bluuebunny/crossref_metadata_2025 huggingface dataset:
Simple blood test for diagnosis of gastrointestinal and pancreas cancer using surface-enhanced Raman scattering.
Authors: Ito Hiroaki , Hasegawa Katsuyuki , Hasegawa Yuuki , Kimura Satoshi , Onimaru Manabu , Ohmori Tohru , Ikeda Haruo , Saito Mitsuo , Kitamura Yohei , Sato Chiaki , Gomi Kuniyo , Sakaue Satoshi , Isozaki Masayuki , Matsukawa Masaaki , Inoue Haruhiro
Published: February 2017

32

Background: Surface-Enhanced Raman Scattering (SERS) has been widely applicated in industrial microanalysis, and researched to apply for various fields, for example biological research. We tried to detect the SERS spectra from blood samples obtained from patients with cancers or benign diseases by using a low intensity laser beam, and compared the SERS spectra pattern among the samples from the patient group. Methods: Blood samples were obtained from patients with gastric cancer (n=30), colorectal cancer (n=20), pancreas cancer (n=5) and benign diseases (n=20). All blood samples were centrifuged at 1600g for 7 minutes, and serum samples were extracted. The serum samples were placed on the phosphor bronze chip with silver nanoscale hexagonal columns (NHCs), and SERS spectra was detected by using low intensity helium-neon red laser beam with 633 nm as wavelength. Results: SERS spectra were detected in all samples within 4 minutes from irradiation. Limiting dilution of detecting SERS was 1/1000 of serum. SERS spectra patterns were different between cancer and benign disease patients, and maximum peak level of the SERS in the samples from cancer patients were significantly higher than those from benign disease patients. There was a difference on the wavelength of Raman shifting at the peak intensity and the pattern of the SERS spectra between the samples from the patients with cancers and benign diseases. And furthermore, there was a difference on the SERS spectra pattern among the samples from the patients with gastric, colon and pancreas cancer. Additionally, it was suggested that the elements combined with the silver NHCs were histone-and-DNA complex. Conclusions: Our data suggest that our simple blood test using SERS is useful for diagnosis of gastrointestinal and pancreas cancer. We have been trying molecular analysis of the element combined with the silver NHCs by next-generation sequencer. Clinical trial information: UMIN000009818.
Phase IB study of FOLFIRINOX plus PF-04136309 in patients with borderline resectable and locally advanced pancreatic adenocarcinoma (PC).
Authors: Wang-Gillam Andrea , Nywening Timothy M. , Sanford Dominic E. , Lockhart Albert C. , Suresh Rama , Tan Benjamin R. , Lim Kian-Huat , Sorscher Steven , Fowler Kathryn , Amin Manik A. , Roshal Anna , Adkins Douglas , Nieman Rebecca , Panni Roheena Z. , DeNardo David G , Goedegebuure Peter S. , Hawkins William G. , Fields Ryan C. , Strasberg Steven M. , Linehan David
Published: February 2017

338

Background: PF-04136309 (a novel CCR2 inhibitor) has shown anti-tumor activity in the preclinical setting in PC by depleting inflammatory monocytes and tumor associated macrophages (TAM) that contribute to an immunosuppressive tumor microenvironment. We hypothesized that combining PF-04136309 with FOLFIRINOX may improve clinical outcomes in PC. Methods: This is a phase Ib study with a dose de-escalation schema given the minimal toxicity of PF-04136309. The study includes Arm A (FOLFIRINOX only), Arm B (FOLFIRINOX plus PF-04136309) and an expansion cohort at the rapid phase II dose (RP2D). FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, LV 400 mg/m2, 5FU bolus 400 mg/m2 and 2,400 mg/m2over 46 hours) was administered every two weeks. PF-04136309 at 500 mg twice daily via oral route was the starting dose level for Arm B. Treatment response was assessed after 6 cycles of treatment. Bone marrow biopsy and EUS/FNA at baseline and post 2 cycles were performed to assess the impact of treatment on the prevalence and function of inflammatory monocytes in the blood, bone marrow and tumor. Results: A total of 41 patients have been enrolled in the study to date (6 in Arm A, 8 in Arm B and 27 in the expansion cohort). The mean age of patients was 61.1 (range 45-75 yrs), male/female: 21/20, Caucasian/others: 32/9, borderline/locally advanced: 7/34. PF-04136309 at the starting dose did not result in additional toxicities when combined with FOLFIRINOX and it is the RP2D. Out of 35 patients treated with FOLFIRINOX plus PF-04136309, 6 are still in treatment, 6 are non-evaluable (withdrew consent or had poor tolerance). Of the 23 evaluable patients, 21 (91.3%) completed all 6 cycles; 12 (52.2%) had PR by RECIST and 11 (47.8%) had SD. Curative resections were achieved in 4 out of 5 with borderline resectable and 2 with locally advanced PC. Moreover, blockade of TAM mobilization was demonstrated by FACS and qPCR analysis of baseline and post-treatment FNA biopsies. Conclusions: Combing PF-04136309 with FOLFIRINOX is safe and tolerable. The regimen resulted in impressive treatment response and it further validated CCR2 inhibition in PC. Survival data and more correlative science will be forthcoming. Clinical trial information: 01413022.
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.
Phase I/II study of ISIS 183750 in combination with irinotecan for advanced solid tumors or colorectal cancer: Final results.
Authors: Makarova-Rusher Oxana V. , Duffy Austin G. , Ulahannan Susanna Varkey , Fioravanti Suzanne , Walker Melissa , Raffeld Mark , Compton Kathryn , Lee Sunmin , Tomita Yusuke , Trepel Jane B. , Figg William Douglas , Greten Tim F.
Published: February 2017

639

Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.
A randomized controlled trial to evaluate laparoscopic versus open complete mesocolic excision (CME) for stage II, III colorectal cancer (CRC): First efficacy results from Japan Clinical Oncology Group Study JCOG0404.
Authors: Inomata Masafumi , Katayama Hiroshi , Mizusawa Junki , Watanabe Masahiko , Sugihara Kenichi , Konishi Fumio , Yamamoto Seiichiro , Saito Shuji , Fujii Shoichi , Saida Yoshihisa , Hasegawa Hirotoshi , Etoh Tsuyoshi , Moriya Yoshihiro , Kitano Seigo
Published: February 2017

656

Background: The benefits of laparoscopic surgery (LAP) compared with open surgery (OP) have been suggested; however, the long-term survival of LAP for advanced CRC requiring CME is still unclear. We conducted a trial to confirm the non-inferiority of LAP to OP in terms of overall survival (OS). Favorable short-term complications and clinical benefits of LAP have already been demonstrated. Overall survival, the primary endpoint, and late post-operative complications are presented here. Methods: Only accredited surgeons from 30 Japanese institutions participated. Eligibility criteria included histologically proven CRC; tumor located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or deeper lesion without involvement of other organs; N0-2 and M0; tumor size =<8 cm; age 20-75 years. Patients with pathological stage III received adjuvant chemotherapy with fluorouracil plus leucovorin. The planned sample size was 1,050 patients with a power of 80%, a one-sided alpha of 5% and the non-inferiority margin of the hazard ratio (HR) as 1.366. Results: A total of 1,057 patients were randomized (OP 528, LAP 529) between October 2004 and March 2009. Conversion to OP was needed for 29 patients in LAP arm. 5-year OS was 90.4% (95% CI: 87.5-92.6%) in OP, and 91.8% (89.1-93.8%) in LAP. The non-inferiority of laparoscopic CME in OS was not demonstrated (HR: 1.06 [90% CI: 0.79-1.41(>1.366)], p=0.073). 5-year RFS was 79.7% (76.0-82.9) in OP and 79.3% (75.6-82.6) in LAP (HR: 1.07 [95%CI: 0.82-1.38]). Proportion of grade (G) 2-4 late complications was 22.6% (OP 12.5%, LAP 10.1%). Late complications (G2-G4) included constipations (OP 6.0%, LAP 4.4%), diarrhea (OP 2.9%, LAP 2.7%), paralytic ileus (OP 1.2%, LAP 1.7%), and bowel obstruction of small intestine (OP 3.1%, LAP 2.1%). Conclusions: The non-inferiority of laparoscopic CME in OS was not demonstrated for stage II, III CRC. However, since OS of both arms are almost identical and better than expected, laparoscopic CME is acceptable as a treatment option for stage II, III CRC. Clinical trial information: C000000105.
A phase I study of cetuximab (cet) in combination with S-1 and irinotecan (iri) (SIRC) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-10).
Authors: Tsuji Akihito , Nakamura Masato , Masuishi Toshiki , Kotaka Masahito , Shimada Ken , Kochi Mitsugu , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Nakajima Toshifusa
Published: February 2017

735

Background: S-1 combined with iri and cet are also effective treatments in patients (pts) with mCRC. However, diarrhea is one of the concerned toxicities overlapping of each 3 drugs. To evaluate the safety of this combination, we conducted a multi-center phase I study. Methods: The phase I trial was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) based on a 3+3 cohort expansion design. The cohort at the level of speculated RD was expanded to 10 pts. The main criteria for eligibility was as follows; histologically confirmed mCRC, ECOG PS 0-1, KRAS wild type. The dose adaptation schedule of iri was 125 mg/m2 for level 1 and 150 mg/m2 for level 2. Patients received cet (initial dose 400, and 250 mg/m2 weekly) followed by SIR (iri on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. Dose-limiting toxicity (DLT) was defined as any of the following findings during cycle 1:1) neutrophil count less than 500/mm3 for 4 days or more; 2) febrile neutropenia; 3) platelet count less than 50,000/mm3; 4) grade 3 or 4 diarrhea; 5) grade 3 or 4 of nonhematologic toxicity, excluding nausea, vomiting, diarrhea, anorexia, and skin toxicities; 5) the number of S-1 administration less than two-third; 6) the delayed start of the second course greater than 1-week as the drug-related toxicity. Results: The MTD was not determined, because DLT was not observed in level 1 (n=3) and level 2 (n=6). Level 2 was speculated to be the RD. Because 4 pts in the expansion cohort experienced no DLT, level 2 was determined as the RD. The completion rate of cycle 4 was 76.9%. Median dose intensities at the level 2 were 97%, 89%, and 91% for iri, S-1, and cet, respectively. During cycle 4 at level 2, grade 3 or worse adverse events were anorexia (20%) and dry skin (10%). The response rate according to RECIST criteria was 62.7% (95% CI, 50.4 to 75.1). Conclusions: We determined 150 mg/m2 of irinotecan as the RD for SIRC. This combination is tolerable at full doses of cet and SIR, with manageable toxicities. We are now planning the further phase II/III trial including SIRC as an experimental arm. Clinical trial information: UMIN000010639.
Management of chemotherapy‐induced anemia (CIA) with biosimilar epoetin alfa (Binocrit) in patients with colorectal cancer (CC): An interim analysis of an ongoing French national observational study (The OncoBOS study).
Authors: Metges Jean Philippe , Crumbach Jean-Pierre , Petran Daniela , Boulanger Vincent , Stamerra Otilia , Desramé Jérôme , Nahon Sophie , Aubron-Olivier Camille , Fernet Domitille , Boschetti Gilles
Published: February 2017

742

Background: OncoBOS is a prospective, non-interventional study describing Binocrit use in routine practice in France in patients receiving chemotherapy treatment (CT) for solid tumors, lymphoma, or myeloma. This interim sub-analysis focuses on patients with CC, receiving usual chemotherapeutic agents. Methods: Patients ≥18 years with CC, CIA, and eligible for treatment with Binocrit were included in this analysis. Patients characteristics, data on CIA and its management, and predominant factors considered by the physician in prescribing Binocrit were recorded at baseline (BL), 3-4 weeks and 12 (±1) weeks later. Hemoglobin (Hb) outcomes assessed included the proportion of patients achieving a Hb increase ≥1 and ≥2 g/dL, and the mean Hb change from BL. Results: 96 patients with CC (51 males [53.1%], mean age 68.5 years) from 28 sites were recruited from September 2011 to April 2014. Mean and median BL Hb levels were 9.9 g/dL and 10 g/dL, respectively. The mean increase in Hb level was 1.2 g/dL after 1 month and 1.7 g/dL after 3 months (p<0.001 vs. BL) of Binocrit treatment. A Hb increase ≥1 g/dL was achieved by 56.8% of patients at week 3-4 and 77.6% at week 12; a Hb increase ≥2 g/dL was achieved by 17.9% and 47.4% of patients at the same time points. Patients received a median dose of 30,000 IU Binocrit once weekly. Four of the 96 patients (4.2%) required a dose increase. Transfusion rates remained low at 2.1% and 1.1% at week 3-4 and week 12, respectively. Oral and intravenous (IV) iron supplementation rates were low: oral iron was received by 4.2% and 4.7% of patients at week 3-4 and week 12, respectively; 15.6% and 9.3% of patients received IV supplementation at the same time points. Physicians considered quality of life (49%), fatigue (24%), and avoidance of blood transfusion (15.6%) as predominant factors in the rationale for CIA management. Over the treatment period, no treatment-related adverse reaction was recorded. Conclusions: This sub-analysis indicates that Binocrit, used in routine practice, is effective and well tolerated for the treatment of CIA in patients with CC, whatever CT received.
Single-agent capecitabine use in patients age 70 or older with colorectal cancer.
Authors: Hall Marcia , Krell Daniel , Glynne-Jones Robert
Published: February 2017

764

Background: Colorectal cancer (CRC) is primarily a disease of the elderly, with a median age at diagnosis of 71. Administration of chemotherapy treatment in elderly patients with CRC is challenging due to multiple factors, including co-morbidities and a decline in organ function and is often associated with more toxicities and hospitalisations. Capecitabine monotherapy is an effective treatment in CRC but is associated with toxicities, commonly necessitating dose reduction (DR) in elderly patients. We present an audit of capecitabine prescribing in patients with CRC over the age of 70. Methods: The medical records of 43 patients over 70 receiving capecitabine monotherapy for CRC in our unit between November 2012 and August 2014 were analysed. The starting dose of capecitabine was established, and dose reductions prior to initial treatment were noted. Subsequent dose reductions, and toxicities necessitating such reductions were recorded. Results: 74 patients (37 male;37 female) were treated, 47 adjuvantly and 27 palliatively. The median age at treatment was 78. Patients received an average of 4.3 cycles (range 1-8), at an average starting dose of 1800mg (range 1000-2700mg). 43/74 (58%) patients received a DR from 1250mg/m2, prior to cycle one, with an average DR of 22% (range 0%-60%). The primary reason for DR was frailty (62%), inadequate GFR (35%), and poor performance status (3%). Secondary reasons included ischaemic heart disease and other comorbidities. 12/43 (28%) patients required a DR at subsequent cycles, due to diarrhoea (50%), fatigue (33%) and PPE (17%). 3/43 (7%) patients terminated their treatment early due to angina, PPE and diarrhoea respectively. 2/27 (9%) metastatic patients received capecitabine (625mg/m2) in combination with bevacizumab. Conclusions: Real-life dosing of capecitabine in the over 70’s, selected as fit but frail is more conservative than the guidelines recommend and was associated with considerable toxicity precluding dose escalation. Even at reduced starting doses toxicity was substantial and a third required a further dose reduction which questions the efficacy of adjuvant chemotherapy in this age group, despite a proactive education patient programme about diarrhoea and PPE.
Multicenter phase III trial of adjuvant chemoradiotherapy in stomach tumors 2 (ARTIST 2).
Authors: Park Se Hoon , Lee Su Jin , Kim Seung Tae , Lee Jeeyun , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki
Published: February 2017

TPS228

Background: Treatment of gastric cancer (GC) has some notable differences between Asia and Western countries including the extent of surgery and the type of adjuvant therapy. In ARTIST trial comparing adjuvant chemotherapy involving capecitabine plus cisplatin with chemoradiotherapy, we reported comparable disease-free survival (DFS) in Korean patients with D2-resected GC. In subset analyses, patients with node-positive disease and intestinal type GC may have benefit with the addition of radiotherapy to adjuvant chemotherapy. Methods: ARTIST 2 (ClinicalTrials.gov, NCT0176146) is a 3-arm, multi-center, open-label phase III trial comparing adjuvant chemotherapy involving S-1 (40 mg/m2 bid 4-weeks-on/2-weeks-off) for one year (arm A) with S-1 plus oxaliplatin (SOX, S-1 40 mg/m2 bid 2-weeks-on/1-week-off plus oxaliplatin 130 mg/m2 iv on day 1) for 8 cycles (arm B) and chemoradiotherapy (arm C). Arm C patients receive SOX for 2 cycles, then concurrent chemoradiotherapy 45 Gy with S-1 40 mg bid daily, followed by additional SOX for 4 more cycles. Patients are randomized 1:1:1 with 3 strata: stage (II or III), type of surgery (subtotal or total gastrectomy) and Lauren classification (diffuse or intestinal type). Eligibility criteria include gastric or gastro-esophageal junction adenocarcinoma, D2 or higher surgery with no residual disease, pathologic stages 2 or 3, lymph node positive disease. Primary endpoint is DFS, and secondary endpoints include overall survival, safety, QOL and molecular biomarkers. To test if experimental arms (arm B or C) lower the hazard of recurrence by 50% (i.e., HR 1.5) compared to arm A, we need 900 patients (300 per arm) with 90% of overall statistical power. First patient entered onto the study in Feb 2013. As of Aug 2014, a total of 118 (13% of target) patients were recruited by 8 Korean tertiary centers. Clinical trial information: NCT0176146.
LUME-Colon 1: A double-blind, randomized phase III study of nintedanib plus best supportive care (BSC) versus placebo plus BSC in patients with colorectal cancer (CRC) refractory to standard therapies.
Authors: Lenz Heinz-Josef , Tabernero Josep , Yoshino Takayuki , Oum'Hamed Zohra , Vlassak Soetkin , Sassi Mouna , Van Cutsem Eric
Published: February 2017

TPS794

Background: Clinical studies with anti-VEGF agents, such as regorafenib (R), demonstrate that angiogenesis is critical to CRC tumor growth and metastasis. R has provided proof of principle in patients with refractory CRC, but is associated with a specific safety profile; there is a need for an effective alternative treatment with a different safety profile. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF signaling that has shown clinical benefit and a manageable safety profile in trials in several tumor types, including NSCLC, ovarian cancer, and renal cell carcinoma. In a recent Phase I study of N in CRC, one patient had a confirmed partial response, and a clinically relevant anti-angiogenic effect was observed in 67% of patients. These findings and a manageable safety profile provide a rationale to examine N in refractory CRC. The objective of this study (NCT02149108; 1199.52) is to evaluate the efficacy and safety of N in patients with refractory CRC after failure with standard chemotherapy and biologic agents. Methods: 764 patients worldwide (≥18 years of age, ECOG-PS 0–1, and histologically/cytologically confirmed CRC adenocarcinoma unamenable to surgery and/or radiotherapy) will be randomized 1:1 to receive either N (200 mg bid) + BSC or placebo (bid) + BSC in 21-day courses until disease progression or undue toxicity. The study is powered to distinguish a clinically meaningful effect in the co-primary endpoints PFS and OS. Secondary endpoints are objective tumor response and disease control. Patients will be stratified at randomization based on previous R treatment (yes vs. no), time from onset of metastatic disease to randomization (<24 months vs. ≥24 months), and region. PFS and OS will be evaluated by the log-rank test to determine the effect of N independently at the two-sided alpha level of 0.05. Other assessments include frequency and severity of adverse events and changes in laboratory parameters to measure safety; health-related quality of life; and biomarker analyses that will focus on exploring predictive biomarkers and drug resistance mechanisms. Results are expected in 2016. Clinical trial information: NCT02149108.
AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Antonarakis Emmanuel S. , Lu Changxue , Chen Yan , Luber Brandon , Wang Hao , Nakazawa Mary , De Marzo Angelo M. , Isaacs William B. , Nadal Rosa , Paller Channing Judith , Denmeade Samuel R. , Carducci Michael Anthony , Eisenberger Mario A. , Luo Jun
Published: February 2017

138

Background: AR-V7 is a truncated form of AR that lacks the ligand-binding domain but remains constitutively active. We previously showed that detection of AR-V7 from circulating tumor cells (CTCs) in men with mCRPC was associated with primary resistance to enzalutamide and abiraterone. Here, we hypothesized that AR-V7[+] patients would retain sensitivity to taxane chemotherapy. Methods: We used a qRT-PCR assay to interrogate CTCs for AR-V7 mRNA in prospectively enrolled patients with mCRPC starting docetaxel or cabazitaxel. We sought associations between AR-V7 status and PSA response rates (the primary endpoint), PSA progression-free survival (PSA-PFS), and clinical/radiographic progression-free survival (PFS). Multivariable regressions were performed to determine the independent effect of AR-V7 status on clinical outcomes. 36 taxane-treated men were required to produce a 2-sided 95% CI for the difference in PSA response rates (between AR-V7[+] and AR-V7[–] men) with an upper bound of 60%, assuming that 30% of men would be AR-V7[+]. Results: 37 taxane-treated patients were enrolled, and 17 (45.9%) had detectable AR-V7 in CTCs. PSA responses were achieved in both AR-V7[+] and AR-V7[–] men (41% vs 65%, P=0.19). Median PSA-PFS was comparable in AR-V7[+] and AR-V7[–] men (4.5 vs 6.2 mo, HR 1.72, P=0.32). Likewise, median PFS was comparable in AR-V7[+] and AR-V7[–] men (5.1 vs 6.9 mo, HR 2.65, P=0.11). After incorporating data from our prior study in 62 abi/enza-treated patients, it was observed that clinical outcomes in AR-V7[+] men were superior with taxanes than with abi/enza, while outcomes did not differ by treatment type in AR-V7[–] men. For example, in AR-V7[+] men, PSA responses were higher in taxane-treated versus abi/enza-treated men (41% vs 0%, P<0.001), and median PSA-PFS and PFS were longer in taxane-treated men (HR for PSA-PFS = 0.19, P=0.001; HR for PFS = 0.21, P=0.003). Conclusions: Detection of AR-V7 in CTCs from men with mCRPC is not associated with primary resistance to taxane chemotherapy, and such patients may retain sensitivity to taxanes. Further, in AR-V7[+] men, taxanes appear to be more efficacious than abi/enza. AR-V7 may represent a treatment-selection marker in mCRPC.