bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial comparing the efficacy and safety of nintedanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Palmer Daniel H. , Ma Yuk Ting , Peck-Radosavljevic Markus , Ross Paul J. , Graham Janet Shirley , Fartoux Laetitia , Deptala Andrzej , Wenz Arne , Hocke Julia , Loembe Arsene-Bienvenu , Meyer Tim 
Published: February 2017

238 Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, phase II study (NCT01004003; 1199.37) evaluated the efficacy and safety of N versus sorafenib (S) in patients with advanced HCC. Methods: Enrolled patients had unresectable advanced HCC, ECOG-PS ≤2, Child–Pugh score 5–6, alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal, and ≥1 untreated measurable lesion or a previously treated lesion with progression (by RECIST 1.0). Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was time to progression (TTP) by independent central review (ICR; RECIST 1.0), and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Ninety-three patients were randomized to receive N (n=62) or S (n=31). At the cutoff date (15 July 2014), 77% of patients had a TTP event, and 70% had an OS event; 3 patients remained on treatment with 1 patient beyond PD. IA TTP was comparable between N and S (median 5.5 vs 3.8 months; HR 1.05 [95% CI: 0.63–1.76]), as was OS (median 11.9 vs 11.4 months; HR 0.88 [95% CI: 0.52–1.47]). ICR TTP data are pending. All patients reported an AE (CTCAE 3.0); more patients treated with S had Grade ≥3 AEs (68% vs 90%). AEs leading to dose reduction were higher with S (19% vs 42%), whereas AEs leading to drug discontinuation were higher with N (45% vs 23%). The only tyrosine kinase inhibitor class-specific AE reported in >15% of patients was hand-foot skin reaction in the S arm. AEs previously observed with N and higher in this arm were diarrhea, vomiting, nausea, and AST increase, while blood bilirubin increase was higher with S. Rash was reported in >15% of patients only in the S arm. Conclusions: N shows similar efficacy to S with respect to TTP and OS, with a manageable safety profile. Further studies of N in patients with advanced HCC are warranted. Clinical trial information: NCT01004003.
Phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer: Clinical update on long term survival and biomarker correlates to overall survival.
Authors: Whiting Chan , Lutz Eric , Nair Nitya , Chang Serena , Lemmens Ed , Chen Shih- Yu , Solt Sara , Ferber Sandy , Maecker Holden , Murphy Aimee , Brockstedt Dirk G. , Jaffee Elizabeth M. , Le Dung T. 
Published: February 2017

261 Background: In a phase 2a randomized study, metastatic pancreatic ductal adenocarcinoma (PDA) patients treated sequentially with two vaccine-based immunotherapies showed extended overall survival (OS) with tolerable side effects. Treatment included low-dose cyclophosphamide (CY) to inhibit T-regulatory cells prior to GVAX, an irradiated GM-CSF-secreting allogeneic PDA cell vaccine, which activates a broad antigenic response, followed by CRS-207, a live-attenuated, mesothelin-expressing Listeria monocytogenes vaccine which stimulates innate and adaptive immunity. Methods: Patients were enrolled with metastatic PDA who received or refused ≥1 prior chemotherapy, had ECOG ≤1 and adequate organ function. Patients were randomized 2:1 to receive 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B). PBMC and serum were collected over the course of treatment for immune and biomarker analyses. CyTOF, ELISPOT, and luminex were used to identify biomarker correlates of OS. Results: We previously reported phase 2a results demonstrating median OS in patients treated in arm A was 6.1 months compared to 3.9 months for those in arm B (HR=0.54, one-sided p=0.011). As of August 2014, 8 patients are still alive (median time on study: 768 days; range: 596-880), with 3 subjects on combination treatment. Mesothelin-specific CD8+T cell responses following CY/GVAX correlated with improved OS in both arms. Elevated frequencies of T cell subsets and a panel of baseline serum cytokines also correlated with longer OS. Strikingly, hierarchical clustering based on expression of biomarkers showed significant clustering of patients according to OS. Conclusions: Treatment with CY/GVAX and CRS-207 was well-tolerated and resulted in improved OS compared to CY/GVAX alone. A larger phase 2b, 3-arm, randomized trial is ongoing and plans to treat 240 adults with previously-treated metastatic PDA with CY/GVAX and CRS-207, CRS-207 alone, or standard chemotherapy. Preliminary results using patients’ PBMCs and sera revealed potential biomarkers for OS. Clinical trial information: NCT01417000. Clinical trial information: NCT01417000.
A phase II study of palbociclib (PD-0332991) in adult patients with advanced hepatocellular carcinoma.
Authors: Littman Susan Joy , Brus Christina , Burkart Ashlie 
Published: February 2017

277 Background: The oral MKI sorafenib has been shown to significantly increase PFS, OS and DCR in treatment-naïve HCC in randomized Ph 3 trials. Despite these landmark studies OS benefit is modest, particularly for those with C-P cirrhosis grades B/C and toxicity is a major management problem. We report results of second-line treatment with palbociclib, PD-0332991, an orally available selective inhibitor of cyclin dependent kinases 4 and 6, which has potent anti-proliferative activity in pre-clinical studies. Methods: This is an open-label, nonrandomized single institution trial for pts with inoperable, advanced HCC, who have failed or are intolerant of first line therapy with sorafenib. Eligible subjects were treated with 125 mg PD-0332991 orally/day, 1-21 of a 28-day cycle, until disease progression, unacceptable toxicity, withdrawal from study or death. Tumor response by CT or MRI was assessed using mRECIST v1.1. Toxicity assessments were per NCI CTCAE v4.0. The primary endpoint is TTP. Secondary endpoints are safety/tolerability, OS & RR. Results: 21 pts (18 M, 3 F) have been enrolled. Median age: 62 (32-78) yrs. 47% Cauc, 19% AA and 33% Asian. 17 C-P A, 4 C-P B. ETOH 19%, HCV 48%, HBV 24%, NASH 5%, unknown 10%. 71% had >1 metastatic site. All had pathologically confirmed Retinoblastoma-positive HCC. Median duration of therapy was 17 (8-69) wks and (4.25 (2-17) cycles. Most common grade 3/4 AEs were neutropenia and thrombocytopenia. Non-serious AEs were anemia, pain, ascites and fatigue. 4 pts were non-evaluable, median OS = 10.5 (5.5-14) wks. In evaluable pts, there was 1 PR and 0 CRs. 6 pts died of ESLD without observable disease progression by RECIST, median OS = 19 (4 - 43) wks. Nine pts had disease control (PR or SD) followed by disease progression, median TTP was 24 (4-64) wks. Prolonged stability was seen in 3 pts. OS was 40 (24-96) wks, excluding 2 pts who are alive at 120 and 59 wks. 2 pts remain on trial. Conclusions: Palbociclib demonstrates activity in patients with advanced HCC after failure of first-line sorafenib. This trial will meet its primary endpoint. Consistent with a cytostatic MOA, some pts experienced HCC stabilization and OS was determined by ESLD. Palbociclib is well tolerated in cirrhotic patients with advanced HCC. Clinical trial information: NCT01356628.
Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Smith Lon S. , Bendell Johanna C. , Strickler John H. , Zalupski Mark , Gluck William , Kapoun Ann , Yen Wan-Ching , Xu Lu , Hill Dawn , Zhou Lei , Dupont Jakob , Cohn Allen Lee 
Published: February 2017

278 Background: Tarextumab (TRXT), fully human IgG2 antibody, inhibits signaling Notch 2, 3 receptors. Tumor regression seen in Notch 3 patient-derived PC xenografts when TRXT added to Nab-P+Gem. The maximum tolerated dose (MTD) of single agent TRXT was 7.5mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was Grade 3 diarrhea. This study evaluates MTD, pharmacokinetics (PK), pharmacodynamics (PD) and early efficacy of TRXT + Nab-P+Gem in mPC. Methods: Cohorts of 3-6 pts treated at 6 dose levels of TRXT. TRXT IV Days 1 + 15 with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1000mg/m2on Days 1, 8, 15 of every 28-day cycle. Biomarker analysis of surrogate tissue and tumor undertaken. Results: By 08/22/14, N= 40 treated. TRXT 15 mg/kg selected as Phase 2 dose. 1 DLT Grade 3 diarrhea in 15 mg/kg cohort. Frequently reported (≥15%) TRXT adverse events(AEs) were: diarrhea(60%), fatigue(43%), anemia(28%), decreased appetite (18%) and nausea(15%); most grade 1 or 2 and managed supportively. Other AEs (≥ 30%) were: cytopenia, alopecia, vomitng and peripheral edema. GEM or Nab-P+Gem did not alter PK of TRXT. Notch pathway-related genes, HEYL, HES2, NOTCH2 and cancer stem cell markers were altered in hair follicles at TRXT > 7.5 mg/kg combined with Nab-P+Gem. Plasma, blood RNA biomarkers were also modulated by TRXT + Nab-P+Gem. Conclusions: TRXT + Nab-P+ Gem is well tolerated. 15 mg/kg is the selected Phase 2 dose of TRXT. Encouraging anti-tumor activity was observed. Final safety, efficacy, PK and PD results in surrogate and serial tumor tissues will be presented. The Phase 2 randomized, placebo-controlled ALPINE study is underway. Clinical trial information: NCT01647828. [Table: see text]
Comparative circulating tumor DNA levels for KRAS mutations in patients with nonresectable pancreatic cancer.
Authors: Johansen Julia S. , Vibat Cecile Rose T. , Calatayud Dan , Jensen Benny Vittrup , Hasselby Jane Preuss , Collisson Eric Andrew , Lu Timothy , Poole Jason C. , Erlander Mark 
Published: February 2017

288 Background: Non-resectable pancreatic cancer patients have a wide range of median time for overall survival (OS). Currently there is a lack of diagnostic tools to predict patient outcome at diagnosis. KRAS mutations are present in the vast majority of pancreatic tumors. The study objective was to determine if quantitative baseline and longitudinal monitoring of KRAS mutations from plasma circulating tumor DNA (ctDNA) could be used to stratify patients for predicting outcome. Methods: Plasma was prospectively collected from the Danish BIOPAC study for non-resectable pancreatic cancer patients undergoing treatment with gemcitabine or FOLFIRINOX. Feasibility of monitoring ctDNA KRAS mutations was assessed in 10 patients with long OS (median 493 days; range 360-1031) and 10 patients with short OS (median 66 days; range 21-136). KRAS G12A/C/D/R/S/V, and G13D mutations were PCR enriched, sequenced by massively parallel deep sequencing, quantitated and standardized by reporting number of copies detected per 105 genome equivalents (GE). Results: In a pilot study of 20 patients, all 18 patients with evaluable DNA had detectable KRAS mutations. Of 18 patients, 12 had baseline plus longitudinal time points (7 short, 5 long OS). Mutant KRAS copies were higher for short OS (median=994; range 0-34305 copies/105 GE) vs. with long OS (median 196; range, 34-278 copies/105 GE). Longitudinally, KRAS mutation levels remained mostly low with long OS (last time point median 204; range 8-873 copies/105 GE) vs. short OS where levels increased or remained high (median 2363; range 71-47919 copies/105 GE). Identical KRAS mutations were consistently detected for a given patient with short OS. However, long OS patients had variable KRAS mutations in longitudinal analysis. Conclusions: High levels of ctDNA KRAS mutations at diagnosis and post-treatment elevation of KRAS mutations were more associated with short OS. Different levels of KRAS mutation at diagnosis may predict patient outcome and could reflect distinct underlying tumor biology. Expansion of this prospective-retrospective biomarker cohort will be reported.
A multinational assessment of gastric and esophageal cancer burden by age, gender, and disease characteristics.
Authors: Lowe Kimberly A , Katz Aaron , Kelsh Michael A. , Vaughan Thomas L. 
Published: February 2017

29 Background: Gastric and esophageal cancers are the fourth and eighth most common cancers worldwide, with an estimated 1.5 million new cases combined in 2008. A comprehensive, international comparison of the descriptive epidemiology of these diseases is lacking. The objectives of this study are to (1) characterize the current and projected incidence rates and the current case fatality of these cancer types by age and gender within countries in Europe, Asia, the Americas, Oceania, and Africa; (2) describe the temporal variation in cardia and non-cardia gastric cancer and squamous and adenocarcinoma esophageal cancer in the U.S. by age and gender. Methods: Data from GLOBOCAN were used to calculate country-specific incidence rates (per 100,000) for 2012, 2015, and 2025, and the country-specific case fatality (%) in 2012. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program in the U.S. were used to estimate gastric cancer incidence rates from 2004-2011 (per 100,000) and 12-month survival (%) stratified by gender, age (0-64/65+), stage at diagnosis, gastric cancer subtype, and esophageal cancer histology. Joinpoint regression was used to quantify changes in the Average Annual Percent Change (AAPC) in these outcomes. Results: GLOBOCAN results showed wide geographic variation in gastric and esophageal cancer incidence rates. In most countries, the case-fatality among males and females 65+ years was > 60%. In the U.S., the annual incidence of all gastric cancer subtypes decreased significantly among males and females 65+ (AAPC= -2.4% & -1.6%, respectively). Esophageal cancer incidence decreased in both genders and age groups, with a significant decline observed among females 65+ with squamous histology (-3.5%). Twelve-month survival in esophageal cancer showed modest improvements, with a significant increase observed among males 65+ with adenocarcinoma histology (2.0%). Conclusions: The worldwide burden of gastric and esophageal cancers is substantial. In the U.S., declines in incidence and modest improvements in survival of these cancers were observed.
Genomic change index (GCI) and liquid biopsies in predicting and monitoring response to therapy in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Kundranda Madappa N. , Beck Julia , Braun Donald Peter , Urnovitz Howard B. , Mitchell William Marvin , Schütz Ekkehard 
Published: February 2017

309 Background: Advanced PDAC is a lethal disease with dismal 5 year survival. The current modalities for monitoring therapy response using serum (CA) 19-9 levels have poor specificity and radiological responses have long lag times. Tests for rapid and accurate clinical assessment are needed for early decision making. Methods: 5 patients (pts) with locally advanced unresectable or metastatic PDAC were treated with gemcitabine and nab-Paclitaxel on a bi-weekly schedule. Tumor tissue was collected at baseline and plasma was collected at each cycle (3 time points). Tumor tissue and leukocyte DNA was used to prepare shotgun sequencing libraries and PCR-based enrichment of 124 genes for paired-end high-throughput sequencing. Copy-number variations were called by comparing tumor vs. leukocytes read counts in genomic windows. Algorithms were used to quantify a Genomic Change Index (GCI) from selected variations of the cancer genome. Somatic mutations were quantified in cell-free plasma DNA (cfDNA) of 3 pts using droplet digital PCR (ddPCR) as a function of treatment. Results: Of the 5 pts evaluated, the lowest GCI’s (<10) was present in a non-responding (NR) pt receiving chemotherapy. 4 pts with varying degrees of clinical, biochemical and radiological (ranging from partial (PR) to stable disease (SD) to complete (CR)] responses, showed elevated GCIs (≥15). Detected tumor mutations were followed by liquid biopsies. In a patient with SD, mutKRAS and mutTP53 cfDNA copies of 20-80 per mL plasma (cp/mL) did not significantly change over time. In a patient with CR and >70% decrease in CA19-9; no copies of mutKRAS and 4-10 cp/mL mutTP53 were detected at the 3 time points measured. In a pt with PR and rising CA19-9, there was also an increase in mutKRAS and mutTP53 cp/mL. Conclusions: 1.) Our pilot study indicates that GCI may be similarly predictive of PDAC response to therapy as we have previously reported with head/neck and colorectal carcinomas. 2.) ddPCR has sufficient sensitivity to monitor tumor mutations in the plasma of PDAC pts and could provide a specific biomarker to monitor response. Both tests are currently being validated with longer follow up and larger number of patients.
Relationship of programmed death 1 (PD-1) expression to the recurrence in gastric cancer.
Authors: Eto Shohei , Iwata Takashi , Yoshikawa Kozo , Higashijima Jun , Nakao Toshihiro , Nishi Masaaki , Takasu Chie , Shimada Mitsuo 
Published: February 2017

31 Background: PD-1 (Programmed Death 1), a member of the B7-CD28 family, is a cell surface coinhibitory receptor expressed on T cells, B cells, monocytes, and natural killer T cells, following activation. Recently, PD-1 expression is involved with malignancy have been reported in cancer cells and virus-infected cells. The aim of this study is to clarify the impact of PD-1 expression on long term outcome of gastric cancer. Methods: Total of 105 patients who were performed gastrectomy in Stage 2/3 gastric cancer. For resected specimen was performed immunostaining of PD-1. We counted PD-1 positive T cells in the tumor across five adjoining high power fields (×400 magnification level). And, we calculated the percentage of the total cell number, it was considered PD-1 positive more than 40%. We investigated clinicopathological factors and survival. Results: 28 cases were PD-1 positive expression. There was no significant difference between the two groups in the clinicopathological factors (age, gender, tumor size, differentiation, depth of invasion, lymph node metastasis, stage, lymphatic invasion and venous invasion). There was no difference in overall survival rate at 3 years (PD-1 positive vs. negative 76% vs. 81%, p=0.552). PD-1 positive expression was significantly poorer in disease-free survival rate (36% vs. 65%, p=0.022). 10 cases were Foxp3 positive expression, and Foxp3 positive expression was related with PD-1 expression. Conclusions: The PD-1 expression in the tumor could be a potential prognostic factor in gastric cancer.
Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): Safety, efficacy, and updated translational results.
Authors: Neuzillet Cindy , Seitz Jean-François , Fartoux Laetitia , Malka David , Lledo Gérard , Tijeras-Raballand Annemilai , De Gramont Armand , Ronot Maxime , Bouattour Mohamed , Dreyer Chantal , Amin Alexandre , Brunisholz - Bourget Philippe , Hadengue Alexandra , Roldan Nelly , Chibaudel Benoist , Raymond Eric , Faivre Sandrine J. 
Published: February 2017

343 Background: There is no validated option beyond gemcitabine plus platinum standard first-line combination for advanced cholangiocarcinoma (CK). Second-line 5FU-based chemotherapy yields a median progression-free survival (PFS) and overall survival (OS) of 3 and 6-7 months, respectively. Intrahepatic CK subtypes overexpress VEGF, providing a rationale for testing sunitinib as second-line treatment in patients (pts) with advanced intrahepatic CK. Methods: A multicenter phase 2 study was designed for pts with locally advanced or metastatic intrahepatic CK after failure of first-line gemcitabine-based chemotherapy. Sunitinib was given at the dose of 37.5 mg/day continuously until disease progression or limiting toxicity. Pts were required to be ECOG PS 0-1 and with adequate liver function (alkaline phosphatase and transaminases < 5ULN, bilirubin <1.5ULN). Main objective was to exceed a median OS of 6.3 months. Secondary endpoints were PFS, response (RECIST 1.1 & Choi criteria), safety, pharmacokinetics (PK) and biomarker analysis (VEGFA, VEGFC, sKIT, HGF, SDF1, and osteopontin). Results: 53 pts were enrolled, with 34 pts evaluable for intermediate safety and efficacy analysis. Median age was 62 years (range 36–80), with 19 females/15 males. ECOG PS was 0/1 in 23/11 pts. Sixteen pts had prior surgical resection and 8 pts received adjuvant chemotherapy. Five pts (15%) had partial responses and 24 stable diseases (71%) by RECIST (disease control rate 85%). Ten pts had disease control > 6 months (range 6-14 months). With a median follow-up of 15.4 months, median OS was 9.6 months [95%CI: 5.8-13.1]. Median PFS was 5.2 months. Frequent adverse events were grade (Gr) 1-2 asthenia (80% of pts), mucositis (80%), diarrhea (60%), and hand-foot syndrome (43%). Gr 3/4 asymptomatic hematological toxicity occurred in 25% of pts (neutropenia n=8, thrombocytopenia n=7), Gr 3 hypertension was observed in 7 pts, and Gr 3 asthenia in 4 pts. Updated PK and biomarker analysis will be presented at the meeting. Conclusions: Second line sunitinib is well tolerated and shows promising activity with a 9.6-month OS in pts with advanced intrahepatic CK. Clinical trial information: NCT01718327.