bluuebunny/crossref_metadata_2025 huggingface dataset:
North Japan multicenter phase II study of oxaliplatin-containing regimen as adjuvant chemotherapy for stage III colon cancer (NORTH/HGCSG1003).
Authors: Shichinohe Toshiaki , Yuki Satoshi , Takahashi Norihiko , Nakatsumi Hiroshi , Kawamoto Yasuyuki , Kusumi Takaya , Ishiguro Atsushi , Sogabe Susumu , Iwanaga Ichiro , Hatanaka Kazuteru , Oomori Kazuyoshi , Nakamura Michio , Senmaru Naoto , Iwai Kazuhiro , Koike Masahiko , Sakamoto Naoya , Taketomi Akinobu , Hirano Satoshi , Ito Yoichi M , Komatsu Yoshito
Published: March 2017

807

Background: FOLFOX and XELOX are standard adjuvant chemotherapy for resected stage III colon cancer. MOSAIC and XELOXA trials were performed outside of Japan, thus, we conducted a phase II study (NORTH/HGCSG1003) to assess the efficacy and safety of FOLFOX as adjuvant chemotherapy for Japanese patients(pts) with resected stage III colon cancer (UMIN ID: 000004590). Methods: This phase II study enrolled patients with resected stage III colon cancer. Patients received 12 cycles of FOLFOX4 or mFOLFOX6. Sample size was determined to be 243 pts. Primary endpoint was disease-free survival (DFS). We assumed an expected 3-year DFS rate of 81.2% in this study. Secondary endpoints included overall survival (OS) and safety. In this meeting, we present for the 3-year DFS rate. Results: From Sep 2010 to Mar 2013, 273 pts were enrolled at 28 institutions. Full analysis included 265 patients who received FOLFOX. Patients characteristics were as follows: median age ; 65(33-84), Male/female ; 131/134, PS 0/1 ; 258/7, stage IIIA/IIIB/IIIC ; 37/197/31, colon/rectosigmoid: 214/51. The most common grade 3-4 adverse events were neutrophil count decreased (48.1%), peripheral sensory neuropathy (6.4%), platelet count decreased (2.3%), and allergic reaction (1.5%). The median number of cycles of FOLFOX was 12, and the completion treatment rate was 80.4%. There was no treatment-related death. The 3-year DFS rate was 75.2 percent (95% confidence interval, 69.6 to 80.0). Conclusions: In Japanese patients with stage III colon cancer, FOLFOX is a well-tolerable regimen as adjuvant chemotherapy. In this trial, the 3-year DFS rate of primary endpoint was not meet the expectation (81.2%). However, the 3-year DFS rate in this trial was similar to several pivotal trials. We plan to do subset analysis. Clinical trial information: UMIN000004590.
Pathologic validation of ablation therapy for gastric epithelial neoplasia: comparison of argon plasma coagulations vs. coagulation forceps.
Authors: Kim Byung-Wook
Published: March 2017

82

Background: Ablation therapy has been introduced as an alternative in the management of gastric epithelial neoplasia. However, most of previous studies were retrospective observational studies and has not been validated pathologically. The aim of this study was to validate the effect of ablation therapy for gastric epithelial neoplasia pathologically. Methods: After ablation therapy either by argon plasma coagulations (APC) or by coagulation forceps for gastric epithelial neoplasia, immediate endoscopic resection for the lesions was performed. Consequent histologic mappings for the lesions were followed for the residual tumors. Factors which can affect the residual tumors were analyzed. Results: Twenty nine patients among 33 patients who underwent APC (87.9%) and 21 patients among 26 patients who underwent coagulation forceps (80.8%) showed residual tumors. Factors such as type of coagulation therapy, size of the lesion, type of the lesion (elevated vs. flat) and coagulation time/cm2 of the lesion were not associated with complete removal of the lesions. Conclusions: Ablation therapy is inadequate for complete removal of gastric epithelial neoplasia and this therapy cannot replace endoscopic resection. Clinical trial information: KCT0001587.
Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer.
Authors: Sun Der Sheng , Hong Soon Auck , Lee Han Hong , Won Hye Sung , Ko Yoon Ho
Published: March 2017

83

Background: Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis and clinical outcomes in a variety of human malignancies. We investigated Cav-1 in primary and metastatic tumor of gastric cancer (GC) and its association with clinical outcomes. Methods: All specimens evaluated were obtained from 145 patients with GC who had undergone curative gastrectomy. The primary outcomes measured were the expression levels of Cav-1 by immunohistochemistry and its association with clinicopathological parameters and patient survival. Results: Among the 145 patients, the frequency of high expression of stromal Cav-1 within primary tumor and tumoral Cav-1 protein in metastatic lymph node were 22.5% (18/145) and 16.6% (15/91). In the multivariate analysis tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882–8.224; P < 0.001) and cancer-specific survival outcome (CSS, HR, 3.985; 95% CI, 1.620 – 8.623; P = 0.002). In addition, it remained as a strong indicator of poor prognosis for RFS (HR, 3.137; 95% CI, 1.445 – 6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.079 – 5.838; P = 0.033). Conclusions: High expression of tumoral Cav-1 protein in metastatic lymph node shows a strong negative association with the clinical outcomes in patients with curatively resected GC, suggesting that this protein have potential uses as novel prognostic markers.
Angiogenesis factors in esophageal tumors of various histogenesis.
Authors: Frantsiyants Elena Mikhaylovna , Kit Oleg Ivanovich , Kolesnikov Evgeniy N. , Cheryarina Natalia D. , Kozlova Larisa , Pogorelova Yulia A.
Published: March 2017

87

Background: Study of biological nature of tumors can provide important information on the malignant process course and contribute to the drug therapy development. The purpose of the study was to analyze levels of some growth factors in tissues of malignant esophageal tumors of various histogenesis. Methods: Levels of VEGF-А and its receptor sVEGF-R1, VEGF-С and its receptor sVEGF-R2, EGF, IFR-1, IFR-2 and TGF-β1 were studied by the ELISA using standard test-systems in tissue samples obtained from 39 patients: 27 – esophageal squamous cell carcinoma (ESCC), 12 – esophageal adenocarcinoma (EA). All patients had stage II disease (G2, pTNM). Results: Development of the pathogenic vascularization mechanism in ESCC and EA tissues was found to have both similar and different characteristics associated with the expression of growth factors. Similarities included activation of VEGF-А, VEGF-С, VEGF-R1, VEGF-R3, TGF-β1 and EGF in tissues of malignant tumors despite their histogenesis, while differences involved IGF-I and IGF-II content. A strong positive correlation between levels of VEGF-А and IGF-1 (r = 76; p < 0.01), but not IGF-II, was registered in EA tissues only, while in ESCC we found the negative correlation between VEGF-А and IGF-1(r = - 81; p < 0.01) and VEGF-А and IGF-2 (r = -79; p < 0.01). The same was observed for VEGF-С: a strong positive correlation with IGF-1(r = 79; p < 0.01), but not with IGF-II in EA, and a strong negative correlation with IGF-1(r = - 83; p < 0.01) and IGF-2 (r = -87; p < 0.01) in ESCC. EGF appears to be the only VEGF-А and VEGF-С inductor in ESCC, as a strong correlation with it was noted: r = 75 (p < 0.01) and r = 77 (p < 0.01) respectively, while activators of angio- and lymphogenesis factors in EA were presented by IGF-1 and EGF (r = 76 at p < 0.01 and r = 79 at p < 0.01 with VEGF-А and VEGF-С, respectively). Conclusions: Apparently, the two histological types of esophageal cancer are two different diseases with their own pathogenesis, prognosis and therefore approach to the targeted therapy.
Effectiveness and limitations of staging laparoscopy for peritoneal metastases in advanced gastric cancer from the results of JCOG0501: A randomized trial of gastrectomy with or without neoadjuvant chemotherapy for type 4 or large type 3 gastric cancer.
Authors: Hato Shinji , Iwasaki Yoshiaki , Mizusawa Junki , Terashima Masanori , Katai Hitoshi , Yoshikawa Takaki , Ito Seiji , Kaji Masahide , Fujita Junya , Hirao Motohiro , Yamada Makoto , Takagi Masakazu , Katayama Hiroshi , Nakamura Kenichi , Sano Takeshi , Sasako Mitsuru
Published: March 2017

9

Background: In type 4 or large type 3 gastric cancer diagnosed as not having distant metastasis by imaging modalities, the incidence of peritoneal metastasis that was unexpectedly found during laparotomy was approximately 40%. Staging laparoscopy (SL) is a valuable method used for staging gastric cancer. This study aimed to clarify the effectiveness and limitations of SL for patients (pts) with type 4 or large type 3 gastric cancer. Methods: JCOG0501 is a randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for treating type 4 or large type 3 gastric cancer. Eligibility criteria included histologically proven gastric adenocarcinoma that was clinically type 4 or large type 3 gastric cancer and was diagnosed as R0/1-resectable using SL. Pts who underwent gastrectomy without neoadjuvant chemotherapy were included in this study. Results: In total, 316 pts (158 pts with and without neoadjuvant chemotherapy each) were enrolled between October 2005 and July 2013 from 44 institutions. Of the 158 pts without neoadjuvant therapy, 2 pts did not receive laparotomy. The remaining 156 pts were included in this analysis. Among them, except for 1 patient (P1), none were diagnosed with peritoneal metastases (P0) during SL. Among these 155 pts, 24 (15.5%) were diagnosed with peritoneal metastases at subsequent laparotomies (false-negative). Most of the overlooked peritoneal disseminated nodules were located in the intestinal mesentery (8 pts), transverse mesocolon (5 pts), or omental bursa (3 pts). The total number of peritoneal disseminated nodules at laparotomy was often ≤ 9 (1–3 nodules in 14 pts, 4–9 in 4 pts). Of the 156 included pts, 142 underwent R0/1-resection (91.0%) because some overlooked nodules were curatively resected. Conclusions: SL is a useful diagnostic tool to plan the management of type 4 and large type 3 gastric cancers, although the high false-negative rate cannot be ignored. In SL, detailed exploration of the mesentery, mesocolon, and omental bursa is recommended.
Phase II multi-institutional prospective trial of nab-paclitaxel as second-line chemotherapy for advanced gastric cancer refractory to fluoropyrimidine with modified dose reduction criteria (CCOG1303).
Authors: Mochizuki Yoshinari , Kobayashi Daisuke , Kojima Hiroshi , Nakayama Hiroshi , Kawase Yoshihisa , Ishigure Kiyoshi , Shikano Toshio , Torii Koji , Kodera Yasuhiro
Published: March 2017

91

Background: Nab-paclitaxel (nab-PTX) is a candidate as second-line chemotherapy for gastric cancer, with the response rate (RR) of 28% and overall survival (OS) of 9.2 months in that setting in Japan (J-0200). Adverse events (AE) of grade 3 or more were frequent and included neutropenia in 49%, leucopenia in 20% and peripheral nerve disorder (PND) in 24%. Modified dose reduction criteria to manipulate the doses earlier might be more practical, given the relative dose intensity (RDI) of paclitaxel (PTX) in the conventional weekly regimen. Phase II prospective trial was conducted to explore the efficacy and safety of nab-PTX with modified dose reduction criteria. Methods: Patients with histologically confirmed metastatic or recurrent gastric adenocarcinoma that progressed during the fluoropyrimidine-containing first-line chemotherapy were eligible. Patients pretreated with PTX were excluded. Nab-PTX (260 mg/m2) was administered triweekly. Dose reduction was regulated according to predefined toxicity criteria which included neutropenia < 1000/mm3 and/or PND with grade 2 or more. Treatment was to be continued until PD, unacceptable toxicity, or patient’s refusal. The primary endpoint was progression free survival (PFS). Secondary endpoints were OS, RR and toxicity. Results: A total of 50 patients were enrolled from 14 institutions, 47 of whom were eligible for efficacy analyses. The median number of treatment given was 4 cycles (range, 1-25). Of total administration throughout the trial of 280 cycles, dose reduction was needed in 52 cycles (22%). The RDI was 80%. The median PFS was 3.5 months (range, 0.4-20.2) that was equivalent to the expected value designed in the study. The median OS was 9.0 months (range, 1.4-22.1) and RR was 16% (95%CI 2-30). AE of grade 3 or more included neutropenia in 49%, leucopenia in 21% and PND in 11%. Febrile neutropenia occurred in 1 patient (2%). The median time to treatment failure was 3.5 months (range, 0.4-18.0). Conclusions: The modified dose reduction criteria for triweekly administration of nab-PTX resulted in decreased incidence of severe PND without fall in efficacy. Clinical trial information: UMIN000012247.
Outcomes of adjuvant chemotherapy after neoadjuvant chemoradiotherapy for esophageal cancer.
Authors: Shridhar Ravi , Huston Jamie , Meredith Kenneth L
Published: March 2017

92

Background: The use of adjuvant chemotherapy (AC) after neoadjuvant Chemoradiotherapy (NCR) and surgery for esophageal cancer is controversial. The purpose of this study is determine if AC is associated with an overall survival (OS) benefit after NCR. Methods: The National Cancer Database was queried to identify esophageal cancer patients who underwent NCR and surgery between 2006 and 2013 and stratified by treatment with AC. Propensity score matching was utilized against age, pathologic tumor and nodal stage, histology, and margin status. Kaplan-Meier and log-rank analysis was used to determine OS benefit. Univariate (UVA) and multivariate (MVA) was performed with Cox proportional hazard ratio analysis. Results: We identified 1816 patients. AC was associated with improved OS. The median and 3-year OS for AC versus none was 36.4 months and 50% versus 30.9 months and 45%, respectively, (p = 0.02), however, the benefit was restricted to node positive (N+) patients. The median and 3-year OS for AC versus none in N+ patients was 31 months and 44% versus 26 months and 36%, respectively, (p = 0.03). UVA revealed that AC only benefitted patients with N+, R0 resection, and adenocarcinoma. UVA revealed that age, pathologic T3-4, N+, high grade, and R1 resection were associated with increased mortality, while removal of > 10 nodes and AC was associated with decreased mortality. MVA revealed that age, pathologic T3-4, N+, high grade, and R1 resection were associated with increased mortality, while removal of > 10 nodes was associated with decreased mortality. MVA revealed that AC was not prognostic for OS in all patients nor in N+ patients. Conclusions: This is the largest analysis on the use of AC after NCR and surgery for esophageal cancer. While there is an OS benefit favoring AC, the benefit is restricted to N+ patients. However, no benefit to AC was seen on MVA. Clinical trials are needed to address the role of AC after NCR in esophageal cancer.
Pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) in patients with gastric cancer and peritoneal metastasis (PIPAC-GA1).
Authors: Struller Florian , Horvath Philipp , Solass Wiebke , Weinreich Frank Jurgen , Konigsrainer Alfred , Reymond Marc A
Published: March 2017

99

Background: Efficacy of 2nd and 3rdline chemotherapy in recurrent gastric cancer with peritoneal metastasis (RGCPM) is limited. We assessed the feasibility, safety and activity of intraperitoneal chemotherapy as PIPAC C/D in RGCPM after > 1 line of intravenous chemotherapy. Methods: Open-label, single-arm, Phase II ICH-GCP Clinical Trial (NCT01854255) Patients were scheduled for 3 courses q42 days of low-dose PIPAC with doxorubicin 1.5 mg/m2 and cisplatin 7.5 mg/m2. Primary endpoint was objective tumor response (RECIST 1.1). Secondary endpoints were safety (CTCAE 4.0), histological tumor regression (PRGS) and overall survival. Results: 25 patients were enrolled. 10/25 (40 %, ITT) patients had an OTR. Complete or major regression on histology was observed in 9/12 (75 %) patients who underwent at least 2 PIPAC cycles. Mean overall survival was 8.4 months (13.1 months in patients with PCI < 12). There were no treatment-related deaths, no grade 4 toxicity and four (16%) grade 3 toxicities. Conclusions: PIPAC C/D is well tolerated and active in patients with RGCPM. Survival is encouraging. Randomized controlled trials should now be designed. Clinical trial information: NCT01854255. [Table: see text]
CheckMate 577: A randomized, double-blind, phase 3 study of nivolumab (Nivo) or placebo in patients (Pts) with resected lower esophageal (E) or gastroesophageal junction (GEJ) cancer.
Authors: Kelly Ronan Joseph , Lockhart Albert C. , Jonker Derek J. , Melichar Bohuslav , Andre Thierry , Chau Ian , Clarke Stephen John , Cleary James M. , Doki Yuichiro , Franke Fabio Andre , Kitagawa Yuko , Mariette Christophe , Montenegro Paola Catherine , Roca Enrique Luis , Ciprotti Marika , Moehler Markus
Published: March 2017

TPS212

Background: Chemoradiotherapy (CRT) followed by surgical resection is a current standard of care (SOC) for pts with E/GEJ cancer, with 3- and 5-year survival rates ranging from 30% to 40%. Currently, no effective adjuvant SOC is available following resection. Expression of programmed death-1 (PD-1) ligands 1/2 (PD-L1/L2) has been associated with a poor prognosis in E/GEJ cancer, suggesting that PD-1 inhibition may improve outcomes. Nivo is a fully human IgG4 monoclonal antibody that targets PD-1, with demonstrated survival benefit in multiple tumor types and long-term responses in some patients. A phase 1/2 study of nivo monotherapy in chemotherapy-refractory pts with gastric/E/GEJ cancer demonstrated tumor regression, a median overall survival (OS) of 5 months, and a 12-month OS rate of 36% in pts with PD-L1+ and PD-L1- tumors (Janjigian Y, et al. J Clin Oncol. 2016;34:suppl; abstract 4010). This multinational, double-blind, phase 3 trial will evaluate nivo as an adjuvant therapy for pts with resected E/GEJ cancer (CheckMate 577; NCT02743494). Methods: In this study, an estimated 760 pts aged ≥ 18 years with stage II/III E/GEJ cancer are randomized to receive nivo or placebo. Prior to randomization, pts must have completed preoperative CRT followed by surgery and been diagnosed with residual pathological disease after being surgically rendered free of disease with negative margins following complete resection. Pts with stage 4 resectable disease, cervical esophageal cancer, or those who have not received concurrent CRT prior to surgery are not eligible for study enrollment. Primary endpoints are OS and disease-free survival. The secondary endpoint is OS rate at 1, 2, and 3 years. Clinical trial information: NCT02743494.
A phase II trial of neoadjuvant chemotherapy with docetaxel/cisplatin/capecitabine in thoracic esophageal squamous cell carcinoma.
Authors: Wu Xiaobin , Ling Jiayu , Li Shanshan , Xiang Jun , Deng Yanhong , Peng Junsheng
Published: March 2017

TPS216

Background: The Optimal care for resectable squamous cell carcinoma of thoracic esophagus is uncertain. Effecacy of cisplatin-based two agent chemotherapy as neoadjuvant treatment remains limited. The combination of docetaxel, cisplatin, and capecitabine (DCX) for squamous cell carcinoma of thoracic esophagus in neoadjuvant set has not been investigated. Here, we conducted a phase II study to assess the efficacy and safety of neoadjuvant chemotherapy with modified DCX followed by surgery in patients with resctable thoracic Esophageal Squamous Cell Carcinoma. Methods: This is a single-arm prospective phase II study in Chinese patients. The main inclusion criteria are as follows: 1) Histologically proven squamous cell carcinoma of thoracic esophagus, T2-3, N0-2, T4aN0, M0 (UICC 7th edition); 2) age: 18-75 years, ECOG PS 0-1; 3) Enteral or parenteral feeding planned before the start of treatment if oral calorie intake < 1200 kcal; 4) written informed consent. Neoadjuvant modified DCX regimen consists of docetaxol 60mg/m2 iv d1 and cisplatin 30mg/m2 iv d1-2 and capecitabine 850mg/m2 bid po d1-14 repeated every 21 days for 4-6 cycles, followed by Ivor Lewis Esophagectomy. Primary endpoint is 2-year overall survival rate. Key secondary endpoints include pathological response, R0/1 resection rate, disease free survival , safety and QOL by EORTC QLQ-C30. This study is recruiting in The Sixth Affiliated Hospital of Sun Yat-sen University and registered as NCT02915965. Clinical trial information: NCT02915965.
T-ACT (WJOG7112G): A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum.
Authors: Esaki Taito , Makiyama Akitaka , Kashiwada Tomomi , Hosokawa Ayumu , Kawada Junji , Moriwaki Toshikazu , Horie Yoshiki , Satake Hironaga , Shinozaki Katsunori , Ishida Hiroyasu , Tanioka Hiroaki , Tsukuda Hiroshi , Uchino Keita , Nishikawa Kazuhiro , Sukawa Yasutaka , Yamanaka Takeharu , Nakamura Shinichiro , Boku Narikazu , Hyodo Ichinosuke , Muro Kei
Published: March 2017

TPS218

Background: Trastuzumab (Tmab) is a key drug for HER2 positive breast and gastric or gastro-esophageal junction (G/GEJ) cancer. While use of Tmab beyond progression (TBP) showed a benefit in HER2-positive metastatic breast cancer, clinical significance of TBP for HER2-positive G/GEJ cancer has not been clarified. Objective:This study compares the efficacy of paclitaxel (PTX) + Tmab with PTX alone in patients with unresectable or metastatic HER2-positive G/GEJ cancer who failed first-line chemotherapy with Tmab + fluoropyrimidine + platinum. Methods: Enrolled patients will be randomized to receive PTX (80 mg/m2, on day 1, 8 15, every 4 weeks) + Tmab (8 mg/kg loading dose and 6 mg/kg thereafter, on day 1, every 3 weeks) or PTX alone. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, disease control rate, safety, and translational biomarker research. A total of 69 events are required to achieve 80% power for one-sided log rank test with 10% significance level, expecting the median PFS of the PTX and the PTX + Tmab arms will be 3 and 5 months. In consideration of patient with censoring and dropout, the planned sample size is totally 90 patients. Major eligibility criteria are: HER2-positive advanced G/GEJ adenocarcinoma; refractory to first-line chemotherapy with fluoropyrimidine, platinum, and Tmab (at least three doses); within 6 weeks after last Tmab administration; no prior therapy with taxane or anti-HER2 drugs except Tmab; ECOG PS 0-2; adequate organ function; left ventricular ejection fraction ≥ 50%. Tumor tissue, blood serum, and circulating tumor DNA are collected before the study treatment for biomarker analyses to explore the predictive marker of the TBP strategy. As of September 2016, 89 patients were randomized. Clinical trial information: 000009297.
iMYC: Proof-of-concept study of ibrutinib in c-MYC and HER2 amplified oesophagogastric carcinoma.
Authors: Davidson Michael , Chong Irene Yu-Shing , Cunningham David , Aronson Lauren , Bryant Hanna , Begum Ruwaida , Swansbury John , Wotherspoon Andrew , Matthews Nik , To Ye Mong , Kalaitzaki Eleftheria , Yuan Lina , Watkins David J. , Starling Naureen , Rao Sheela , Chau Ian
Published: March 2017

TPS221

Background: The MYC proto-oncogene is among the most frequently dysregulated genes in human cancer and is amplified in 10-30% of oesophagogastric (OG) cancers. Such genes which code for transcription factors are challenging to target directly with small molecule inhibitors or monoclonal antibodies. High-throughput siRNA screening of OG cell lines has found silencing of Bruton’s tyrosine kinase (BTK) to result in selective lethality in the presence of MYC amplification. Sensitivity to the orally available BTK inhibitor ibrutinib has been confirmed in-vitro in MYC, HER2 and co-amplified OG cancer cell lines (Chong, Ann Onc 2014), suggesting it may be a potentially effective therapeutic strategy in both MYC and HER2 amplified OG cancer. Methods: i MYC is an open label, phase II non-randomised study to assess the efficacy of ibrutinib in advanced pre-treated OG cancer. A novel FISH assay for tumour MYC amplification has been developed and pts are pre-screened for MYC and HER2 amplification. Eligibility includes metastatic or locally advanced inoperable OG cancer (SCC or adeno), MYC (ratio >2.5) and/or HER2 (ratio>2) amplification, progression after at least 1 prior line of chemotherapy +/- trastuzumab for advanced disease, PS 0-2 and no history of significant cardiovascular or bleeding disorders. Of the first 9 pts, at least 4 will demonstrate MYC amplification and remaining 5 will show either MYC or HER2 amplification, or co-amplification of both. Pts will be treated with ibrutinib monotherapy until progression or unacceptable toxicity. A Simon 2 stage design will be used for the primary endpoint of response rate, with interim analysis after 9 pts and maximum recruitment to 17 pts. Secondary endpoints include PFS, OS and exploratory translational and imaging biomarker analysis. Mandatory biopsy will be obtained at baseline and optional biopsies will be undertaken at day 10-14, week 8 and progression. The trial represents the first attempt at targeting MYC amplification via synthetic lethal gene interactions in OG cancer through the novel application of an existing anti-cancer drug. As of September 2016, 61 patients have consented for pre-screening, 19 completed MYC analysis and first patient has started treatment. Clinical trial information: 02884453.
KEYNOTE-240: Randomized phase III study of pembrolizumab versus best supportive care for second-line advanced hepatocellular carcinoma.
Authors: Finn Richard S. , Chan Stephen L. , Zhu Andrew X. , Knox Jennifer J. , Cheng Ann-Lii , Siegel Abby B. , Bautista Oliver , Watson Pat , Kudo Masatoshi
Published: March 2017

TPS503

Background: There are no approved therapies for patients with hepatocellular carcinoma (HCC) after disease progression on sorafenib, or for patients with intolerance to sorafenib. HCC often arises in the background of chronic inflammation and is also associated with an immunosuppressed microenvironment, providing a strong rationale to evaluate immunotherapy in HCC. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-240 study (ClinicalTrials.gov, NCT02702401) was designed to compare the efficacy and safety of the anti–PD-1 antibody pembrolizumab + best supportive care (BSC) vs placebo + BSC in patients with previously treated advanced HCC. Methods: Eligibility criteria include age ≥18 years, confirmed diagnosis of Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC stage B disease not amenable to or refractory to locoregional therapy, disease not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation), documented progression after treatment with sorafenib or intolerance to sorafenib, Child-Pugh liver score A, and ECOG performance status 0-1. ~408 patients will be randomly assigned 2:1 to receive pembrolizumab 200 mg IV every 3 weeks (Q3W) + BSC or placebo Q3W + BSC for up to 35 cycles or until disease progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision. Randomization will be stratified by geographic region, macrovascular invasion, and α-fetoprotein. BSC will be provided by the investigator per local treatment practices. Response will be assessed every 6 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary objectives are comparison of progression-free survival per RECIST v1.1 by central imaging vendor review and overall survival between treatment arms. Secondary objectives are comparison of objective response rate, duration of response, disease control rate, and time to progression per RECIST v1.1 by central imaging vendor review, and evaluation of safety and tolerability. Enrollment in KEYNOTE-240 is ongoing. Clinical trial information: NCT02702401.
A phase II multicenter study evaluating combination immunotherapy with pembrolizumab and peginterferon alfa-2b for advanced cholangiocarcinoma.
Authors: He Aiwu Ruth , Morse Michael , Iyer Renuka V. , Sohal Davendra , Wang Hongkun , Dorsch-Vogel Karen , Pishvaian Michael J. , Salem Mohamed E. , Smaglo Brandon George , Marshall John
Published: March 2017

TPS507

Background: No effective therapy is available for patients (pts) with advanced cholangiocarcinoma (CC) after disease progression on first-line chemotherapy. In Phase I studies, pembrolizumab (pem) showed activity in pts with advanced CC. Interferon alpha-2b was shown to increase tumor immune infiltrates. In order to improve the response rate (RR) of pts with CC to pem, we propose to combine sylatron with pem in an open-label, single-arm, multicenter Phase II study. Methods: To be eligible for study, pts must have CC, manifesting as either intrahepatic, extrahepatic or gallbladder cancer that is unresectable, metastatic, and has either failed to respond to or demonstrated progression on frontline chemotherapy. Forty-four pts will be enrolled on study to receive SC sylatron (200 mg) weekly for 12 weeks, and IV pem (200mg) once every 3 weeks, starting on week 4 (at the same time as the 4th dose of sylatron), until pts experience disease progression or unacceptable toxicity, or withdraw consent. CT scans will be performed every 9 weeks. The primary endpoints are overall RR (ORR) and the safety and tolerability of combined pem and sylatron therapy. Secondary endpoints include OS, PFS, and ORR by irRECIST. An initial 3-week window will exist in which to evaluate the effect of sylatron alone (following prior chemotherapy) on the tumor microenvironment: one biopsy (biopsy 1) will be obtained before the start of sylatron therapy, and another (biopsy 2) after the third but before the fourth injection of sylatron (and the initiation of pem plus sylatron combination therapy). The effect of sylatron on the CC immune microenvironment will be studied by comparing biopsies 1 and 2. Immune microenvironment in pem + sylatron responders will be compared with non-responders. The study will assess whether the addition of sylatron improves the RR of pem from 17% to 35% in pts with advanced CC. Simon’s two-stage optimum design will be used to test the null hypothesis that P ≤ 0.17 vs. the alternative hypothesis that P ≥ 0.350. This study design provides 80% power (one-sided significance level of 0.05). The time-to-event endpoints (PFS, OS) will be estimated using Kaplan-Meier methodology.
Phase I/IB multicenter study of afatinib in combination with capecitabine in patients (pts) with refractory solid tumors and pancreatico-biliary cancers.
Authors: Chang Amy E. , Shahda Safi , Harris William Proctor , Cohen Stacey , Coveler Andrew L. , O'Neil Bert H. , Gadi Vijayakrishna K. , Hibbert Reina , Lee Hannah H , Younger Anne , McCormick Kinsey Ann , Pritchard Colin , Redman Mary Weber , Chiorean E. Gabriela
Published: March 2017

TPS515

Background: The epidermal growth factor receptor (EGFR)/HER2 pathway is overactive in several solid tumors, including gastroesophageal, hepatic, colorectal, and pancreatico-biliary cancers. Afatinib is an irreversible inhibitor of the Erb family approved for metastatic non-small cell lung cancer with EGFR mutations. Afatinib downregulates thymidine synthase (TS) the intracellular target of fluoropyrimidine chemotherapy such as capecitabine. Treatment of colorectal cancer cell lines with cytotoxic drugs can up-regulate EGFR expression, and increase sensitivity to EGFR inhibition. Based on this preclinical rationale, and given that capecitabine is commonly used in refractory gastrointestinal cancers, we have developed a phase I/Ib trial to evaluate the safety and maximum tolerated dose (MTD) of afatinib with capecitabine in advanced solid tumors, and assess preliminary antitumor activity in pts with refractory pancreatico-biliary cancers at MTD. Methods: Eligible pts have metastatic solid tumors (phase I) or pancreatico-biliary cancers (phase Ib), ECOG PS 0-2 (PS 0-1 phase Ib), any number of prior therapies (phase I), or ≤ 2 prior therapies (phase Ib), no prior erlotinib (phase Ib), and have archived paraffin embedded tumor tissue, or ability to undergo tumor biopsy at baseline. Tumor tissue is analyzed with UW-OncoPlex, a multiplexed gene sequencing panel of 200+ cancer-related genes, to identify predictive biomarkers of benefit. The study design is standard “3+3”. Afatinib is administered orally (PO) daily (QD) in escalating doses of 20, 30 and 40 mg, with capecitabine at 1000 mg/m2 PO BID Days 1-14, in 21-day cycles (C). Dose limiting toxicity (DLT) is assessed in C1. Once the MTD is identified, the phase Ib expansion cohorts will enroll 15 pts each with refractory pancreatic and biliary cancers, with afatinib dosed at MTD and standard dose capecitabine. The study was activated in November 2015, and to date 4 pts were enrolled in cohort 1, 3 pts in cohort 2, and 2 pts in cohort 3. The phase I is ongoing and the phase Ib is expected to start enrollment in December 2016. Clinical trial information: NCT02451553.
5-fluorouracil, oxaliplatin and dasatinib (FOLFOX-D) for previously untreated metastatic pancreatic adenocarcinoma.
Authors: George Thomas J. , Dang Long H. , Daily Karen Colleen , Starr Jason Scott , Parekh Hiral D. , Ivey Alison Marguerite , Delitto Daniel , Allegra Carmen Joseph , Hughes Steven J. , Lu Xiaomin , McEwan Margaret A. , Cioffi Jessica L , Trevino Jose Gilberto
Published: March 2017

TPS517

Background: Systemic chemotherapy for pancreatic adenocarcinoma improves survival and cancer related symptoms. Most targeted agents combined with gemcitabine have consistently failed to demonstrate clinical benefits. Src is overexpressed in pancreatic cancer and promotes an aggressive cancer phenotype. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation through inhibition of Src, Bcr-Abl, CKit and other pathways. Inhibition of Src is associated with biologic modifications favorably modifying the pancreatic cancer phenotype and has synergy with restoring inherent chemosensitivity. Src inhibition can also increase oxaliplatin activity and modulate Tcell responses. The addition of D to the well-established backbone of FOLFOX represents a multifaceted line of scientific investigation. Methods: This is a multicenter phase II trial to determine activity and toxicity of FOLFOX + D in previously untreated metastatic pancreatic adenocarcinoma. Eligible pts must have at least 1 measurable target lesion by RECIST, ECOG PS 0-2, normal QTc and adequate organ function. Pts received standard cycles of mFOLFOX6 repeated q14d with continuous D (150mg PO daily). Tumor assessments occur q8w. Endpoints included progression-free survival (primary; PFS), objective and biochemical response rates, clinical benefit rate, freedom from metastases, overall survival (OS), toxicity, and quality of life. Exploratory tissue, circulating tumor cell and serum analyses to identify predictors of response are planned, particularly in those demonstrating durable disease control or exceptional response. Sample size was based on a 50% improved median PFS from 4 (historical) to 6 months. NCT01652976. Results: Enrollment continues on this prospective phase II study with 38 of 42 evaluable patients. There are no unexpected toxicities noted thus far. Clinical trial information: NCT01652976. [Table: see text]
A multicenter prospective study on the efficacy and safety of denosumab in gastrointestinal cancer patients receiving short-term periodic steroid premedication for prevention of chemotherapy-induced nausea and vomiting: ESPRESSO-02/HGCSG1602.
Authors: Nakamura Michio , Yagisawa Masataka , Sawada Kentaro , Muranaka Tetsuhito , Nakatsumi Hiroshi , Kawamoto Yasuyuki , Yuki Satoshi , Dazai Masayoshi , Ishiguro Atsushi , Kobayashi Yoshimitsu , Sogabe Susumu , Miyagishima Takuto , Iwanaga Ichiro , Tateyama Miki , Hatanaka Kazuteru , Ono Kota , Sakata Yuh , Komatsu Yoshito
Published: March 2017

TPS809

Background: We previously reported that short-term periodic premedication of glucocorticoids (GCs) used with chemotherapy for gastrointestinal cancer (GIC) caused the reduction of bone mineral densities (BMD) and the increase of serum bone alkaline phosphatase (BAP) (ESPRESSO-01 study; ASCO-GI 2016 Abst.523). Surprisingly, it seems that the BMD decreasing levels due to only the 16-week GC usage in GIC chemotherapy were comparable to that of the 12-month adjuvant aromatase inhibitor therapy for early stage breast cancer patients or the 12-month androgen deprivation therapy for nonmetastatic prostate cancer patients. So we conducted this study to evaluate the efficacy and safety of denosumab for prevention of chemotherapy-induced BMD decreasing. Methods: This is a multicenter single-arm prospective study to evaluate the efficacy and safety of denosumab in GIC patients receiving the short-term periodic steroid premedication. The key eligibility criteria are as follows: 1) Histologically confirmed adenocarcinoma in GIC, including esophageal, gastric, pancreatic, and biliary cancer. ; 2) A schedules of periodical intravenous steroid administration as premedication that was weekly, biweekly, and triweekly, and in which > 4-week steroid-free intervals were not allowed. ; 3) High risk patient with steroid induced secondary osteoporosis. ; 4) No prior treatment for osteoporosis. The dose of denosumab (Prolia) is 60mg administered as a single subcutaneous injection within a week before the induction of chemotherapy. All participants should receive adequate calcium and vitamin D supplementation. The primary endpoint is to investigate the BMD change and bone turnover markers (serum NTX and BAP levels) between baseline and 16 weeks after induction of chemotherapy. And the secondary endpoints are to compare and evaluate the difference of primary site, treatment regimen, dose intensity of steroids, newly bone fractures, and the FRAX output. This study is sponsored by Hokkaido Gastrointestinal Cancer Study Group. Clinical trial information: UMIN000023855.
Cetuximab metastatic colorectal cancer strategy (ERMES) study: A phase III randomized two arm study with FOLFIRI + cetuximab until disease progression compared to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until disease progression in first-line treatment of patients with RAS and BRAF wild type metastatic colorectal cancer.
Authors: Pinto Carmine , Normanno Nicola , Orlandi Armando , Maiello Evaristo , Bilancia Domenico , Corsi Domenico C. , Tamburini Emiliano , Pisconti Salvatore , Ferraú Francesco , Di Costanzo Francesco , Gori Stefania , Daniele Bruno , Tonini Giuseppe , Zaniboni Alberto , Soto-parra Hector , Frassinetti Giovanni Luca , Iaffaioli Rosario Vincenz , Zampino M. Giulia , Repetto Lazzaro , Barone Carlo Antonio ,   ERMES Study Group
Published: March 2017

TPS810

Background: The optimal duration and content of first-line therapy in mCRC pts once they have achieved objective response is controversial. In the FIRE-3 trial, ETS was significantly associated with PFS and OS. Based on this evidence it can be hypothesized that once this goal has been achieved, further exposure to combined antineoplastic treatment may not result in improvement or preservation of such result but only in an increase of toxicity. We designed a strategy study to compare FOLFIRI + cetuximab until PD to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until PD in first line treatment of RAS/BRAF WT mCRC pts. Methods: This is a multicenter, open-label, randomized phase III trial. Untreated and unresecteble RAS/BRAF WT mCRC pts were randomized 1:1 to receive Cetuximab (400 mg/mq w1 and then 250 mg/mq weekly) + FOLFIRI until PD (standard arm) or Cetuximab (400 mg/mq week 1 and then 250 mg/mq weekly) + FOLFIRI for 8 cycles followed by Cetuximab monotherapy until PD (experimental arm). Tumor assessment is planned every 8 weeks. The objective of the study is to demonstrate a not inferior efficacy and a better toxicity profile for the experimental treatment compared to the standard treatment. The co-primary endpoints are PFS and incidence of G 3-4 AEs. Secondary endpoints are OS, ORR, ETS (8 weeks) and safety. A prospective multiple gene mutation analysis by NGS of both tumor tissue and blood will be performed to find potential predictive factors and surrogate markers of treatment efficacy. The two co-primary endpoints will be compared between the two arms using a fixed-sequence testing procedure to control for the family-wise type I error rate of 0.05 in a strong sense. This sequence considers that a reduction of grade 3-4 AEs is only of relevance, if non-inferiority is shown regarding PFS. 600 evaluable pts will be enrolled and randomized. Study recruitment started on January 2015, currently 139 pts have been randomized. Clinical trial information: NCT02484833.
ISO-005; An open-label, multiple-site, dose cohort, phase I/II study in patients with stage IV colorectal cancer.
Authors: Taflin Helena Anna , Wettergren Yvonne , Odin Elisabeth , Haux Johan , Gustavsson Bengt , Carlsson Goran Ulf
Published: March 2017

TPS811

Background: Chemotherapy treatment of Colorectal Cancer, usually includes combinations with 5-Fluorouracil (5-FU). 5-FU is always combined with Leucovorin, (LV), which significantly enhances the therapeutic effect of 5-FU. The principal mechanisms of action are the same for Modufolin as for LV. However, in contrast to LV, Modufolin does not require metabolic activation to exert its effects - a clear advantage since the activation capacity shows great intra- and inter-individual variability leading to insufficient and unpredictable responses to LV in some patients. Methods: ISO-CC-005 is a multiple-site, international phase I/II study in patients with Stage IV Colorectal Cancer eligible for 5- FU/LV therapy alone or in combination with oxaliplatin or irinotecan. The study will investigate the tolerability of Modufolin at four dose levels and is designed as a safety study. Tolerability will be assessed by analysing the number and severity of DLTs associated with the chemotherapeutic agents, adversed events and the number of dose adjustments observed for each of the chemotherapeutic agents used in the different treatment arms. 39 valid patients are planned for inclusion, who will receive Modufolin twice every two weeks during four chemotherapy cycles. The study is on-going and still recruting eligible patients. Clinical trial information: NCT02244632.
Phase 1 study of infusional or bolus deflexifol (a novel formulation of 5FU, folinic acid, and cyclodextrin) after failure of standard treatment.
Authors: Clingan Philip R. , Ackland Stephen P. , Ranson Marie , De Souza Paul , Tafreshi Ali , Aghmesheh Morteza , Brungs Daniel , Garg Madhu Bala , Parker Suzanne , Jokela Rebecca
Published: March 2017

TPS812

Background: 5FU is a commonly used anti-cancer agent first synthesized in 1957, and is now most commonly used in combination with FA, which enhances its clinical activity. Physical incompatibilities between 5FU and LV necessitate the infusion of each component separately, often through a central line due to high pH; resulting in adverse events, which leads to poor outcomes due to treatment interruption and discontinuation. A novel all in one reformulation of 5FU/LV at physiological pH has been developed as an alternative to serial administration of 5FU and LV in a high Ph solution [Locke JM, Anticancer Drugs 2009]. Preclinical testing demonstrated that the reformulation is stable bioequivalent to 5FU with reduced side effects [Stutchbury TK, Anticancer drugs 2011]. Methods: An open label phase 1 dose escalation study is underway in 2 schedules (bolus and infusion) to assess the safety and tolerability in patients with advanced malignancy after failure of standard treatment (including fluoropyrimidine regimens). To determine the maximum tolerated dose defined as: 2 out of 6 patients experience DLTs dose escalation is halted and declared DLT Dose. The previous dose level will be considered for expansion to x6 patients to confirm Maximum Tolerated Dose (MTD). Also to determine pharmacokinetic profile. Patients enrolled in Cohorts 1 to 4, have been completed without DLT. Dose-limiting toxicity (DLT) is defined as: Any Grade 3 or 4 non-haematologic toxicity (CTACE criteria). Patients developing Grade 3 or 4 diarrhoea, failing maximal anti-diarrheal medications. Febrile neutropenia, Grade 4 neutropenia > 7 days, Grade 4 thrombocytopenia > 7 days Any grade of thrombocytopenia associated with bleeding. Currently proceeding with (bolus 575mg/m2 weekly x 6, infusion 3600mg/m2/46h q2W). Limited sampling PK of 5-FU and dihydoFU is being conducted (3 at each of the 5 dose levels, doses 1 and 6). In both schedules to assess PK variability, adequacy of dosing in comparison to previous reports. The incidence of AEs and SAEs (CTACE 4.03) will be summarized by severity and relationship to study treatment. Clinical trial information: 044867.
Consolidation chemotherapy for locally advanced mid- or low rectal cancer after neoadjuvant concurrent chemoradiotherapy: A multicenter, randomized controlled trial (KONCLUDE).
Authors: Kim Chang Woo , Kim Ik Yong , Lee Suk-Hwan
Published: March 2017

TPS813

Background: Chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced mid or low rectal cancer with improved local control. However, systemic recurrence after the standard therapy is the most important failure of treatment, and several efforts have been trying to overcome it. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase the proportion of pathologic complete response (pCR), subsequently could show better oncologic outcomes. Methods: Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to underwent TME followed by adjuvant chemotherapy of 8 cycles (control arm) or receive 3 cycles of chemotherapy before TME, and receive 5 cycles of chemotherapy (experimental arm). The primary endpoints are pathologic complete response and 3-year disease-free survival, and the secondary endpoints are radiotherapy-related complications, R0 resection, tumor response rate, surgery-related morbidity, and peripheral neuropathy 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in two primary endpoints, compared with the control arm. Based on the superiority design, an one-sided log-rank test with α-error of 0.025 and a power of 90% was conducted. Allowing for a drop-out rate of 10%, 316 patients (158 per arm) will need to be recruited. The accrual period is 2 years and the follow-up period is 3 years. Discussion: KONCLUDE (A Korean society of coloproctology trial: cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: A multicenter, randomized controlled trial) is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer. Clinical trial information: 02843191.