bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deposition characteristics and resulting DNA damage patterns of liposomal irinotecan (nal-IRI) in pancreatic cancer xenografts.
Authors: Leonard Shannon C. , Paz Nancy , Klinz Stephan G , Gaddy Daniel , Lee Helen , Hendriks Bart S , Fitzgerald Jonathan B 
Published: January 2019

335 Background: Liposomal irinotecan (nal-IRI, ONIVYDE) is approved in the US, EU and other countries in combination with 5-fluorouracil/leucovorin for treatment of patients with metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. We report pharmacokinetic and extended pharmacodynamic effects of nal-IRI in pancreatic tumor models compared to non-liposomal irinotecan HCl. Methods: AsPC-1, BxPC-3 and CFPAC-1 tumors were grown in NOD-SCID mice. For efficacy animals were dosed q7d with 25-50 mg/kg irinotecan HCl or at 5x lower doses of nal-IRI. For PK-PD studies doses of 10-50 mg/kg of fluorescently-labeled nal-IRI were used; samples were collected up to 72 hr for irinotecan HCl and up to 168 hr for nal-IRI. Tumor samples were evaluated for liposome localization, macrophage and tumor markers, vessels, DNA damage and apoptosis. Results: nal-IRI yields sustained circulation and delivery of its payload to tumors compared to irinotecan HCl. This results in improved control of growth rates across a range of pancreatic tumor models even at 5x lower doses. DNA damage in BxPC-3 tumors has a comparable extent with both formulations, but is maximal at 6 hr after irinotecan HCl (50 mg/kg) and at 72 hr after nal-IRI (10 mg/kg). Liposomes deposit in tumors heterogeneously around functional vessels. Accumulation peaks at 6 - 24 hr with similar deposition patterns in cell- or patient-derived xenografts. Liposomes are predominantly taken up by macrophages and to a lesser extent by tumor or other stromal cells. DNA damage is mostly confined to tumor cells, a majority of which have not internalized liposomes. DNA damage and apoptosis are seen only minimally in non-tumor cells even when displaying high liposome uptake. Conclusions: nal-IRI improves tumoral deposition of its payload in pancreatic tumor models. Deposition is heterogeneous and restricted to perivascular areas. DNA damage predominantly in tumor cells outside of the liposomal deposition area suggests sufficient intratumoral levels of the SN-38 active metabolite, possibly after payload release by stromal macrophages and concomitant conversion. Effects of repeated dosing cycles should be explored.
A randomized phase II clinical trial of gemcitabine, oxaliplatin, erlotinib combination chemotherapy versus gemcitabine and erlotinib in previously untreated patients with locally advanced or metastatic pancreatic cancer.
Authors: Lim Sung Hee , Yun Jina , Lee Min-Young , Kim Han Jo , Kim Kyoung Ha , Kim Se Hyung , Lee Sang-Cheol , Bae Sang Byung , Kim Chan Kyu , Lee Namsu , Lee Kyu Taek , Park Sung Kyu , Hong Dae Sik , Choi Hyun Jong , Moon Jong Ho 
Published: January 2019

344 Background: Erlotinib is the only targeted agent in combination with gemcitabine showing significantly improved outcomes in pancreatic cancer. Although combining platinum agent with gemcitabine has not provided clear survival benefit over gemcitabine alone, gemcitabine plus platinum resulted in improved response rate and progression-free survival (PFS). We tried to evaluate whether the addition of oxaliplatin to gemcitabine/erlotinib confers a clinical benefit to patients with locally advanced or metastatic pancreatic cancer. Methods: Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned to receive GEMOX-T (gemcitabine 1000mg/m2 IV and oxaliplatin 50mg/m2 IV on day 1, 8 plus erlotinib 100mg daily, every 3weeks) or GT (gemcitabine 1000mg/m2 IV on day 1, 8 plus erlotinib 100mg daily, every 3weeks). The primary endpoint was overall response and secondary endpoints included PFS, overall survival (OS) and toxicity. Results: Between May 2013 and April 2016, 65 patients were randomly assigned to treatment group (33 in GEMOX-T arm, 32 in GT arm). The median age of all patients was 61 years (range, 41-76) and about 80% of patients had metastatic disease. The overall response rate was 18.2 % in GEMOX-T arm and 6.2% in GT arm ( P = 0.051). The disease control rate was significantly superior in GEMOX-T arm compared to GT arm (72.7% vs. 43.8%, P = 0.019), with 1 patient in GEMOX-T group continuing the treatment with stable disease. After a median follow up of 19.7 months, there was significant difference in PFS: the median PFS were 3.9 months for GEMOX-T arm and 1.4 months for GT arm (Hazard ratio: 0.58, 95% CI 0.35-0.96, P = 0.037). However, it did not translate to improvement of OS (median OS; 6.2 m for GEMOX-T arm, 5.1 m for GT arm, P = 0.118). The most common grade ≥ 3 hematologic adverse events were neutropenia (16.9%) and anemia (13.8%). Conclusions: The addition of oxaliplatin to 1st line gemcitabine/erlotinib regimen demonstrated higher response rate and significantly improved PFS in patients with locally advanced or metastatic pancreatic cancer.
Independent imaging review (IIR) results in a phase 3 trial of lenvatinib (LEN) versus sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC).
Authors: Lencioni Riccardo , Kudo Masatoshi , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Cheng Ann-Lii , Piscaglia Fabio , Han Guohong , Ikeda Masafumi , Simon Krzysztof , Komov Dmitry , OuYang Xuenong , Evans T.R. Jeffry , Sung Max W. , Binder Terri A. , Damon Andrew , Kraljevic Silvija , Ren Min , Ryoo Baek-Yeol 
Published: January 2019

345 Background: LEN showed treatment effect on OS by statistical demonstration of noninferiority to SOR in a phase 3 study in pts with uHCC, with significant improvement ( P < 0.00001) in median PFS (7.4 vs 3.7 mos; HR: 0.66; 95% CI, 0.57−0.77), median TTP (8.9 vs 3.7 mos; HR: 0.63. 95% CI, 0.53−0.73), and ORR (24% vs 9%). Tumor assessments were by investigator review (IR) per modified RECIST (mRECIST). We present IIR results to assess concordance for IR vs IIR and mRECIST vs RECIST 1.1 by IIR. Methods: In this open-label study, pts with uHCC, ≥ 1 measurable target lesion, BCLC stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy were randomized 1:1 to LEN (body weight ≥60 kg: 12 mg/d; <60 kg: 8 mg/d) or SOR 400 mg twice daily. Primary endpoint was OS. Secondary efficacy endpoints were PFS, TTP, and ORR by mRECIST. IR tumor assessments were done every 8 wks. Post hoc exploratory blinded IIR studies were done using mRECIST and RECIST 1.1 (first timepoint at wk 8). Results: A total of 954 pts enrolled (LEN: 478; SOR: 476), of which 952 (99.8%) pts were IIR assessable (table). Adjudication rate (AR; percentage of cases adjudicated due to disagreement) for timepoint of PD was similar for mRECIST (47%) and RECIST 1.1 (45%); for responder (CR or PR)/nonresponder (SD, PD, or not evaluable [NE]), it was 32% for mRECIST and 17% for RECIST 1.1. PFS and TTP results were nearly the same per mRECIST by IIR as by IR and the same by IIR per mRECIST and RECIST 1.1. Very good concordance was seen between IIR and IR in best overall response (BOR) per mRECIST with the greatest discordance due to more pts being assessed as PR than SD for LEN. Conclusions: IIR supports IR results. ORR was higher in both arms by IIR vs IR but relative ORR was preserved in LEN vs SOR. Higher AR for IIR per mRECIST on response may be due to the greater number of responders or disease complexity. Median PFS and TTP were the same by IIR per mRECIST and RECIST 1.1, showing these data can be compared between methods. Clinical trial information: NCT01761266. [Table: see text]
The Canadian Cancer Trials Group PA.7 trial: Results from the safety run in of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D), and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Renouf Daniel John , Dhani Neesha C. , Kavan Petr , Jonker Derek J. , Wei Alice Chia-chi , Hsu Tina , Tang Patricia A. , Graham Barbara , Gallinaro Lisa , Hasan Tasnia , Li Weiwei , Hart Kate , Tu Dongsheng , O'Callaghan Christopher J. 
Published: January 2019

349 Background: GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) is assessing the efficacy and safety of GEM and Nab-P vs. GEM, Nab-P, D, and T in patients (pts) with mPDAC (n = 190). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) are eligible. A safety run in was planned for 10 pts receiving GEM, Nab-P, D and T. The study is then planned to randomize pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate and quality of life. Results: 11 pts were enrolled in the safety run in (2 final pts enrolled on the same day). Median (Med) age = 59; 9 male/ 2 female; 2 ECOG 0/ 9 ECOG 1; no pts had prior adjuvant therapy. Med follow-up was 8.3 months at the time of data lock. Med number of treatment cycles was 6 (3-10). The most common Grade 3 or greater adverse events included fatigue (27%), anemia (36%), abnormal WBC (27%), hyponatremia (27%), hypoalbuminemia (45%), and abnormal lipase (45%). 1 pt (9.1%) experienced grade 3 colitis. 8/11 pts (73%) had a partial response, with the med duration of 7.4 months. Disease control rate was 100%. Med PFS was 7.9 months (95% C.I. 3.5-9.2 months). 6-month survival rate was 80% (95% C.I 40.9%-94.6%). Med OS has not been reached. Conclusions: The combination of GEM, Nab-P, D and T was well tolerated and promising efficacy signals were noted. The originally designed randomized phase II study is ongoing, and an international randomized phase III trial is planned. Clinical trial information: NCT02879318.
A phase II trial of gemcitabine (G), cisplatin (C), and nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs): Updated survival analysis.
Authors: Shroff Rachna T. , Javle Milind M. , Xiao Lianchun , Kaseb Ahmed Omar , Varadhachary Gauri R. , Wolff Robert A. , Raghav Kanwal Pratap Singh , Iwasaki Michiko , Masci Peter , Ramanathan Ramesh K. , Ahn Daniel H. , Bekaii-Saab Tanios S. , Borad Mitesh J. 
Published: January 2019

350 Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 30) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 30). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with 51 being response-evaluable having received more than 1 cycle of therapy (age: median 60 yrs [range 31-77], ECOG PS 0/1 (22/38), M/F (33/27), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (38/9/13). Median follow-up was 14 mos and median number of treatment (trmt) cycles = 5.24. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/30 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 3 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 19 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. The mPFS = 11.4 mos (95% CI: 6.1, 16.1) and mOS = 19.2 (95%CI: 13.6, NA), 1-year survival rate 67.6%. 51 pts evaluable for response: disease control rate (PR+CR+SD)-84.3% and RR-39%. 12 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging efficacy having met its mPFS endpt and an impressive mOS higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.
Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).
Authors: Giommoni Elisa , Maiello Evaristo , Vaccaro Vanja , Rondini Ermanno , Vivaldi Caterina , Tortora Giampaolo , Toppo Laura , Giordano Guido , Latiano Tiziana Pia , Antonuzzo Lorenzo , Lamperini Cinzia , Boni Luca , Di Costanzo Francesco 
Published: January 2019

351 Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.
Living with neuroendocrine tumors: Assessing quality of life (QoL) through a mobile application.
Authors: Adams Jared , Ray David , Willmon Renee , Kaleis Linda , Gautam Anand , Pulgar Sonia J. , Dasari A. 
Published: January 2019

359 Background: The study aim was to understand neuroendocrine tumor (NET) patients’ (pts) QoL through PROMIS-29, symptom tracking and patient journaling via the Carcinoid Health Storylines mobile application (app). Methods: This 12-week prospective, observational study was conducted among US NET pts recruited through the Carcinoid Cancer Foundation on either Lanreotide depot (L) or octreotide LAR (O) via surveys at baseline, week (w) 6, and w 12 with PROMIS-29 and symptom questionnaires at baseline, w 4 & w 8. Pts were asked to monitor symptoms, mood, bowel movement frequency, food, activity and sleep in their app 5x / week. Demographics and medical history were collected at baseline. Results: Of the 120 NET pts, 78% were female (mean age=57); 76% were gastroenteropancreatic NETs and 88% with metastases. L and O use was at 41% and 59% respectively. 82% completed ≥ 1 follow-up survey; the most common symptoms at baseline were fatigue (76.7%), diarrhea (62.5%), abdominal discomfort (64.1%) and trouble sleeping (57.5%). The baseline PROMIS-29 assessment revealed high proportions endorsing clinically significant depression (17.7%), anxiety (24.2%), fatigue (58.8%), dissatisfaction with social role (i.e. daily routine, 42.2%), difficulty with physical functioning (i.e. run errands, 16%) and insomnia (34.9%). Thus, 26.9% reported their QoL being poor and yet, a high percentage of patients were hopeful and reported their life as being meaningful (72.3%). Reported symptoms decreased significantly from initial to subsequent surveys (e.g. 59.3% to 33% for diarrhea; p=0.002). App tracking effectively captured day to day variations in reported symptoms and weekly averages correlated well with symptom surveys and PROMIS-29 scores. Seventy-seven pts journaled with 26 providing unsolicited injection experience (L =10; O =16). Conclusions: This study suggests that the use of apps for recording daily symptoms in NET pts, with decreased symptom reporting over time perhaps due to reduced recall bias from frequent tracking, or a potential therapeutic effect of journaling. Apps should be developed further to record the experiences and needs of NET pts.
Comparative effectiveness of nab-paclitaxel plus gemcitabine versus FOLFIRINOX in metastatic pancreatic cancer: A nationwide chart review in the United States.
Authors: Kim Sunnie S. , Signorovitch James , Yang Hongbo , Patterson-Lomba Oscar , Xiang Cheryl , Ung Brian , Parisi Monika , Marshall John 
Published: January 2019

376 Background: nab-Paclitaxel plus gemcitabine ( nab-P+G) and FOLFIRINOX (FFX) are among the most common first-line (1L) therapies for metastatic adenocarcinoma of the pancreas (mPC), yet there is no head-to-head trial comparing their efficacy and real-world data is limited. As new second-line (2L) therapies become available, it is important to understand the real-world effectiveness associated with different treatment sequences. Methods: This retrospective cohort study compared the efficacy and safety of 1L nab-P+G vs. FFX, overall and under specific treatment sequences. Medical records were reviewed by 215 physicians across the US who provided information for mPC patients who initiated 1L with nab-P+G or FFX between 04/01/2015-12/31/2015. The outcomes of interest were overall survival (OS) and tolerability. OS was evaluated using Kaplan-Meier curves, and compared between cohorts using Cox proportional hazards model adjusting for baseline characteristics. Results: Medical records were reviewed for 654 patients receiving nab-P+G (n = 337) or FFX (n = 317) as 1L therapy for mPC. Patients in the nab-P+G cohort were older, less likely to have ECOG ≤ 1 and had more comorbidities than patients in the FFX cohort. There was no statistically significant difference in OS (adjusted HR = 0.99, p = 0.96), with median OS (mOS) being 12.1 and 13.8 months for nab-P+G and FFX, respectively. Among the subgroup of patients with ECOG ≤ 1, mOS was 14.1 and 13.7 months, respectively (adjusted HR = 1.00, p = 0.99). Among patients with 1L nab-P+G and FFX, 36.1% and 41.3% received 2L therapy and experienced mOS of 16.3 and 16.6 months, respectively (HR = 1.04, p = 0.76). Among commonly observed adverse events (AEs) (≥ 5% of patients in both cohorts), the rates of diarrhea, fatigue, mucositis, nausea and vomiting were higher in the FFX than nab-P+G cohort (all p < 0.05). Conclusions: In a nationwide sample of mPC patients, real-world survival outcomes were similar between patients receiving 1L nab-P+G or FFX. both overall and among patients who went on to receive active 2L treatments. In addition, nab-P+G was associated with significantly lower rates of common AEs compared with FFX.
Costs of care with liver directed therapy (LDT) and sorafenib (S) in patients (pts) with hepatocellular carcinoma (HCC).
Authors: Singavi Arun K. , Szabo Aniko , Thomas James P. , Ritch Paul S. , Alqwasmi Abdel , White Sarah , Rilling William S. , George Ben 
Published: January 2019

383 Background: 80% of HCC pts present with advanced disease, treatment for such pts is palliative in nature. It is important to ascertain cost associated with such palliative therapy, considering modest survival benefit afforded by these treatments. Methods: Utilizing a non-Medicare national claims database (MarketScan), we analyzed a cohort of pts with HCC diagnosis (Dx). Consistent with literature, pts selected had at least two claims with HCC code (155.0) between 1/1/2010 and 12/31/2013, at least 2 claims with chronic liver condition within 1 year of the HCC Dx, no claims for other malignancies for 1 year before HCC Dx, and excluded hepatectomy or transplant. Follow up was from date of first HCC claim to end of continuous insurance coverage (EOC) with prescription drug claim tracking, or 12/31/2015. Pts were divided into 4 groups based on receipt of S, LDT, combined therapy (LDT+S), or best supportive care (BSC) after HCC Dx. Costs obtained by adding payment (Pmt) amounts for all inpatient, outpatient, and drug claims over follow-up period. Demographics and costs were summarized using means for continuous and frequencies for categorical variables. No adjustment for censoring was done, as no reason available for EOC. Average monthly cost was computed for each pt, and then averaged over pts. Results: Data were available for 6,987 patients over specified period, 67% were males, mean age was 60.2 years. Cost data by therapy received are summarized in the table below. Conclusions: Majority of HCC pts in this database were treated with BSC. Time to EOC tracked was significantly shorter for pts treated with S, compared to other 3 groups. Monthly cost associated with LDT, LDT+S, and S were not substantially different, but higher than cost associated with BSC. Prospectively collected survival, quality of life and cost data are important to ascertain true impact of palliative therapy in pts with advanced HCC. [Table: see text]