bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final results of a phase Ib study of gemcitabine plus PEGPH20 in patients with stage IV previously untreated pancreatic cancer.
Authors: Hingorani Sunil R. , Harris William Proctor , Beck Joseph Thaddeus , Berdov Boris A. , Wagner Stephanie Ann , Pshevlotsky Eduard M. , Tjulandin Sergei , Gladkov Oleg , Holcombe Randall F. , Jiang Ping , Devoe Craig E. 
Published: February 2017

359 Background: Poor outcome in pancreatic cancer (PDA) has been associated with tumor stroma limiting access of chemotherapy drugs. PEGPH20 (PEG), PEGylated recombinant human hyaluronidase, which depletes hyaluronan (HA) in tumors, has demonstrated anti-tumor activity in preclinical PDA models. In a KPC model of PDA, PEG + gemcitabine (Gem) significantly prolonged survival compared to Gem alone. In Phase 1 PEG monotherapy studies, the MTD was 3µg/kg. The most common adverse events (AEs) were musculoskeletal events. Methods: This was a phase 1b study to determine the recommended phase 2 dose of PEG + Gem in patients (pts) with previously untreated Stage IV pancreatic cancer. PEG was given at 1, 1.6, or 3µg/kg IV twice weekly Wks 1–4 and weekly Wks 5–7, followed by 1 wk rest. Gem was given at 1000mg/m2IV once weekly for Wks 1–7, then 1 wk rest. Thereafter, PEG + Gem were given once weekly for 3 wks in 4-wk cycles. Dexamethasone was given pre and post PEG doses. Due to evolving SOC, the study was discontinued before initiation of the phase 2 randomization. Results: Twenty-eight pts were enrolled in the study. The majority of the patients (89%) had metastatic sites in the liver. Four, 4 and 20 pts received PEG at 1, 1.6 and 3µg/kg, respectively. The most common AEs related to PEG were muscle spasm (54%), myalgia (39%), arthralgia (29%), peripheral edema (29%), fatigue (25%), and extremity pain (18%). Median progression free survival (PFS) and overall survival (OS) were assessed and were 154 and 200 days, respectively. In an exploratory analysis, tumor biopsies from 17 pts were evaluated for HA levels (HAhigh or HAlow). 6 pts were determined to have HAhigh tumors and 11 pts had HAlow tumors. The median PFS and OS for HAhigh pts were 219 days (95% CI: 159-276) and 395 days (95% CI: 210-578). For HAlowpts median PFS and OS were 108 (95% CI: 14-163) and 174 days (95% CI: 34-293). Conclusions: PEG + Gem is generally well tolerated in advanced pancreatic cancer and shows promising clinical activity, especially in pts with HAhigh tumors. ClinicalTrials.gov Identifier: NCT01453153.
Modified gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer (MPC): A single-institution experience.
Authors: Krishna Kavya , Blazer Marlo A. , Wei Lai , Ahn Daniel H. , Wu Christina Sing-Ying , Ciombor Kristen Keon , Mikhail Sameh , Noonan Anne M. , Goldberg Richard M. , Bekaii-Saab Tanios S. 
Published: February 2017

366 Background: The combination of gemcitabine and nab-paclitaxel (GA) in first line treatment (tx) of MPC has a modest survival advantage over gemcitabine (gem) alone, but adds significant toxicities (tox) and increased cost. Based on data suggesting that biweekly administration (adm) of gem-based combinations preserves efficacy and improves tox profile, our institution adopted a modified regimen of GA (mGA). Methods: This is a retrospective analysis of a prospectively maintained database of patients (pts) with pancreatic cancer treated with gem (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1 and 15 of a 28-day cycle. Survival curves were estimated using Kaplan-Meier method, with alive pts censored at time of last follow-up. Cost of tx includes cost of drugs, adm, and tox. Results: Of total 69 pts treated with mGA for MPC, locally advanced, or borderline resectable disease, 63 pts were evaluable for tox (table 1). A total of 49 pts (47 evaluable for response) received mGA for previously untreated MPC, with median progression free survival of 4.8 months(mo) (95% CI 2.6,7.4) and overall survival of 11.1 mo (95% CI 5.3,not reached). Overall, 27% of pts experienced neurotoxicity with rate of grade 3 tox of < 2%, and 8% required growth factors (GF). Average cost savings was $5500/pt/month with mGA compared to standard GA, excluding GF cost which was lower with mGA. Conclusions: A less intense regimen of GA maintains efficacy while significantly improving tox profile and cost in pts with MPC. [Table: see text]
First-in-human study of MM-141: A novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3.
Authors: Isakoff Steven J. , Saleh Mansoor N. , Lugovskoy Alexey , Mathews Sara , Czibere Akos Gabor , Shields Anthony Frank , Bahleda Rastislav , Soria Jean-Charles , Arnedos Monica 
Published: February 2017

384 Background: MM-141 is a novel tetravalent bispecific monoclonal antibody that binds IGF-1R and ErbB3 and blocks both ligand dependent and independent IGF-1R/ErbB3/PI3K/AKT/mTOR signaling. MM-141 potentiated gemcitabine, nab-paclitaxel, docetaxel, irinotecan, tamoxifen, and everolimus in preclinical models. A multi-arm Phase 1 study is ongoing and the monotherapy dose-escalation portion of the study is completed. Hepatocellular carcinoma (HCC) patients were enrolled to an expansion cohort of Arm A to receive MM-141 as a monotherapy. Another arm of treatment combined MM-141 with gemcitabine and nab-paclitaxel. Methods: This is a Phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of MM-141 as monotherapy (n=15) and in combination with everolimus (Arm B) or with nab-paclitaxel and gemcitabine (Arm C). Three HCC patients in the Arm A expansion cohort received MM-141 as a monotherapy at a weekly dose of 20 mg/kg. These patients underwent mandatory pre-treatment and optional post-treatment biopsies. Patients in the dose-escalation portion of Arm C received MM-141 at a weekly dose of 12 or 20 mg/kg or a bi-weekly dose of 40 mg/kg in combination with gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2). Results: 15 patients with advanced solid tumors were enrolled into the dose escalation portion of Arm A. No dose-limiting toxicities were observed at any of the studied doses. The safety, tolerability, PK and PD profile support weekly and bi-weekly MM-141 dosing. The Arm A expansion enrolled 3 patients with sorafenib-refractory HCC. The analysis of pre- and post-treatment biopsies confirmed that IGF-1R and ErbB3 are expressed in patients previously exposed to sorafenib, and their levels are decreased after MM-141 exposure. Arm C, combining MM-141, gemcitabine, and nab-paclitaxel in a “3+3” dose-escalation design is on-going. Conclusions: MM-141 was well tolerated as a monotherapy and translational analysis of pharmacodynamic parameters suggest appropriate target engagement. Combination data with gemcitabine/nab-paclitaxel will be presented and preparations for a randomized Phase 2 study in front-line pancreatic cancer are underway. Clinical trial information: NCT01733004.
Recurrence-free survival results from a pilot study of adjuvant gefitinib in resected hepatocellular carcinoma (HCC).
Authors: Chopra Akhil , Lopes Gilberto , Bharwani Lavina D. , Chan Chung Yip , Chung Alexander , Cheow Peng Chung , Ho Choon Kiat , Liau Kui Hin , Woon Winston , Low Jee Keem , Chang Alex Yuang-Chi 
Published: February 2017

404 Background: Epidermal growth factor receptor (EGFR) pathway activation or over-expression plays an important role both in cirrhosis and hepatocellular carcinogenesis. We hypothesized that gefitinib (G), an oral tyrosine kinase inhibitor of EGFR, should reduce recurrence rate and/or prolong recurrence free survival when given in adjuvant setting. Methods: We designed a multicenter pilot study with a plan to enroll 40 HCC patients with complete resection and or with positive resection margin or residual disease < 0.5 cm (microscopic disease). Treatment consisted of G 250 mg orally daily for 6 months starting within 6 weeks of surgery. Follow-up included serum alpha-fetoprotein levels and imaging studies every 3 months for the first 2 years, every 6 months for years 3-5 and yearly thereafter. Main endpoints were recurrence-free survival, toxicity and correlative genetic studies. All statistical analyses were carried out on an intention-to-treat basis. The end point of recurrence free survival will be presented here. Results: 65 patients consented to the study, 40 were eligible and 25 were screen failures due to: diagnosis other than HCC (6 patients); poor post-operative recovery (9 patients); unresectable disease (3 patients); withdrawal of consent (2 patients); 1 patient had 2 cancers, and 4 developed metastatic disease.39 patients had R0 resection, whereas 1 patient had R1 resection. 4 female, 36 male. All patients completed 6 months of adjuvant G. Toxicities were mild; mainly grade 1 and 2 skin toxicity, diarrhea and pruritis. Median age - 63 years, median Child score-6, median TNM stage - II, median size - 4.9cm. 20 patients had liver cirrhosis. With a median duration of follow up of 4.1 years, the median recurrence free survival was 24 months. (95% CI 20-48). Conclusions: A median recurrence free survival of 24 months in patients with resected hepatocellular carcinoma treated with 6 months of adjuvant gefitinib compares favorably to historical data. Toxicity of gefitinib was mild and easily manageable. We await results of correlative genetic studies to identify potential prognostic and predictive biomarkers before considering embarking on a larger study. Clinical trial information: NCT00282100.
Nab-paclitaxel (Nab-P) and gemcitabine (G) as first-line chemotherapy (CT) in advanced pancreatic cancer (APDAC) elderly patients (pts): A “real-life” study.
Authors: Giordano Guido , Vaccaro Vanja , Lucchini Eleonora , Musettini Gianna , Bertocchi Paola , Bergamo Francesca , Giommoni Elisa , Santoni Matteo , Russano Marco , Campidoglio Serena , Santini Daniele , Zaniboni Alberto , Zagonel Vittorina , Cascinu Stefano , Vasile Enrico , Melisi Davide , Milella Michele , Febbraro Antonio 
Published: February 2017

424 Background: Nab-P and G represents a standard of care in first line APDAC treatment. Neverthless, activity, efficacy and safety of Nab-P + G have not been established in elderly pts and clinical trials on APDAC treatment contain fewer elderly pts compared with everyday clinical practice. Aim of this analysis is to evaluate outcomes and toxicities of elderly pts treated with first line Nab-P + G in a “real world” population. Methods: Clinical records of APDAC pts receiving Nab-P 125 mg/m2 and G 1000 mg/m2on days 1,8 and 15 of a 28 day cycle as first line CT were retrospectively reviewed, investigating activity (Disease Control Rate, DCR: Stable Disease + Partial Response + Complete Response, SD+PR+CR), efficacy (Progression Free Survival, PFS and Overall Survival, OS) and safety. Analysis was then performed in ≥ 70 years group of pts. OS and PFS were estimated with Kaplan-Meyer method with 95% CI. Cox-regression model was applied to the data with univariate and multivariate approach. Results: 105 pts (M/F:58/47), median age 64 (range 37-77) ECOG Performance Status of 0/1/2: 46/41/17 respectively were included in our analysis. 37 pts (35%) were ≥ 70 years old. In overall population Nab-P+G was administered for a median number of 6 cycles (range 1-12). 4 CR, 24 PR and 28 SD were observed (DCR: 53%), median PFS was 7 months (95% C.I. 5.93 - 8.08) and median OS was 11 months (95% C.I. 9.58 – 12.41). Pts aged ≥ 70 received a median number of 5 cycles (range 1 - 10). DCR was 48% (9 PR + 9 SD) with no differences in PFS (6.5 months, 95%C.I. 5.36 – 7.64, p=0.49) and OS (10 months, 95% C.I. 8.53 – 11.47 p=0.67) with < 70 years old pts. Treatment was mildly tolerated and toxicity profile appeared to be different in elderly pts than younger ones with more G3-4 non-haematological (27% vs 15% p=0.03) and fewer haematological (12% vs 29% p=0.004) events respectively. Conclusions: These data, evaluated under daily practice conditions, in absence of clinical trials on APDAC elderly pts, show that pts aged ≥ 70 may benefit of first-line Nab-P and G combination, as well as younger ones, both in terms of response and survival experiencing a tolerable, but significantly different toxicity profile.
Phase I trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer.
Authors: Mahipal Amit , Springett Gregory M. , Burke Nancy , Bertels Barbara , Wapinsky Georgine , Almhanna Khaldoun , Kim Richard D. 
Published: February 2017

467 Background: Despite recent advances, patients with metastatic pancreatic cancer have a very poor prognosis with a median survival of less than 1 year. Sex steroid hormones may play an important role in the growth and progression of pancreatic cancer. Anti-androgen drugs have demonstrated to have activity in pre-clinical pancreatic cancer models. In this Phase 1a/Ib trial, we evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel. Methods: Pts with histologically confirmed metastatic pancreatic adenocarcinoma were included in this trial as a first-line treatment. Standard 3+3 dose escalation design was used to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg daily. Gemcitabine 1,000 mg/m2 was administered IV on days 1, 8 and 15 of 28-day cycle. The dose of nab-paclitaxel was 125 mg/m2 IV on days 1, 8 and 15. The DLT period was 28-days or until the beginning of the second cycle. Imaging studies were performed every 2 cycles. Results: Eight pts with stage IV pancreatic cancer have been enrolled in this trial, 5 pts at the first dose level and 3 pts at the second dose level. The median age was 64 years (50-80 years). All pts were male with an ECOG performance status of 1. Five pts had liver metastases. One patient was non-evaluable for DLT. No DLTs have been observed. Grade 3 treatment related AEs include febrile neutropenia (n=1), Neutropenia (n=1), ALT elevation (n=1). Grade 2 anemia and thrombocytopenia was seen in one patient. Grade 1 AEs included anemia (n=2), neutropenia (n=4), thrombocytopenia (n=3), diarrhea (n=1), fatigue (n=2), pruritis (n=1), nausea (n=1), hyponatremia (n=1) and AST elevation (n=1). Three pts had restaging studies performed and all had stable disease by RECIST criteria. There were decreases in size of target lesions in all the 3 patients along with a decrease in CA 19-9 levels. Conclusions: Enzalutamide at the dose of 160 mg daily is safe to administer in combination with gemcitabine and nab-paclitaxel. No unexpected toxicity has been observed. Cytopenias secondary to chemotherapy is common. Preliminary signals of efficacy were observed with this combination. Clinical trial information: NCT02138383.
The nationwide genomic screening project for gastrointestinal cancer in Japan (GI-SCREEN): Simultaneous identification of KRAS, NRAS, BRAF, and PIK3CA mutation in advanced colorectal cancer (aCRC) (GI-SCREEN 2013-01).
Authors: Shitara Kohei , Fujii Satoshi , Denda Tadamichi , Kajiwara Takeshi , Yuki Satoshi , Nakajima Takako Eguchi , Takashima Atsuo , Kawasaki Kenta , Tamura Takao , Esaki Taito , Naruge Daisuke , Ebi Hiromichi , Kudo Toshihiro , Taniguchi Hiroya , Akagi Kiwamu , Yamanaka Takeharu , Ochiai Atsushi , Doi Toshihiko , Ohtsu Atsushi , Yoshino Takayuki 
Published: February 2017

578 Background: Recent studies confirmed that minor KRAS or NRAS mutations are associated with the resistance to anti-EGFR therapy for advanced colorectal cancer (aCRC). Although the impact of BRAF or PIK3CA mutation on efficacy of anti-EGFR therapy is still controversial, targeting agents for these mutations are under developing. Efficient screening systems for these relatively minor mutations with short turnaround time are necessary for the successful development of targeted therapies. Methods: This study was initiated in February 2014 as one of new nationwide genomic screening projects for advanced gastrointestinal cancer patients in Japan. Patients with aCRC who are planned to receive systemic chemotherapy were eligible. A total of 36 mutations of KRAS codon 61, 146, NRAS codon 12, 13, 61, BRAF codon 600, PIK3CA codon 542, 545, 546 and 1047 in genomic DNA of cancer cells were simultaneously analyzed at a quality-controlled central laboratory using Luminex (xMAP) technology in a single reaction using 50 ng of DNA. Results: As of August 31, 2014, this study is ongoing with the participation of 16 major cancer centers in Japan. A total of 437 aCRC patients were enrolled to this study and 361 tumor samples has been analyzed with success rate for genomic analysis of 100%. Among the 237 patients with KRAS exon 2 wild type, 28 patients (11.8%) had other RAS mutations and 15 patients (6.3%) had BRAF mutation. Twenty-seven of 437 patients had PIK3CA mutations (6.2%). One patient with BRAF mutation was enrolled in early clinical trials of BRAF inhibitors in combination with anti-EGFR antibody and most of other patients are still treated with standard chemotherapies, which may become future candidates for early clinical trials. Conclusions: From our preliminary results, this nationwide screening system enabled to detect rare mutations using limited amounts of samples from aCRC, which may facilitate the enrollment of patients in IND registration trials for targeted therapies as well as optimal individualized treatment.
HIF-1 alpha expression as a predictor of bevacizumab efficacy in metastatic colorectal cancer.
Authors: Marisi Giorgia , Ulivi Paola , Scarpi Emanuela , Passardi Alessandro , Frassineti Giovanni Luca , Valgiusti Martina , Zoli Wainer , Amadori Dino 
Published: February 2017

601 Background: Assome controversies exist regarding the efficacy of bevacizumab (B) for the treatment of metastatic colorectal cancer (mCRC), novel predictive biomarkers are needed to improve patient selection and optimize the use of this agent. We analyzed the potential usefulness of five circulating biomarkers as predictors of B efficacy and in monitoring the disease. Methods: Peripheral blood samples collected at different times (baseline, first clinical evaluation and disease progression) were available for 62 of the 376 patients enrolled in the prospective multicentric ITACa trial (NCT01878422) and randomized to receive FOLFOX4/FOLFIRI (CT) with or without B. Thirty-one of the 62 patients received CT plus B and31 received CT only (control group). All patients were evaluated for response according to RECIST criteria. mRNA was isolated and used for gene expression analysis of HIF-1α, COX2, VEGF-A, EPHB4 and eNOS by a quantitative RT-PCR method. Baseline expression levels of the markers and their modulation during therapy were correlated with objective response (OR) (median test), progression-free (PFS) and overall survival (OS) (Cox proportional hazards model). Potential predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Results: Non-responders (stable and progressive disease) had a median baseline HIF-1α expression significantly higher than responders (complete and partial response) (1.70 vs. 0.94; IQR 1.05-2.32 vs. 0.70-1.12) (p=0.016) in the B-treated group only. In univariate analysis, the high HIF-1α levels of this group were significantly associated with a shorter PFS (HR=1.96, 95% CI 1.17-3.30) (p=0.011) but not with OS. The HIF-1α-treatment interaction was p=0.088. No significant association was found between the other 4 genes and OR, PFS or OS. The results obtained on the modulation of gene expression during treatment are currently being analyzed. Conclusions: Our preliminary datasuggest that high pre-treatment HIF-1α expression levels could represent a predictive biomarker of resistance to bevacizumab. Partially funded by Roche S.p.A. and the Italian Medicines Agency (AIFA).
Variations in Y chromosome-related genes and clinical outcome in metastatic colorectal cancer.
Authors: Stremitzer Stefan , Stintzing Sebastian , Heinemann Volker , Zhang Wu , Yang Dongyun , Ning Yan , Sunakawa Yu , Sebio Ana , Yamauchi Shinichi , Matsusaka Satoshi , Parekh Anish , Mendez Angela , Elkhoueiry Rita , Lenz Heinz-Josef 
Published: February 2017

634 Background: Males have a higher cancer risk and worse clinical outcome in metastatic colorectal cancer compared to females, which has been related to loss of Y chromosome. In this study, we investigated single nucleotide polymorphisms (SNPs) in Y chromosome-related genes and their association with clinical outcome in patients from the FIRE-3 study (NCT00433927). Methods: Three SNPs (FOXL2 rs11924939 C>T, DMRT1 rs755383 T>C and DMRT1 rs3739583 A>T) were investigated in genomic DNA isolated from tissue samples of 295 patients (KRAS exon 2 wild-type) from the bevacizumab-arm of the FIRE-3 study. The median age of 195 (66.6%) male and 98 (33.4%) female patients was 65 months (range 27-76). Seventy-four (25.6%) patients had right-sided tumors and 215 (74.4%) had left-sided tumors. Results: The C/C genotype of DMRT1 rs755383 T>C was associated with significantly longer progression-free survival (PFS) in univariable (C/C 14.3 months, T/T or T/C 10.0 months, hazard ratio (HR) 0.58; P=0.033) and in multivariable Cox regression analysis adjusted for baseline characteristics (HR 0.63; P=0.026). This difference was confirmed in male patients (C/C 15.9 months, T/T or T/C 10.1 months, HR 0.58; P=0.038 and HR 0.53; P=0.023) and patients with left-sided tumors (C/C 14.6 months, T/T or T/C 10.4 months, univariable HR 0.61; P=0.044 and multivariable HR 0.60; P=0.046). The T/T genotype of FOXL2rs11924939 C>T was associated with longer PFS in patients with right-sided tumors (T/T 13.4 months, C/C or C/T 7.8 months, univariable HR 0.47; P=0.043 and multivariable HR 0.30; P=0.031) and shorter PFS in left-sided tumors (T/T 6.9 months, C/C or C/T 11.3 months, univariable HR 1.83; P=0.017 and multivariable HR 1.99; P=0.009). Conclusions: In this study, we demonstrated for the first time that SNPs in Y chromosome-related genes are associated with outcome in metastatic colorectal cancer in a gender- and location-specific way. These results highlight the value of the SNPs as potential biomarkers.