology 23 (Supplement 11): xi15–xi16, 2012 doi:10.1093/annonc/mds548
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RANDOMIZED PHASE II TRIAL OF GEMCITABINE PLUS S-1 COMBINATION THERAPY VERSUS S-1 IN ADVANCED BILIARY TRACT CANCER: RESULTS OF THE JAPAN CLINICAL ONCOLOGY GROUP STUDY (JCOG0805)
Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0-1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1000 mg/m2, i.v., days 1 and 8; S-1: 60 mg/m2, p.o., days 1–14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1–28, every 6 weeks). We assumed that the percentage of 1-year survival of one regimen is 30 and that of the other regimen is more than 40. To ensure at least 85% probability of correct selection, 98 eligible patients are required. The decision rule was that the regimen with higher percentage of 1-year survival will be considered as more promising regimen. Results: From February 2009 to April 2010, 101 patients (GB, n = 38; IHBD, n = 35; EHBD, n = 20; AV, n = 8) were randomized (GS, n = 51; S-1, n = 50). For the GS arm and S-1 arm, the percenatge of 1-year survival was 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95% CI 0.54–1.36]; P = 0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29–0.67]; P < 0.0001). Grade 3/4 hematological toxic effects were more frequent in the GS arm than in the S-1 arm ( percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0, respectively. Although two treatment-related deaths occurred in the GS arm ( pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxic effects were infrequent and reversible in both arms. Conclusions: The GS arm was superior in the percentage of 1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC. IS1
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PHASE III TRIAL OF EVEROLIMUS IN ADVANCED PANCREATIC NEUROENDOCRINE TUMORS (RADIANT-3): OVERALL POPULATION AND JAPANESE SUBGROUP ANALYSIS
T. Okusaka1, T. Ito2, M. Ikeda3, H. Igarashi2, C. Morizane1, K. Nakachi3, T. Tajima4, A. Kasuga4, Y. Fujita4, J. Furuse5 1 Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan, 2Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan, 4Oncology Development Department, Novartis Pharma K.K., Tokyo, Japan, 5Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan Background: In the phase III RADIANT-3 trial, everolimus (RAD001), an oral mTOR inhibitor, demonstrated a statistically and clinically significant improvement
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A PHASE 3 TRIAL OF GANITUMAB WITH GEMCITABINE AS FIRST-LINE TREATMENT OF METASTATIC PANCREATIC CANCER: A SAFETY UPDATE FROM THE GAMMA TRIAL
C. Fuchs1, M. Ikeda2, T. Okusaka3, S. Ohkawa4, N. Mizuno5, V. Haddad6, J. McGreivy7, D. Chang8 1 Dana-Farber Cancer Institute, Boston, MA, USA, 2National Cancer Center Hospital East, Kashiwa, Chiba, Japan, 3National Cancer Center Hospital, Tokyo, Japan, 4Kanagawa Cancer Center, Yokohama, Kanagawa, Japan, 5Aichi Cancer Center Hospital, Nagoya, Aichi, Japan, 6Amgen Ltd., Cambridge, UK, 7Amgen Inc., San Francisco, CA, USA, 8Amgen Inc., Thousand Oaks, CA, USA Background: Ganitumab is an investigational, fully human, monoclonal antibody inhibitor of IGF1R. In a randomized, phase 2 study in patients with metastatic pancreatic cancer (MPC), the addition of ganitumab 12 mg/kg every 2 weeks to gemcitabine (G) prolonged progression-free survival (PFS) and overall survival (OS) (Kindler H, et al. Ann Oncol 2010; 21: 741P). GAMMA (GEM and AMG 479 in Metastatic Adenocarcinoma of the Pancreas) is assessing the safety and efficacy of ganitumab plus G as first-line treatment (tx) in MPC patients (ClinicalTrials.gov ID: NCT01231347). Methods: This is an ongoing, global, phase 3, double-blind study. Patients are randomized 2:2:1 to receive placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (IV; days 1 and 15 Q28D) with G 1000 mg/m2 (IV; days 1, 8, and 15 Q28D). The planned sample size is 825. Key eligibility criteria: untreated metastatic adenocarcinoma of the pancreas, ECOG score ≤1, ≥18 years old, adequate organ function, and fasting (or non-fasting) glucose ≤160 mg/dl. Primary end point: OS. Key secondary end points: PFS, 1-year survival rate, patient-reported outcomes, and safety. Patients receiving 20 mg/kg ganitumab are expected to achieve ganitumab levels above the median in phase 2. A log-rank test stratified by ECOG, presence of liver metastases, and geographic region will compare OS independently for each ganitumab arm at an overall one-sided 2.5% significance level for declaring superiority of ganitumab plus G versus placebo plus G. This study includes multiple planned safety analyses conducted by an independent data monitoring committee. The current predefined safety analyses occurred when 150 patients received ≥1 cycle of tx. Results: As of 16 September 2011, 207 patients are included in this aggregate analysis: 50% male; median age, 63 years (range 36–83); ECOG score 0/1, 50%/50%. Of the 207 patients, 204 patients received study tx, and 61 patients ended study tx. Ten patients (5%) died during or within 30 days of the end of tx. Seven events were attributed to or associated with disease progression. One event of cardiac failure was reported to be possibly tx related. Pulmonary embolism was suspected but not confirmed. Conclusions: The GAMMA study continues as per protocol. The only grade 3/4 adverse event occurring in more than 5% of patients to date is neutropenia.
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Serials Department on July 13, 2015
M. Ikeda1, T. Okusaka2, J. Mizusawa3, A. Takashima3, C. Morizane2, M. Ueno4, Y. Hamamoto5, H. Ishii6, H. Hara7, A. Fukutomi8, M. Furukawa9, M. Nagase10, T. Yamaguchi11, N. Boku8, J. Furuse12 1 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 2Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 3Japan Clinical Oncology Group Data Center, Multi-institutional Clinical Trials Support Center, National Cancer Center, 4 Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 5Department of Oncology, Tochigi Cancer Center, 6Hepatobiliary and Pancreatic Division, Cancer Institute Hospital, 7Department of Gastroenterology, Saitama Cancer Center, 8Divison of Gastrointestinal Oncology, Shizuoka Cancer Center, 9Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, 10Department of Clinical Oncology, Jichi Medical University, 11Department of Gastroenterology, Chiba Cancer Center, 12 Department of Medical Oncology, Kyorin University School of Medicine
in progression-free survival (PFS) over placebo in patients with advanced pancreatic neuroendocrine tumors ( pNET). The purpose of this presentation is to show the efficacy and safety in the Japanese subgroup analysis. Methods: The subgroup analysis for the Japanese patients (n = 40) was carried out comparing everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17); both in conjunction with best supportive care (BSC), in the following end points: PFS, disease control rate (DCR), adverse drug reaction (ADR) and median duration of exposure. Results: PFS was significantly prolonged in patients treated with everolimus compared with placebo (hazard ratio, 0.19; 95% confidence interval (CI), 0.08–0.48; log-rank P < 0.001) with a median of 19.45 months (95% CI, 8.31–not available) in the everolimus arm and 2.83 months (95% CI, 2.46–8.34) in the placebo arm. DCR was 86.9% in the everolimus arm and 35.3% in the placebo arm. The majority of ADRs were grade 1 or 2 in severity. Most common ADRs in the everolimus arm were rash (n = 20; 87%), stomatitis (n = 17; 74%) and infections (n = 15, 65%). Grade 3/4 ADRs occurred in 69.5% of the everolimus arm and 29.4% of the placebo arm. The most frequent grade 3/4 ADRs were neutropenia (% in the everolimus arm; 17.4% versus % in the placebo arm; 17.6%), anemia (8.7% versus 0%), pneumonitis (8.7% versus 0%) and leukopenia (8.7% versus 0%). The median duration of exposure to everolimus was 60 versus 12 weeks on placebo. Treatment discontinuation for ADR was 17% in the everolimus arm versus 0% in the placebo arm. Conclusions: Everolimus demonstrated a statistically and clinically meaningful improvement in PFS over placebo and was well tolerated in Japanese patients. These results suggest that everolimus can be a standard treatment of Japanese patients with advanced pNET.
abstracts
International Session 1: ‘Hepato-biliary-pancreatic’
abstracts IS1
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SYNERGISTIC ANTI-TUMOR EFFECT OF SORAFENIB IN COMBINATION WITH AKT INHIBITORS IN HEPATOCELLULAR CARCINOMA
W.-C. Feng1,2,5, C.-H. Hsu2,3,5, S.-D. Lin3,5, H.-H. Lin2, D.-W. Hsu3,5, C.-C. Huang3,5, L.-P. Chow1*, A.-L. Cheng2,3,4,5* 1 Graduate institute of Biochemistry and Molecular Biology, 2Graduate Institute of Oncology, National Taiwan University School of Medicine, Taipei, Taiwan, 3 Departments of Oncology, 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 5Cancer Research Center, National Taiwan University School of Medicine, Taipei, Taiwan
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EXPLORING THE ANTI-TUMOR EFFICACY OF COMBINATION THERAPY WITH INHIBITORS TARGETING THE INSULIN-LIKE GROWTH FACTOR (IGF) AND PI3K/AKT/ MTOR SIGNALING PATHWAYS FOR HEPATOCELLULAR CARCINOMA (HCC)
D.-L. Ou1,2, C. Hsu3,4, B.-S. Lee2,3, Y.-C. Chang2,3, Y.-C. Cheng5, A.-L. Cheng1,3,4 1 Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan, 2National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan, 3Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 5Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan Background: The IGFR signaling pathway plays important roles in carcinogenesis and drug resistance of many cancers, including HCC, but inhibitors targeting the IGF signaling pathway showed limited therapeutic efficacy. This study explored the efficacy of combining inhibitors targeting the IGF and PI3K/AKT/mTOR signaling pathways in HCC. Methods: HCC cell lines tested included Hep3B, Huh7, and PLC5. The MTT agents tested included NVP-AEW541 (IGF receptor kinase inhibitor, Novartis), MK2206 (Akt inhibitor, MSD), BEZ235 (PI3K/mTOR inhibitor, Novartis), and RAD001 (mTOR inhibitor, Novartis). The potential synergistic antitumor effects were tested by MTT assay and median dose effect analysis in vitro and by xenograft models in vivo. Apoptosis was analyzed by flow cytometry and western blotting. The activity of pertinent signaling pathways and expression of apoptosis-related proteins were measured by western blotting and by an apoptosis protein array (Proteome ProfilerTM, R&D Systems). Results: Synergistic growth-inhibitory and apoptosis-inducing effects in HCC cells were found most prominently in NVP-AEW541/ MK2206 combination, followed by NVP-AEW541/BEZ235 combination. These synergistic anti-tumor effects correlated with a more sustained inhibition of Akt and 4EBP-1 phosphorylation. Potential downstream mediators identified by the apoptosis array included survivin and clapsin. The synergistic anti-tumor effects of NVP-AEW541/MK2206 and NVP-AEW541/BEZ235 combinations were confirmed in vivo by xenograft models, with acceptable toxicity profiles. Conclusions: Combination therapy of IGF receptor inhibitors with inhibitors targeting the PI3K/AKT/mTOR pathway may have therapeutic efficacy in HCC (supported by grants NHRI-EX100-9911BC, DOH100-TD-B-111-001, and NSC 100-2314-B-002-058-MY3).
xi | abstracts
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THE USE OF SECOX (SORAFENIB, OXALIPLATIN, CAPCITABINE) AS THE TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA (HCC): A SINGLE-CENTER ANALYSIS
T. Yau1,2, J. Chiu1, Y. F. Tang2, P. Chan3, R. Leung1, H. Wong1, S.-T. Fan2, R. Poon2 1 Department of Medicine, Queen Mary Hospital, Hong Kong, 2Department of Surgery, Queen Mary Hospital, Hong Kong, 3Department of Medicine, Ruttonjee Hospital, Hong Kong Background: Combining sorafenib with chemotherapy can potentially provide a new regime with enhanced benefit. Phase II study has demonstrated promising activity in combining sorafenib, oxaliplatin and capecitabine (SECOX) in treating advanced HCC. We reported our experience in using this regime in our centre. Methods: This retrospective study included all consecutive advanced HCC patients treated in our centre with SECOX regimen: daily oral sorafenib 400 mg B.D., oxaliplatin 85 mg/m2 infusion on D1, and oral capcitabine 850 mg/m2 B.D. from day 1 to 7 every 2 weeks. Univariate and multivariateble analyses were employed to explore the potential predictive factors for overall survival benefits treated with this combination. Results: Eighty-nine patients were included in the analysis with 29 patients previously enrolled in the phase II trial and 60 patients treated outside the clinical trial in our centre. Of 89 patients received SECOX (male, 85%; median age, 53 years; hepatitis B carrier, 91%), 72 (81%) patients had CP A and 17 (29%) patients had CP B. Moreover, 42.7% patients had ECOG performance status (PS) 0, 53.9% patients had PS 1 and 3.4% patients had PS 2. The most common grade 3 or 4 drug-related toxic effects were hand-foot syndrome (10.5%), diarrhea (5.8%), and hypertension (5.8%). G3/4 thrombocytopenia was found in 18.1% and neutropenia was present in 6.0%. The overall response rate was 14.6%, with one (1.1%) patient had complete response and 12 (13.5%) patients achieved partial response. Moreover, 30 (33.7%) patients had stable disease. Overall, 48.3% patients derived benefits from SECOX. The progression-free survival (PFS) was 4.1 months (95% CI 3.6–4.6) and median overall survival (OS) was 11.0 months (95% CI 8.2–12.3). Patients with CP A cirrhosis had better PFS (4.2 versus 2.9 months, P = 0.027) and OS (11.8 versus 5 months, P = 0.003) than CP B patients. Multivariateble analysies revealed that both ECOG 1-2 (P = 0.0056) and baseline AFP level ≥400 ng/ml vascular involvement (P = 0.04812) were associated with worse overall survival. Conclusions: The SECOX regime had promising activity in advanced HCC with good tolerability, especially in Child-Pugh A patients with a good performance status.
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HOSPITAL VOLUMES OF PERCUTANEOUS RADIOFREQUENCY ABLATION ASSOCIATED WITH ITS TREATMENT OUTCOMES FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA
Y.-Y. Shao1,7, L.-C. Lu1,4, R. N. C. Kuo3,5, Z.-Z. Lin1,4, Y.-C. Yeh3, W.-Y. Shau6, C.-H. Hsu1,7, A.-L. Cheng1,2,7, M.-S. Lai3,5,8 1 Departments of Oncology, 2Internal Medicine, 3Center for Comparative Effectiveness Research, Clinical Trial Center, National Taiwan University Hospital, Taipei, Taiwan, 4Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin County, Taiwan, 5Taiwan Cancer Registry, Taipei, Taiwan, 6 Division of Health Technology Assessment, Center For Drug Evaluation, Taipei, Taiwan, 7Graduate Institute of Oncology, College of Medicine, 8Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan Background: Hospital volumes of several major operations were associated with treatment outcomes. The study aims to explore the impact of hospital volumes of radiofrequency ablation (RFA) on the prognosis of patients who received RFA for hepatocellular carcinoma (HCC). Methods: We searched for all patients who were diagnosed to have stage I or II HCC from 2004 to 2006 and received RFA as the first-line therapy in a population-based cohort. Clinical parameters and hospitals which provided the service were recorded. Overall survival (OS) and liver cancer-specific survival (CSS) were then compared according to the hospital volumes. The Cox’s proportional hazards model was used for multivariate analysis. Results: A total of 661 patients received RFA for stage I–II HCC in 28 hospitals. Hospitals were classified as high-volume and low-volume hospitals (first-line RFA for HCC for >10 patients and ≤10 patients per year, respectively). There were 480 (72.6%) patients treated in the high-volume hospitals, and 181 (27.4%) patients treated in the low-volume hospitals. The patient age, gender, tumor sizes and stages were not significantly different between high-volume and low-volume hospitals. Patients treated in high-volume hospitals had significantly longer OS and CSS than patients treated in low-volume hospitals (5-year OS: 58.7 versus 47.2%, P = 0.001; 5-year CSS: 67.1 versus 57.1%, P = 0.009). After adjusting for age, gender, tumor stage and size, hospital level and year of diagnosis, the high volume was still an independent predictor for longer OS (hazard ratio [HR]: 0.57; P < 0.001) and CSS (HR: 0.57; P = 0.003). Among high-volume hospitals, a higher volume (>30 per year) was not associated with even better outcome. Conclusions: Patients who received first-line RFA for HCC in high-volume hospitals had better survival outcomes.
Volume 23 | Supplement 11 | October 2012
Downloaded from http://annonc.oxfordjournals.org/ at Serials Department on July 13, 2015
Background: Sorafenib is currently the only approved agent for hepatocellular carcinoma (HCC). However, its clinical efficacy in HCC is limited. Previous studies indicate that compensatory activation of AKT may contribute to the resistance to sorafenib. We hypothesized that combination of sorafenib and AKT inhibitors could enhance the antitumor effect of sorafenib in HCC. Methods: We analyzed the cellular and molecular effects of sorafenib in combination with inhibitors of AKT in human HCC cell lines, and evaluated their combinational effects against HCC in vitro and in vivo. Results: HCC cells, including Huh7, Hep3B, and SKhep1 cells, expressed high levels of p-AKT in a prompt and sustained manner upon treated with sorafenib. Down-regulation of AKT by siRNA or inhibition of phospho-AKT by AKT inhibitors (MK-2206 or perifosine) enhanced the anti-proliferative effect of sorafenib in cultured HCC cells. The combination indexes of sorafenib and AKT inhibitors were <1 in multiple HCC cells, indicating a synergistic antitumor effect for the combination. Combination of sorafenib and AKT inhibitors induced more significant apoptosis in HCC cells, as quantified by flow cytometry and cleavage of PARP, than either single agent. In the subcutaneous xenograft model of Huh7 cells, the combination of sorafenib and MK-2206 resulted in a better effect in delaying the growth of HCC xenografts. Conclusions: Inhibition of AKT by AKT inhibitors improved the antitumor effect of sorafenib against HCC in vitro and in vivo. Combination of AKT inhibitors and sorafenib warrants further consideration for clinical development in HCC. (The study was supported by NSC97-2628-B-002-004-MY3 and NSC100-2325-B-002-043-.)
Annals of Oncology
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RANDOMIZED PHASE II TRIAL OF GEMCITABINE PLUS S-1 COMBINATION THERAPY VERSUS S-1 IN ADVANCED BILIARY TRACT CANCER: RESULTS OF THE JAPAN CLINICAL ONCOLOGY GROUP STUDY (JCOG0805)
Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0-1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1000 mg/m2, i.v., days 1 and 8; S-1: 60 mg/m2, p.o., days 1–14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1–28, every 6 weeks). We assumed that the percentage of 1-year survival of one regimen is 30 and that of the other regimen is more than 40. To ensure at least 85% probability of correct selection, 98 eligible patients are required. The decision rule was that the regimen with higher percentage of 1-year survival will be considered as more promising regimen. Results: From February 2009 to April 2010, 101 patients (GB, n = 38; IHBD, n = 35; EHBD, n = 20; AV, n = 8) were randomized (GS, n = 51; S-1, n = 50). For the GS arm and S-1 arm, the percenatge of 1-year survival was 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95% CI 0.54–1.36]; P = 0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29–0.67]; P < 0.0001). Grade 3/4 hematological toxic effects were more frequent in the GS arm than in the S-1 arm ( percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0, respectively. Although two treatment-related deaths occurred in the GS arm ( pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxic effects were infrequent and reversible in both arms. Conclusions: The GS arm was superior in the percentage of 1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC. IS1
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PHASE III TRIAL OF EVEROLIMUS IN ADVANCED PANCREATIC NEUROENDOCRINE TUMORS (RADIANT-3): OVERALL POPULATION AND JAPANESE SUBGROUP ANALYSIS
T. Okusaka1, T. Ito2, M. Ikeda3, H. Igarashi2, C. Morizane1, K. Nakachi3, T. Tajima4, A. Kasuga4, Y. Fujita4, J. Furuse5 1 Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan, 2Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan, 4Oncology Development Department, Novartis Pharma K.K., Tokyo, Japan, 5Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan Background: In the phase III RADIANT-3 trial, everolimus (RAD001), an oral mTOR inhibitor, demonstrated a statistically and clinically significant improvement
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A PHASE 3 TRIAL OF GANITUMAB WITH GEMCITABINE AS FIRST-LINE TREATMENT OF METASTATIC PANCREATIC CANCER: A SAFETY UPDATE FROM THE GAMMA TRIAL
C. Fuchs1, M. Ikeda2, T. Okusaka3, S. Ohkawa4, N. Mizuno5, V. Haddad6, J. McGreivy7, D. Chang8 1 Dana-Farber Cancer Institute, Boston, MA, USA, 2National Cancer Center Hospital East, Kashiwa, Chiba, Japan, 3National Cancer Center Hospital, Tokyo, Japan, 4Kanagawa Cancer Center, Yokohama, Kanagawa, Japan, 5Aichi Cancer Center Hospital, Nagoya, Aichi, Japan, 6Amgen Ltd., Cambridge, UK, 7Amgen Inc., San Francisco, CA, USA, 8Amgen Inc., Thousand Oaks, CA, USA Background: Ganitumab is an investigational, fully human, monoclonal antibody inhibitor of IGF1R. In a randomized, phase 2 study in patients with metastatic pancreatic cancer (MPC), the addition of ganitumab 12 mg/kg every 2 weeks to gemcitabine (G) prolonged progression-free survival (PFS) and overall survival (OS) (Kindler H, et al. Ann Oncol 2010; 21: 741P). GAMMA (GEM and AMG 479 in Metastatic Adenocarcinoma of the Pancreas) is assessing the safety and efficacy of ganitumab plus G as first-line treatment (tx) in MPC patients (ClinicalTrials.gov ID: NCT01231347). Methods: This is an ongoing, global, phase 3, double-blind study. Patients are randomized 2:2:1 to receive placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (IV; days 1 and 15 Q28D) with G 1000 mg/m2 (IV; days 1, 8, and 15 Q28D). The planned sample size is 825. Key eligibility criteria: untreated metastatic adenocarcinoma of the pancreas, ECOG score ≤1, ≥18 years old, adequate organ function, and fasting (or non-fasting) glucose ≤160 mg/dl. Primary end point: OS. Key secondary end points: PFS, 1-year survival rate, patient-reported outcomes, and safety. Patients receiving 20 mg/kg ganitumab are expected to achieve ganitumab levels above the median in phase 2. A log-rank test stratified by ECOG, presence of liver metastases, and geographic region will compare OS independently for each ganitumab arm at an overall one-sided 2.5% significance level for declaring superiority of ganitumab plus G versus placebo plus G. This study includes multiple planned safety analyses conducted by an independent data monitoring committee. The current predefined safety analyses occurred when 150 patients received ≥1 cycle of tx. Results: As of 16 September 2011, 207 patients are included in this aggregate analysis: 50% male; median age, 63 years (range 36–83); ECOG score 0/1, 50%/50%. Of the 207 patients, 204 patients received study tx, and 61 patients ended study tx. Ten patients (5%) died during or within 30 days of the end of tx. Seven events were attributed to or associated with disease progression. One event of cardiac failure was reported to be possibly tx related. Pulmonary embolism was suspected but not confirmed. Conclusions: The GAMMA study continues as per protocol. The only grade 3/4 adverse event occurring in more than 5% of patients to date is neutropenia.
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Serials Department on July 13, 2015
M. Ikeda1, T. Okusaka2, J. Mizusawa3, A. Takashima3, C. Morizane2, M. Ueno4, Y. Hamamoto5, H. Ishii6, H. Hara7, A. Fukutomi8, M. Furukawa9, M. Nagase10, T. Yamaguchi11, N. Boku8, J. Furuse12 1 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 2Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 3Japan Clinical Oncology Group Data Center, Multi-institutional Clinical Trials Support Center, National Cancer Center, 4 Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 5Department of Oncology, Tochigi Cancer Center, 6Hepatobiliary and Pancreatic Division, Cancer Institute Hospital, 7Department of Gastroenterology, Saitama Cancer Center, 8Divison of Gastrointestinal Oncology, Shizuoka Cancer Center, 9Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, 10Department of Clinical Oncology, Jichi Medical University, 11Department of Gastroenterology, Chiba Cancer Center, 12 Department of Medical Oncology, Kyorin University School of Medicine
in progression-free survival (PFS) over placebo in patients with advanced pancreatic neuroendocrine tumors ( pNET). The purpose of this presentation is to show the efficacy and safety in the Japanese subgroup analysis. Methods: The subgroup analysis for the Japanese patients (n = 40) was carried out comparing everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17); both in conjunction with best supportive care (BSC), in the following end points: PFS, disease control rate (DCR), adverse drug reaction (ADR) and median duration of exposure. Results: PFS was significantly prolonged in patients treated with everolimus compared with placebo (hazard ratio, 0.19; 95% confidence interval (CI), 0.08–0.48; log-rank P < 0.001) with a median of 19.45 months (95% CI, 8.31–not available) in the everolimus arm and 2.83 months (95% CI, 2.46–8.34) in the placebo arm. DCR was 86.9% in the everolimus arm and 35.3% in the placebo arm. The majority of ADRs were grade 1 or 2 in severity. Most common ADRs in the everolimus arm were rash (n = 20; 87%), stomatitis (n = 17; 74%) and infections (n = 15, 65%). Grade 3/4 ADRs occurred in 69.5% of the everolimus arm and 29.4% of the placebo arm. The most frequent grade 3/4 ADRs were neutropenia (% in the everolimus arm; 17.4% versus % in the placebo arm; 17.6%), anemia (8.7% versus 0%), pneumonitis (8.7% versus 0%) and leukopenia (8.7% versus 0%). The median duration of exposure to everolimus was 60 versus 12 weeks on placebo. Treatment discontinuation for ADR was 17% in the everolimus arm versus 0% in the placebo arm. Conclusions: Everolimus demonstrated a statistically and clinically meaningful improvement in PFS over placebo and was well tolerated in Japanese patients. These results suggest that everolimus can be a standard treatment of Japanese patients with advanced pNET.
abstracts
International Session 1: ‘Hepato-biliary-pancreatic’
abstracts IS1
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SYNERGISTIC ANTI-TUMOR EFFECT OF SORAFENIB IN COMBINATION WITH AKT INHIBITORS IN HEPATOCELLULAR CARCINOMA
W.-C. Feng1,2,5, C.-H. Hsu2,3,5, S.-D. Lin3,5, H.-H. Lin2, D.-W. Hsu3,5, C.-C. Huang3,5, L.-P. Chow1*, A.-L. Cheng2,3,4,5* 1 Graduate institute of Biochemistry and Molecular Biology, 2Graduate Institute of Oncology, National Taiwan University School of Medicine, Taipei, Taiwan, 3 Departments of Oncology, 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 5Cancer Research Center, National Taiwan University School of Medicine, Taipei, Taiwan
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EXPLORING THE ANTI-TUMOR EFFICACY OF COMBINATION THERAPY WITH INHIBITORS TARGETING THE INSULIN-LIKE GROWTH FACTOR (IGF) AND PI3K/AKT/ MTOR SIGNALING PATHWAYS FOR HEPATOCELLULAR CARCINOMA (HCC)
D.-L. Ou1,2, C. Hsu3,4, B.-S. Lee2,3, Y.-C. Chang2,3, Y.-C. Cheng5, A.-L. Cheng1,3,4 1 Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan, 2National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan, 3Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, 4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 5Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan Background: The IGFR signaling pathway plays important roles in carcinogenesis and drug resistance of many cancers, including HCC, but inhibitors targeting the IGF signaling pathway showed limited therapeutic efficacy. This study explored the efficacy of combining inhibitors targeting the IGF and PI3K/AKT/mTOR signaling pathways in HCC. Methods: HCC cell lines tested included Hep3B, Huh7, and PLC5. The MTT agents tested included NVP-AEW541 (IGF receptor kinase inhibitor, Novartis), MK2206 (Akt inhibitor, MSD), BEZ235 (PI3K/mTOR inhibitor, Novartis), and RAD001 (mTOR inhibitor, Novartis). The potential synergistic antitumor effects were tested by MTT assay and median dose effect analysis in vitro and by xenograft models in vivo. Apoptosis was analyzed by flow cytometry and western blotting. The activity of pertinent signaling pathways and expression of apoptosis-related proteins were measured by western blotting and by an apoptosis protein array (Proteome ProfilerTM, R&D Systems). Results: Synergistic growth-inhibitory and apoptosis-inducing effects in HCC cells were found most prominently in NVP-AEW541/ MK2206 combination, followed by NVP-AEW541/BEZ235 combination. These synergistic anti-tumor effects correlated with a more sustained inhibition of Akt and 4EBP-1 phosphorylation. Potential downstream mediators identified by the apoptosis array included survivin and clapsin. The synergistic anti-tumor effects of NVP-AEW541/MK2206 and NVP-AEW541/BEZ235 combinations were confirmed in vivo by xenograft models, with acceptable toxicity profiles. Conclusions: Combination therapy of IGF receptor inhibitors with inhibitors targeting the PI3K/AKT/mTOR pathway may have therapeutic efficacy in HCC (supported by grants NHRI-EX100-9911BC, DOH100-TD-B-111-001, and NSC 100-2314-B-002-058-MY3).
xi | abstracts
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THE USE OF SECOX (SORAFENIB, OXALIPLATIN, CAPCITABINE) AS THE TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA (HCC): A SINGLE-CENTER ANALYSIS
T. Yau1,2, J. Chiu1, Y. F. Tang2, P. Chan3, R. Leung1, H. Wong1, S.-T. Fan2, R. Poon2 1 Department of Medicine, Queen Mary Hospital, Hong Kong, 2Department of Surgery, Queen Mary Hospital, Hong Kong, 3Department of Medicine, Ruttonjee Hospital, Hong Kong Background: Combining sorafenib with chemotherapy can potentially provide a new regime with enhanced benefit. Phase II study has demonstrated promising activity in combining sorafenib, oxaliplatin and capecitabine (SECOX) in treating advanced HCC. We reported our experience in using this regime in our centre. Methods: This retrospective study included all consecutive advanced HCC patients treated in our centre with SECOX regimen: daily oral sorafenib 400 mg B.D., oxaliplatin 85 mg/m2 infusion on D1, and oral capcitabine 850 mg/m2 B.D. from day 1 to 7 every 2 weeks. Univariate and multivariateble analyses were employed to explore the potential predictive factors for overall survival benefits treated with this combination. Results: Eighty-nine patients were included in the analysis with 29 patients previously enrolled in the phase II trial and 60 patients treated outside the clinical trial in our centre. Of 89 patients received SECOX (male, 85%; median age, 53 years; hepatitis B carrier, 91%), 72 (81%) patients had CP A and 17 (29%) patients had CP B. Moreover, 42.7% patients had ECOG performance status (PS) 0, 53.9% patients had PS 1 and 3.4% patients had PS 2. The most common grade 3 or 4 drug-related toxic effects were hand-foot syndrome (10.5%), diarrhea (5.8%), and hypertension (5.8%). G3/4 thrombocytopenia was found in 18.1% and neutropenia was present in 6.0%. The overall response rate was 14.6%, with one (1.1%) patient had complete response and 12 (13.5%) patients achieved partial response. Moreover, 30 (33.7%) patients had stable disease. Overall, 48.3% patients derived benefits from SECOX. The progression-free survival (PFS) was 4.1 months (95% CI 3.6–4.6) and median overall survival (OS) was 11.0 months (95% CI 8.2–12.3). Patients with CP A cirrhosis had better PFS (4.2 versus 2.9 months, P = 0.027) and OS (11.8 versus 5 months, P = 0.003) than CP B patients. Multivariateble analysies revealed that both ECOG 1-2 (P = 0.0056) and baseline AFP level ≥400 ng/ml vascular involvement (P = 0.04812) were associated with worse overall survival. Conclusions: The SECOX regime had promising activity in advanced HCC with good tolerability, especially in Child-Pugh A patients with a good performance status.
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HOSPITAL VOLUMES OF PERCUTANEOUS RADIOFREQUENCY ABLATION ASSOCIATED WITH ITS TREATMENT OUTCOMES FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA
Y.-Y. Shao1,7, L.-C. Lu1,4, R. N. C. Kuo3,5, Z.-Z. Lin1,4, Y.-C. Yeh3, W.-Y. Shau6, C.-H. Hsu1,7, A.-L. Cheng1,2,7, M.-S. Lai3,5,8 1 Departments of Oncology, 2Internal Medicine, 3Center for Comparative Effectiveness Research, Clinical Trial Center, National Taiwan University Hospital, Taipei, Taiwan, 4Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin County, Taiwan, 5Taiwan Cancer Registry, Taipei, Taiwan, 6 Division of Health Technology Assessment, Center For Drug Evaluation, Taipei, Taiwan, 7Graduate Institute of Oncology, College of Medicine, 8Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan Background: Hospital volumes of several major operations were associated with treatment outcomes. The study aims to explore the impact of hospital volumes of radiofrequency ablation (RFA) on the prognosis of patients who received RFA for hepatocellular carcinoma (HCC). Methods: We searched for all patients who were diagnosed to have stage I or II HCC from 2004 to 2006 and received RFA as the first-line therapy in a population-based cohort. Clinical parameters and hospitals which provided the service were recorded. Overall survival (OS) and liver cancer-specific survival (CSS) were then compared according to the hospital volumes. The Cox’s proportional hazards model was used for multivariate analysis. Results: A total of 661 patients received RFA for stage I–II HCC in 28 hospitals. Hospitals were classified as high-volume and low-volume hospitals (first-line RFA for HCC for >10 patients and ≤10 patients per year, respectively). There were 480 (72.6%) patients treated in the high-volume hospitals, and 181 (27.4%) patients treated in the low-volume hospitals. The patient age, gender, tumor sizes and stages were not significantly different between high-volume and low-volume hospitals. Patients treated in high-volume hospitals had significantly longer OS and CSS than patients treated in low-volume hospitals (5-year OS: 58.7 versus 47.2%, P = 0.001; 5-year CSS: 67.1 versus 57.1%, P = 0.009). After adjusting for age, gender, tumor stage and size, hospital level and year of diagnosis, the high volume was still an independent predictor for longer OS (hazard ratio [HR]: 0.57; P < 0.001) and CSS (HR: 0.57; P = 0.003). Among high-volume hospitals, a higher volume (>30 per year) was not associated with even better outcome. Conclusions: Patients who received first-line RFA for HCC in high-volume hospitals had better survival outcomes.
Volume 23 | Supplement 11 | October 2012
Downloaded from http://annonc.oxfordjournals.org/ at Serials Department on July 13, 2015
Background: Sorafenib is currently the only approved agent for hepatocellular carcinoma (HCC). However, its clinical efficacy in HCC is limited. Previous studies indicate that compensatory activation of AKT may contribute to the resistance to sorafenib. We hypothesized that combination of sorafenib and AKT inhibitors could enhance the antitumor effect of sorafenib in HCC. Methods: We analyzed the cellular and molecular effects of sorafenib in combination with inhibitors of AKT in human HCC cell lines, and evaluated their combinational effects against HCC in vitro and in vivo. Results: HCC cells, including Huh7, Hep3B, and SKhep1 cells, expressed high levels of p-AKT in a prompt and sustained manner upon treated with sorafenib. Down-regulation of AKT by siRNA or inhibition of phospho-AKT by AKT inhibitors (MK-2206 or perifosine) enhanced the anti-proliferative effect of sorafenib in cultured HCC cells. The combination indexes of sorafenib and AKT inhibitors were <1 in multiple HCC cells, indicating a synergistic antitumor effect for the combination. Combination of sorafenib and AKT inhibitors induced more significant apoptosis in HCC cells, as quantified by flow cytometry and cleavage of PARP, than either single agent. In the subcutaneous xenograft model of Huh7 cells, the combination of sorafenib and MK-2206 resulted in a better effect in delaying the growth of HCC xenografts. Conclusions: Inhibition of AKT by AKT inhibitors improved the antitumor effect of sorafenib against HCC in vitro and in vivo. Combination of AKT inhibitors and sorafenib warrants further consideration for clinical development in HCC. (The study was supported by NSC97-2628-B-002-004-MY3 and NSC100-2325-B-002-043-.)
Annals of Oncology