bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (PCa): Long-term analysis of the GETUG-AFU 15 phase III trial.
Authors: Gravis Gwenaelle , Boher Jean-Marie , Joly Florence , Oudard Stephane , Albiges Laurence , Priou Franck , Latorzeff Igor , Delva Remy , Krakowski Ivan , Laguerre Brigitte , Rolland Frederic , Theodore Christine , Deplanque Gael , Ferrero Jean-Marc , Pouessel Damien , Mourey Loic , Beuzeboc Philippe , Habibian Muriel , Soulie Michel , Fizazi Karim 
Published: February 2017

140 Background: ADT is standard treatment for metastatic PCa. Recently, the E3805 trial reported a survival benefit for (ADT+D) in high volume disease (HVD) patients, whereas the GETUG-15 trial did not demonstrate a survival improvement among a less selected group of patients (pts) with hormone-naïve metastatic PCa. We report an updated analysis of overall survival (OS) of the GETUG 15 trial and aligned the definition of HVD and low volume disease (LVD) subgroups. Methods: Long-termOS was analyzed in the intention-to-treat population (n=385 pts). Additionally, we retrospectively assessed the tumor volume as defined per E3805criteria in all patients enrolled in GETUG 15. Results: See Table. With a median follow-up of 82.9 months (95%CI [80.5-84.3]) (vs 50 months (95%CI [80.5-84.3] in the original analysis), 212 patients (55%) have died. The median OS is 46.5 [39.1-60.6] and 60.9 months [46.1-71.4] in the ADT and in the ADT + D arms, respectively (HR: 0.9 [95%CI: 0.7-1.2]). In HVD patients (n=183, 47.5%), median OS rates were 35.1 months [29.9-44.2] in the ADT alone arm and 39 months [28-52.6] in the ADT+D arm (HR: 0.8 [0.6-1.2]). Conclusions: With longer follow-up, the addition of docetaxel to ADT did not significantly improve OS in patients with hormone-naïve metastatic prostate cancer. In the retrospective analysis using aligned definition of volume of metastasis as E3805, the HVD outcomes were similar to E3805 for ADT alone and there was a non-significant 4 months increase in OS with ADT+D, in this underpowered subset. Clinical trial information: 00104715. [Table: see text]