bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 in combination with gemcitabine and nab-paclitaxel (nab-PTX) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Shahda Safi , El-Rayes Bassel F. , O'Neil Bert H. , Starodub Alexander , Hanna Wahid Tewfik , Borodyansky Laura , Oh Cindy , Li Chiang , Bekaii-Saab Tanios S. 
Published: February 2017

284 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that works by blocking STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo, in mono- and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with mPDAC was performed to determine RP2D, safety, tolerability, and preliminary anti-cancer activity of BBI-608 in combination with Gemcitabine and nab-PTX. BBI-608 was administered at 240 mg BID in combination with Gemcitabine 125 mg/m2 and nab-PTX 1000 mg/m2administered weekly for 3 out every 4 weeks until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 31 pts were enrolled and received BBI-608 in combination with Gemcitabine and nab-PTX for a total sum of 83 study cycles. 25 of 31 pts (80.6%) were treatment-naïve and 6 pts (19.4%) received 1 prior line of systemic therapy. Most common adverse events included grade 1 diarrhea, abdominal pain, nausea, and fatigue. Combination treatment was well tolerated with no dose-limiting toxicity observed and safety profile similar to that of each agent individually. One patient experienced grade 3 event of dehydration related to protocol therapy which resolved with hydration. Of the 8 pts enrolled in the RP2D determination portion of the study, 7 pts were evaluable for response with disease control (PR + SD) was observed in 7/7 pts (100%). Tumor regression was observed in 6/7 (85.7%) with 3 PR (41.3%, 37.6% and 33.3% regression) and 3 SD (25.8%, 21.1%, and 19.9% regression). The median progression free survival was 7.8 months with PR or SD of > 6 months in 6/8 pts (75%). Conclusions: This phase Ib study demonstrated that BBI-608 at 240 mg BID can be safely combined with Gemcitabine and nab-PTX. Encouraging anti-tumor activity with durable response was observed in pts with mPDAC. Clinical trial information: NCT02231723.
Neoadjuvant nab-paclitaxel and gemcitabine (AG) in borderline resectable (BR) or unresectable (UR) locally advanced pancreatic adenocarcinoma (LAPC) in patients ineligible for FOLFIRINOX.
Authors: Peterson Shawn , Loaiza-Bonilla Arturo , Ben-Josef Edgar , Drebin Jeffrey A. , Westendorf-Overley Colleen , Anthony Lowell Brian , DeSimone Philip A. , Goel Gaurav , Kudrimoti Mahesh R. , Dineen Sean Patrick , Tzeng Ching-Wei David , Hosein Peter J 
Published: February 2017

328 Background: AG is superior to gemcitabine in patients with advanced pancreas cancer. There are limited data on the use of AG in BR or UR LAPC. Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) is an option for such patients, many are not eligible due to age, poor performance status (PS) or comorbidities. Herein, we report our experience with neoadjuvant AG for BR/UR LAPC in patients ineligible for FOLFIRINOX. Methods: In this retrospective series, we included patients with BR/UR LAPC who received neoadjuvant AG. The treatment algorithm included AG for 3-4 months followed by radiation, then re-evaluation for surgery. The published AG regimen doses were modified based on patient tolerance. The primary outcome measure was R0 resection rate. Secondary outcomes were response rate, tolerability, and overall survival (OS). Results: Between 10/2013-9/2015, 20 patients (14 BR, 6 UR) at two institutions were treated with this approach. Median age was 69 years (range 44-90); 11/20 were female; PS ranged from 0-3; 14 patients have completed therapy and 6 remain on treatment. Five were converted to resectability by imaging and subsequently underwent operation; 4 had R0 resections (29% of patients who have finished therapy). To date, 6 patients died from progressive disease (PD), 2 are alive with PD and 12 remain alive on therapy or surveillance. All patients who achieved R0 resections are alive and disease free. The best response to AG was a partial response in 4 patients (20%), stable disease in 11, and progression in 2 with 3 patients still pending re-evaluation. Mean dose intensity was 77% for AG. Toxicities were similar to the published AG regimen. Conclusions: In this small series, both the R0 resection rate and the response rate were at least 20%, despite frequent dose reductions and relatively low dose intensity. Elderly and/or poor PS patients with LAPC have been historically excluded from curative-intent strategies. Our data suggest that these patients may now have a possibility for cure with the use of neoadjuvant AG.
A phase 1b study of the anti-cancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) +/- nab-paclitaxel in patients with pancreatic cancer.
Authors: Hidalgo Manuel , Cooray Prasad , Carrato Alfredo , Jameson Michael B. , Parnis Francis , Jeffery Mark , Grimison Peter S. , Stagg Robert J. , Holmgren Eric , Kapoun Ann M. , Dupont Jakob , Tebbutt Niall C. 
Published: February 2017

341 Background: Delta-like ligand 4 (DLL4) activates the Notch pathway. DEM is a humanized anti-DLL4 antibody that inhibits tumor growth & decreases cancer stem cell frequency in human tumor xenograft models. DEM also has an antiangiogenic effect & synergistic activity when combined with GEM & nab-paclitaxel in pt derived xenograft models of pancreatic cancer. Methods: Pts with 1st line pancreatic cancer were enrolled. Pts in cohorts 1-3 received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks including 3 truncated pts) & GEM 1000 mg/m2 7 of 8 wks, then 3 of 4 wks. Pts in cohorts 4, 5, 6 & 7 received truncated DEM (2.5, 3.5 or 5 mg/kg every 2 wks through Day 70) & nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 3 of 4 wks. The primary objective was to determine the MTD. Other objectives were safety, efficacy, immunogenicity, PK & biomarkers. Results: Fifty-six pts were enrolled; 8, 8, 8, 6, 8, 9 & 9 pts received 2.5 mg/kg every 2 wks, 2.5 mg/kg every 4 wks, 5 mg/kg every 4 wks, 2.5 mg/kg every 2 wks (truncated), 5 mg/kg every 2 wks (truncated), 3.5 mg/kg every 2 wks (truncated) & 3.5 mg/kg every 2 wks (truncated), respectively. Related AEs in > 20% of pts were fatigue (36%), nausea (32%), vomiting (23%), hypertension (21%) & diarrhea (20%). Hypertension was managed with anti-hypertensives. Increased BNP is an early indicator of the cardiac effects of DEM & mildly elevated values were used to initiate a cardioprotective ACE inhibitor or carvedilol. Two pts who received DEM continuously developed reversible pulmonary hypertension & 1 of these pts developed heart failure. As a result, DEM was limited to 70 days in cohorts 4, 5, 6 & 7. In cohorts 1-3, 4 of 16 (25%) pts had a PR. In cohorts 4, 5, 6 & 7, 14 of 28 (50%) pts had a PR & 11 had SD. The truncated DEM pts had a median PFS of 9.0 mos (95% CI: 3.7 mos-NR) & a median survival of 10.1 mos (95% CI: 6.5-16.2 mos), respectively. Conclusions: This therapy was generally well tolerated with fatigue, nausea & vomiting being the most common related AEs. Truncated DEM dosing (i.e., limited to 70 days) avoided clinically significant cardiopulmonary toxicity. Encouraging clinical activity was observed. Biomarker analysis showed modulation of the Notch pathway. Final data will be presented. Clinical trial information: NCT01189929.
Is neoadjuvant chemoradiation important in borderline resectable pancreatic cancer (BRPC)? Clinical and surgical outcomes associated with preoperative FOLFIRINOX alone in BRPC.
Authors: Kim Sunhee S. , Nakakura Eric K. , Wang Zhen J. , Kim Grace E. , Corvera Carlos U. , Harris Hobart W. , Kirkwood Kimberly S. , Hirose Ryutaro , Tempero Margaret A. , Ko Andrew H. 
Published: February 2017

351 Background: Neoadjuvant therapy is recommended to increase the likelihood of margin-negative (R0) resection for BRPC. However, there is no consensus regarding the optimal treatment paradigm, including the respective roles of chemotherapy and radiation (RT), in this setting. Methods: Retrospective analysis was conducted of BRPC pts treated with neoadjuvant FOLFIRINOX followed by surgical resection at a single tertiary care referral center over a 4-year period. Data collected included baseline pt characteristics, toxicity profiles, radiographic and serum CA19-9 response, perioperative complication rate, R0 resection rate, histopathologic response, and frequency and patterns of recurrence. Results: 26 BRPC pts received neoadjuvant FOLFIRINOX, 22 w/o addn RT. Abutment of the SMV (n = 9, 40.9%), SMA (n = 4, 18.2%), CHA (n = 4, 18.2%), and narrowing of the SMV (n = 4, 18.2%) were the most common vascular involvement. 9 (40.9%) pts had both arterial and venous involvement. Median baseline CA19-9 level was 278.5 U/ml. Pts received a median of 9 treatment cycles (range, 4-12). Radiographic response was categorized as shrinkage (n = 11, 50%), stable (n = 9, 40.9%), or progression (n = 2, 9.1%). The Whipple procedure was the most common operation performed (n = 17, 77.3%), with 12 pts (54.5%) requiring vascular reconstruction. Clavien-Dindo complication rates of grade 0, I, II, and IIIa occurred in 25.9%, 11.1%, 44.4%, and 14.8% of pts, respectively. R0 resection rate was 90.9%, with 13 (59.1%) having negative lymph nodes. Treatment response of Evans grade III or IV, corresponding to < 10% residual tumor cells, was seen in 8 pts (36.4%), including one pathologic CR (4.5%). AJCC Stage: ypT3N0 (36.4%), ypT3N1 (18.2%), ypT1N1 (18.2%). With a median f/u time of 22.1 months, 8 pts (36.4%) have progressed, inc 7 (87.5%) with distant disease. Median PFS is 22.5 mos. Conclusions: This is one of the largest series to report on the use of neoadjuvant chemotherapy w/o RT in BRPC pts. FOLFIRINOX alone in this setting is associated with high R0 resection rates and favorable clinical outcomes, and should be further assessed in prospective study design for BRPC.
A phase Ib dose escalation, safety, and tolerability study of sonidegib in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Macarulla Teresa , Tabernero Josep , Palmer Daniel H. , Sharma Sunil , Yu Kenneth H. , Sellami Dalila B. , Zhou Jocelyn , Yi Wu , Boss Hildegard , Kwak Eunice L 
Published: February 2017

371 Background: Sonidegib (LDE225) is a potent, selective, and orally bioavailable inhibitor of smoothened receptor that demonstrated preclinical activity in combination with gemcitabine (GEM). Here, we present data from a phase 1b trial of sonidegib in combination with GEM in patients (pts) with pancreatic adenocarcinoma (PA). Methods: Pts with histologically or cytologically confirmed, locally advanced, or metastatic PA who had not been treated previously or had progressed despite prior chemotherapy (other than GEM) were included in the study. Dose escalation started with sonidegib 400 mg, once a day, in combination with GEM 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle. Results: A total of 18 pts were enrolled (9 pts each the in dose escalation and dose expansion phases). Pts discontinued the study because of disease progression (n = 11, 61.1%), consent withdrawal (n = 3, 16.7%), administrative problems (n = 3, 16.7%), and grade 3 or 4 blood creatine kinase (CK) elevation (n = 1, 5.6%). Three of 9 pts in dose escalation phase experienced dose-limiting toxicities during the first 8 weeks including grade 3 mucositis (n = 1), grade 3 CK elevation (n = 1), and grade 3 aspartate aminotransferase elevation (n = 1). Drug-related adverse events (AEs) of all grades were reported in 14 pts (77.8%) and grade 3 or 4 AEs were reported in 10 pts (55.6%). The most commonly reported AEs were anemia and nausea. No pharmacokinetic (PK) interaction was observed. Based on considerations of the statistical model, clinical assessment of safety, tolerability, PK, and pharmacodynamic results, maximum-tolerated dose and recommended dose were established as 400 mg of sonidegib in combination with the fixed standard dose of GEM (1000 mg/m2).The objective response rate was 11.1% and the median progression-free survival (PFS) was 4.9 months. Conclusions: The combination of sonidegib and GEM was generally well tolerated with moderate activity. Although no formal comparison can be made due to small sample size of this study, this combination provided a median PFS comparable to the current standard of care without conferring any additional clinical benefit. Clinical trial information: NCT01487785.
Knowledge-based planning for stereotactic body radiation therapy (SBRT) of the liver.
Authors: Gits Hunter C , Dow Janell , Matuszak Martha , Feng Mary Uan-Sian 
Published: February 2017

375 Background: SBRT is emerging as a treatment option for patients with unresectable liver tumors. However, generating high quality liver SBRT plans is technically challenging and user-dependent. Aiming for high tumor doses and low normal tissue doses can demand lengthy planning times and result in plans of inconsistent quality. This study investigates knowledge-based planning (KBP) as a standardized method to ensure efficacy, safety, and efficiency for SBRT plans and allow for broader use of this therapy. Methods: SBRT treatment plans were manually optimized for 55 liver cancer cases by an expert liver dosimetrist in a commercial treatment planning system (Varian Eclipse v13.6). Each volumetric modulated arc therapy plan was approved by a physician using strict criteria for target coverage and normal tissue sparing. The plans were used to create a custom model in a KBP system (RapidPlan, Varian Eclipse v13.6) designed to improve both efficiency and standardization of quality. To validate the model, 15 new cases were optimized manually by an expert liver dosimetrist and then semi-automatically using the KBP model. The validation plans were compared based on target coverage, normal tissue sparing, and planning time. Results: Compared to manual plans created by an expert liver dosimetrist, KBP-generated plans showed similar target coverage and improved normal tissue sparing with similar planning times. Mean and minimum target doses were similar, as was D98, p > 0.2 for all. Normal tissue complication probability for liver damage was marginally lower with KBP, mean 3 vs. 1%, p = 0.07. Doses to adjacent organs including stomach, heart, and bowel were similar. Manual planning required a median and mean time of 15 and 20 minutes, respectively, range 8-55 min. KBP required similar times of 12 and 19 min, range 8-50 min. 9 of 15 KBP cases were automated, while 6 plans required dosimetrist improvement. Conclusions: Using KBP, high quality plans for liver SBRT can be created automatically or semi-automatically. These plans are comparable to those generated by an expert liver dosimetrist. KBP could be used to standardize treatments between institutions, particularly when experience with liver SBRT is limited.
Curative resection for hilar cholangiocarcinoma: Does adjuvant therapy impact overall survival? A multi-institution analysis from the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Krasnick Bradley , Jin Linda , Davidson Jesse , Ethun Cecilia Grace , Pawlik Timothy M. , Poultsides George A. , Tran Thuy , Idrees Kamran , Isom Chelsea A , Weber Sharon M. , Salem Ahmed I. , Hawkins William G. , Strasberg Steven M. , Martin Robert C. G. , Scoggins Charles Raben , Shen Perry , Mogal Harveshp , Schmidt Carl Richard , Maithel Shishir Kumar , Fields Ryan C. ,   Extrahepatic Biliary Tumors
Published: February 2017

388 Background: Surgical resection is the cornerstone of curative therapy for localized hilar cholangiocarcinoma. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall survival (OS) in those patients undergoing curative resection for hilar cholangiocarcinoma. Methods: We reviewed 294 patients who underwent curative resections for hilar cholangiocarcinoma between 1998 and 2015 from ten institutions participating in the U.S Extrahepatic Biliary Malignancy consortium. We analyzed the impact of AT on the primary outcome of OS. Probability of OS was calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis. Statistical significance was set at p≤0.05. Results: Mean age was 65 years. OS at 5 years was 16%. A total of 146 patients (50%) received AT. Of these patients, 44 patients underwent solely chemotherapy, 5 underwent only radiation therapy (XRT), and 97 underwent combined therapy. On univariate analysis, patients who received AT and those who did not had similar demographic and preoperative features, with the major difference being in the rate of lymph node (LN) positive disease (50% AT group vs. 19% no AT group, p<0.01). In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.578, p<0.01, 95% CI 0.38-0.86), even when adjusting for age, tumor size, R0 resection status, ASA classification, and LN positivity (Table). Conclusions: AT is associated with improved OS in resected hilar cholangiocarcinoma. This association remains even after adjusting for poor prognostic features. We acknowledge that there is an inherent selection bias when looking at those who underwent AT, and thus future prospective randomized trials are needed. [Table: see text]
Trends in treatment and survival for advanced pancreatic cancer: Progress or progression?
Authors: Eskander Mariam F. , Kasumova Gyulnara G. , Li Chun , Ng Sing Chau , Miksad Rebecca A. , Tseng Jennifer F. 
Published: February 2017

421 Background: There are increasing therapeutic options for patients with advanced pancreatic cancer but it is unknown whether the overall prognosis of unresectable patients is improving. Here, we examine trends in treatment and survival in Stage III/IV pancreatic cancer. Methods: National Cancer DataBase 1998-2012 queried for unresected pancreatic adenocarcinoma patients from Commission on Cancer hospitals with Stage III and IV disease. Trends in stage at diagnosis and type of chemotherapy (single vs. multi-agent) assessed via Cochran Armitage trend tests. Timing of treatment compared by Kruskal-Wallis. Kaplan-Meier analysis and Cox proportional hazards models used to assess the association between 2-year time intervals (1998-2011) and survival. Results: 34,163 unresected patients with Stage III and 100,396 with stage IV identified. Rates of chemotherapy increased over time for stage III (p<0.0001) and stage IV (p<0.0001). Among patients who received systemic therapy, rates of multiagent chemotherapy have increased for both stage III (p<0.0001) and IV (p<0.0001). Time from diagnosis to treatment did not change (p=0.5121). Overall survival differed by year group for stage III (5.2 mos in 1998-1999 vs. 9.0 mos 2010-2011, log-rank p<0.0001) and stage IV (3.1 vs. 3.6 mos; log-rank p<0.0001). Among patients who received chemotherapy, overall survival also differed (Stage III, 7.6 vs. 11.4 mos, log-rank p<0.0001; Stage IV, 5.0 vs. 6.0 mos, log-rank p<0.0001). After stratification by clinical stage, type of chemotherapy, tumor location, and facility type, year remained a significant predictor of survival (p<0.0001). Conclusions: Survival of patients with Stage III and IV pancreatic cancer has significantly improved over the last fifteen years. This improvement in survival is not fully explained by changes in chemotherapy. [Table: see text]
Clinical and immune characteristics of rapid dropout and long-term survival in a phase II safety and efficacy study of combination CRS-207/GVAX immunotherapy in pancreatic cancer.
Authors: Le Dung T. , Whiting Chan C. , Lutz Eric R. , Nair Nitya , Engstrom Amanda , Lemmens Ed , Tagliaferri Margit Cecile , Murphy Aimee L. , Brockstedt Dirk G. , Jaffee Elizabeth M. 
Published: February 2017

459 Background: Baseline patient characteristics may impact duration on study and survivorship of patients in immunotherapy trials. In this study, GVAX pancreas (GM-CSF–secreting allogeneic pancreatic tumor cells) was administered with low-dose cyclophosphamide (Cy), with or without subsequent CRS-207 (live-attenuated Listeria monocytogenes–expressing mesothelin) infusion. Baseline clinical and immunological data were examined for two patient subsets based on duration on study. Methods: Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to 2 doses of Cy/GVAX followed by 4 doses of CRS-207 or 6 doses of Cy/GVAX every 3 weeks. Stable patients were offered additional courses. Patients were evaluated for post-randomization duration on study of < 60 days (rapid dropouts, RD) and > 18 months (long-term survivors, LTS). Baseline characteristics of these subsets were examined. Results: A total of 93 patients were randomized. Fifteen patients were RD; 13 were LTS. More RDs versus LTS had liver metastasis and lymph node involvement. On average, fewer RD patients had radiotherapy prior to randomization and fewer had prior surgical intervention. RD averaged 1.73 prior metastatic cancer treatment regimens versus 1.31 in LTS. RD also had higher average baseline CA 19-9 levels. Immune analysis showed higher circulating terminal effector CD8+ T cells and lower serum IL-6 in LTS compared to RD. Serum IL-6 concentration remained lower in LTS at four weeks following initiation of treatment. For patients who received CRS-207, CD8+ T cells specific to listeriolysin O (LLO) and mesothelin were higher in LTS than RD, as determined by ELISPOT. Conclusions: Baseline clinical and immunological characteristics may impact patient duration on immunotherapy trials. Immune monitoring and biomarker analysis in this study is ongoing to identify circulating cellular, tumor biomarkers and genomic (miRNA and mRNA) signatures that may correlate with survival. These findings warrant continued exploration of patient characteristics to identify best candidates for immunotherapy trials. Clinical trial information: NCT01417000.