bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-line treatment with modified FOLFOX6 (mFOLFOX6) + panitumumab (pmab) or bevacizumab (bev) in wild-type (WT) RAS metastatic colorectal carcinoma (mCRC): Tumor response outcomes beyond RECIST.
Authors: Rivera Fernando , Karthaus Meinolf , Hecht J. Randolph , Fasola Gianpiero , Canon Jean-Luc Re , Koukakis Reija , Terwey Jan-Henrik , Schwartzberg Lee Steven 
Published: February 2017

660 Background: In the PEAK study, pmab + FOLFOX6 was associated with longer OS than bev + FOLFOX6 in first-line RAS WT mCRC. RECIST overall response rates (ORR) were similar between treatment arms. Here, we report exploratory analyses of tumour assessments beyond RECIST. Methods: PEAK was a randomised phase II study of first-line pmab + mFOLFOX6 vs bev + mFOLFOX6 in previously untreated mCRC. ORRs (investigator assessed), median duration of response (DoR; from first confirmed response to disease progression or death [secondary endpoint]) and depth of response (DpR; defined as the percentage of tumour shrinkage at nadir or progression) in RAS WT pts were calculated by treatment. Early tumour shrinkage (ETS) was defined as the proportion of patients with ≥30% tumour shrinkage at week 8 (exploratory analysis). Results: Overall, 169 pts withRAS WT mCRC were included in the ORR analysis and 154 had tumour-shrinkage data available at baseline and week 8. Significantly more pts in the pmab + mFOLFOX6 arm had ETS at week 8 vs. the bev + mFOLFOX6 arm (Table). ORRs were similar in the two arms, while DoR was significantly longer and DpR significantly greater with pmab + mFOLFOX6 (Table). ≥30% vs. <30% tumour shrinkage at week 8 was associated with longer median PFS (HR: 0.52 [95% CI: 0.29–0.92] and HR: 0.65 [95% CI: 0.38–1.13]) and OS (HR: 0.44 [95% CI: 0.15–1.32] and HR: 0.23 [95% CI: 0.08–0.66]) for pmab + mFOLFOX6 and bev + mFOLFOX6, respectively. Conclusions: Although ORR appeared to be similar or only numerically improved in the pmab arm of PEAK, the responses observed appeared to occur earlier, last longer and be deeper in our exploratory analyses. This is consistent with the observed OS and PFS benefit, and with data reported earlier from the FIRE3 study. Clinical trial information: NCT00819780. [Table: see text]
The impact of early tumor shrinkage on survival in WJOG4407G trial, a randomized phase III trial of mFOLFOX6 plus bevacizumab versus FOLFIRI plus bevacizumab in first-line treatment for metastatic colorectal cancer.
Authors: Nagase Michitaka , Yamazaki Kentaro , Tamagawa Hiroshi , Ueda Shinya , Tamura Takao , Murata Kohei , Tsuda Takashi , Baba Eishi , Tsuda Masahiro , Moriwaki Toshikazu , Esaki Taito , Tsuji Yasushi , Muro Kei , Taira Koichi , Denda Tadamichi , Ando Masahiko , Morita Satoshi , Boku Narikazu , Hyodo Ichinosuke ,   West Japan Oncology Group
Published: February 2017

679 Background: Early tumor shrinkage (ETS) has been reported as an important predictor of favorable outcomes in patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy. We investigated the impact of ETS on survival in a randomized phase III study (WJOG4407G), which directly compared mFOLFOX6+bevacizumab (Bev) with FOLFIRI+Bev as first-line treatment. Methods: The subjects of this study were patients with measurable lesions whose tumor responses at 8 weeks were evaluated. ETS was defined as 20% or more decrease in the sum of the longest diameters of target lesions (RECIST ver.1.0) at 8 weeks. Progression-free survival (PFS) and overall survival (OS) were compared between patients with ETS and without ETS in each treatment. Results: Of 402 patients enrolled in the WJOG4407G trial, 354 (mFOLFOX6+Bev/FOLFIRI+Bev 175/179) patients were evaluated for this analysis. In this population, response rate, median PFS, and median OS of mFOLFOX+Bev/FOLFIRI+Bev were 65.7/68.2%, 10.7/12.1 months (HR 0.916, 95%CI 0.725-1.157, p=0.281), and 28.9/31.9 months (HR 0.870, 95%CI 0.653-1.159, p=0.272), respectively. One hundred (57.1%)/113 (63.1%) patients in the FOLFOX+Bev/FOLFIRI+Bev groups achieved ETS. No significant difference of the ratio of the patients with ETS between both groups was observed (p=0.099). In the FOLFIRI+Bev group, both PFS and OS were significantly longer in patients with ETS than those without ETS while there were no remarkable differences in the mFOLFOX6+Bev group (see Table). Conclusions: There were substantial differences in PFS and OS between the patients with and without ETS in the FOLFIRI+Bev group, but not in the FOLFOX+Bev group. The impact of ETS on survival is suggested to be different according to chemotherapy regimens. Clinical trial information: UMIN000001396. [Table: see text]
Maintenance therapy with the TLR-9 agonist MGN1703 in the phase II IMPACT study of metastatic colorectal cancer patients: A subgroup with improved overall survival.
Authors: Schmoll Hans-Joachim , Riera-Knorrenschild Jorge , Kopp Hans-Georg , Mayer Frank , Kroening Hendrik , Nitsche Dieter , Kuhlmann Jan , Ziebermayr Reinhard , Andel Johannes , Arnold Dirk , Schmidt Manuel , Wittig Burghardt , Scheithauer Werner 
Published: February 2017

680 Background: Patients with mCRC and disease control after induction with first-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase II IMPACT trial, aiming to assess the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent TLR9 agonist, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after first line induction therapy in mCRC. Methods: The trial was prematurely closed after randomization of 59 patients. The final analysis showed a superior effect of MGN1703 compared to placebo with hazard ratios (HR) for the primary endpoint PFS on maintenance of 0.55 (p=0.041) and 0.56 (p=0.070) by local investigator assessment or independent radiological review, respectively. Exploratory PFS analyses of pretreatment characteristics identified patients with normalized CEA, objective response, and the presence of activated NKT cells at the end of induction chemotherapy to benefit the most from maintenance with MGN1703. We analysed the impact of these factors on the secondary endpoint overall survival (OS). Results: At time of final study analysis, OS data were not mature. Only 35% of MGN1703 patients had an event, as opposed to 50% of placebo patients. The HR for OS of whole study population was 0.63 (median 22.6 vs. 15.1 months, p=NS). The subgroup of patients randomized into the study with confirmed RECIST response had a HR of 0.40 (median 24.5 vs. 15.1 months, p=NS), suggesting this may be the population with greater benefit. HR for patients with normalized CEA or with activated NKT cells were 0.69 and 0.43, respectively. Based on this evidence, in the phase III IMPALA study patients with objective response after standard induction therapy are randomized to standard treatment or switch maintenance with MGN1703. CEA and activated NKT cells are stratification factors for the study and will be prospectively assessed. Conclusions: The pretreatment characteristics predictive of a PFS benefit in the IMPACT study seem to retain their value also in exploratory analyses for OS. This information has been used to design the phase III IMPALA study, currently recruiting patients. Clinical trial information: NCT01208194.
A phase III study of xilonix in refractory colorectal cancer patients with weight loss.
Authors: Fisher George A. 
Published: February 2017

685 Background: Xilonix, an anti-interleukin-1α true human monoclonal antibody is being assessed as cancer therapy to improve overall survival (OS) in advanced colorectal cancer (CRC) patients. Methods: An open label multicenter randomized comparator controlled study to evaluate efficacy and safety of Xilonix in CRC complicated with cachexia. Eligible patients had metastatic CRC, failed oxaliplatin or irinotecan based chemotherapy, and lost ≥5% total body weight in the previous 6 months (m). Patients were 1:1 randomized to Xilonix (3.75 mg/kg intravenously every two weeks) or megestrol acetate (MA, oral 800 mg daily) until progression. Primary endpoint was OS. Secondary endpoints included assessment of patient well-being using the EORTC QLQ-C30 questionnaire. Platelets support tumor growth and metastasis and platelet counts increase during cancer progression. IL-1α on platelets may be a target of Xilonix and thus platelet count was a key pharmacodynamic measure. Results: 40 patients were enrolled between March 2013 and July 2014, at which time the study was halted to revise inclusion criteria to reduce screen failures. An eligibility violation excluded 1 Xilonix patient from analysis (Xilonix n=19, MA n=20). MA treatment arm had a 39% shorter median OS (2.0 versus 2.8 months) and a trend in increased risk of death (hazard ratio 2.17, p=0.17). Physical and role function worsened in patients receiving megesterol (median change of -13.3 (p=0.02), -16.7 (p=0.02) respectively), whereas in Xilonix treated patients these functions did not decline during therapy (median change 0, p=0.88 and 0, p=0.69, respectively). Xilonix patients had treatment-related reduction in platelets compared to the MA group (median -60,000/mm3, vs 10,000/mm3, p=0.03). No infusion reactions, no discontinuations due to adverse events (AEs) and no related SAEs were reported for Xilonix. Conclusions: The trend in OS for Xilonix patients was encouraging and consistent with improved function and intended pharmacodynamic activity. An amended Phase III protocol has been developed to simplify enrollment for an ongoing study of Xilonix in an advanced CRC population. (NCT01767857) Clinical trial information: NCT01767857.
Results of functional testing and pharmacokinetics comparing ABP 215 to bevacizumab.
Authors: Markus Richard , Kaur Primal , Chow Vincent , Zhang Nan , Born Teresa , Huynh Quyen , Maher Gwen , Velayudhan Jyoti , Howard Monique , Reynhardt Kaz , Goletz Theresa 
Published: February 2017

711 Background: ABP 215 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). Biosimilar mAbs are likely to have differences in product quality attributes due to different expression systems, bioprocess and purification, so demonstration of functional similarity and pharmacokinetic (PK) equivalence is the foundation for biosimilarity. Objectives: To assess functional similarity and PK equivalence of ABP 215 and BEV sourced from EU and US. Methods: Functional similarity testing included binding to VEGF and VEGF isoforms by surface plasmon resonance and to FcRn and FcγRIIIa. Inhibition of proliferation and VEGFR2 autophosphorylation was compared in endothelial cells. PK equivalence was evaluated in a randomized, single-dose, 3-arm study in healthy adult male subjects. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (Cmax). Secondary endpoints were safety, tolerability, and immunogenicity. Results: ABP 215 and BEV (EU) are functionally similar as previously presented. Binding affinity to VEGF was similar between ABP 215 (117 pM) and BEV (US) (126 pM) as was binding to VEGF165 and VEGF121. Binding to FcRn was similar between ABP 215 (95-102%) and BEV (96-111%). Binding to FcγRIIIa was also similar; ABP 215 (108-115%) and BEV (85-93%). Potency in proliferation inhibition was similar between ABP 215 (91-97%) and BEV (91-96%), as was inhibition of autophosphorylation. After a single dose, geometric mean (GM) of Cmax and AUCinf for ABP 215 were 87.2 µg/mL and 29,400 µg.h/mL, for BEV (US) were 89.1 µg/mL and 29,600 µg.h/mL, for BEV (EU) were 84.7 µg/mL and 30,600 µg.h/mL. The 90% CIs of GM ratio for Cmax and AUCinf were within pre-specified equivalence criterion of 0.80 to 1.25 confirming PK equivalence. There were no adverse events (AEs) or serious AEs leading to study discontinuation. Treatment-related AEs were reported for 22.1% in ABP 215, 16.4% in BEV (US) and 22.4% in BEV (EU) groups; no subjects developed anti-drug antibodies. Conclusions: ABP 215 is similar to BEV in sensitive functional tests and equivalent to BEV based on results of the phase 1 PK study.
The optimization of 5-fluorouracil (5FU) dose by pharmacokinetic (PK) monitoring in Asian patients with advanced-stage gastrointestinal (GI) cancer.
Authors: Soh I Peng Thomas , Mogro Maria Jannet , Soo Ross A. , Pang Angela , Tan Chee Seng , Chuah Benjamin , Zee Ying Kiat , Wong Andrea Li Ann , Ow Samuel Guan Wei , Sundar Raghav , Lim Joline Si Jing , Huang Yiqing , Ling Winnie Hui Yee , Yong Wei-Peng 
Published: February 2017

770 Background: PK guided dose management and systemic plasma levels of 5FU have shown correlation with both reduced toxicity and improved efficacy. However, data for Asian patients are lacking. Levels are highly variable with doses based on body surface area. Methods: Area under the curve (AUC) was estimated using a nanoparticle immunoassay from Saladax Biomedical (My5-FU). Patients with GI cancers receiving de Gramont, FOLFIRI or mFOLFOX6 regimens had 5 PK sampling time points obtained (reduced to 2 samplings after first 15 patients). If target AUC (18-28 mg.h/L) was reached for 2 consecutive cycles, monitoring is performed for alternate cycles. With dose adjustments, PK sampling will be done in the next cycle. Results: 50 patients (33 males, 17 females) enrolled, with 349 PK samplings done, and 291 analyzable. 31 (62%) had mFOLFOX6, 18 (36%) FOLIRI and 1 (2%) de Gramont. Colorectal cancer (76%) and gastric cancer (12%) were the most common cancer types. Median AUC (35 evaluable) was 24.2 in C1, 23.65 in C2 (n=38), 20.6 in C3 (n=38) and 22 mg.hr/L in C4 (n=35). Proportion of patients achieving target AUC were 54.3%, 32%, 39.5% and 51% respectively and did not change significantly despite PK guided doses adjustments (C1 vs. C4 p=0.81, C2 vs. C3 p= 0.63, C2 vs. C4 p=0.085, C3 vs. C4 p=0.31). Higher than expected rate of G3/4 neutropenia (52%) and fewer mucositis (0%) and diarrhea (8%) were observed. Other toxicities (all grades) were fairly consistent with historical data. There were no inter-cycle differences in rates of toxicity, and no relationship with G3/4 toxicities and high AUC levels were observed. Correlation of response rates, efficacy with AUC were omitted due to heterogeneous tumor types. Conclusions: Contrary to past studies, PK guided 5FU did not result in a greater number of patients achieving target AUC in Asian patients. Furthermore, AUC levels of 5FU did not correlate with toxicity. Larger numbers are needed to confirm the clinical utility and benefit of PK guided 5FU in Asian patients. Clinical trial information: NCT00943137.
Association between single nucleotide polymorphisms (SNPs) of genes involved in spindle assembly checkpoint (SAC) and clinical outcomes in advanced gastric cancer (AGC) patients (pts) treated with taxane-based chemotherapy.
Authors: Yamauchi Shinichi , Okazaki Satoshi , Barzi Afsaneh , Zhang Wu , Yang Dongyun , Cao Shu , Ning Yan , Sunakawa Yu , Stremitzer Stefan , Matsusaka Satoshi , El-khoueiry Rita , Mendez Angela , Parekh Anish , Lenz Heinz-Josef 
Published: February 2017

79 Background: Taxanes which disrupt the microtubule function and inhibit the process of cell division have shown encouraging activity in the treatment of AGC. Resistance to these agents often becomes a problem in clinical settings and its mechanism hasn’t been dissolved conclusively. SAC is a safety device ensures the proper chromosome segregation in mitosis and is required for taxane-induced cell death. We hypothesized genetic variants in SAC genes may be associated with clinical outcomes in pts with AGC treated with taxane. Methods: Genomic DNA was isolated from blood or tissue samples of 39 U.S. pts (median age 57; median follow-up 6.4 months) for evaluation set and 39 Japanese (JPN) pts (median age 63; median follow-up 9.4 months) for validation set, with AGC treated with taxane. Twenty-five functionally significant SNPs in SAC genes (MAD1, MAD2, BUB3, BUBR1, RAN, TPX2, CDC20, AURKA, AURKB, RCC1, ANAPC10, ANAPC13) were analyzed by PCR-based direct sequencing and evaluated for association with outcomes. Results: In univariate analysis, rs4236271 (MAD1), rs6954673 (MAD1), and rs2064863 (AURKA) showed a significant difference in 6-month (mo) progression-free survival (PFS) rate [(C/C 42%, C/T 12%; HR 2.66, P=0.008), (C/C 75%, C/T or T/T 24%; HR 5.10, P=0.008), and (T/T 50%, T/G 15%, G/G 57%; HR1.55, P=0.046), respectively] and 18-mo overall survival (OS) rate [(C/C 40%, C/T 8%; HR3.69, P<0.001), (C/C 56%, C/T or T/T 19%; HR3.60, P=0.004), and (T/T 59%, T/G 15%, G/G 29%; HR 2.02, P=0.047), respectively] in evaluation set. In multivariate analysis, rs4236271 and rs6954673 remained significant in PFS (HR 7.24, P=0.005, HR 14.49, P=0.015, respectively) and OS (HR 7.39, P=0.001, HR 6.37, P=0.002, respectively). In validation set, rs6954763 showed a significant difference in 18-mo OS rate (C/C 16%, C/T or T/T 47%, HR 3.55, P=0.014), but the impact of C/C genotype on OS in the JPN pts was the opposite to the U.S. pts. Conclusions: These results suggest that MAD1 polymorphisms may serve as a prognostic marker in pts with AGC. Further studies using larger population are needed to corroborate our results.
Lapatinib combined with ECF/x as first-line metastatic gastric cancer (GC) according to HER2 and EGFR status: A randomized placebo controlled phase II (EORTC 40071).
Authors: Moehler Markus Hermann , Schad Arno , Mauer Murielle E. , Messina Carlo G. M. , Mahachie John Jestinah. M. , Lang Istvan , Van Cutsem Eric , Freire João , Lutz Manfred P. , Roth Arnaud 
Published: February 2017

80 Background: ECF/X (epirubicin (E) + cisplatin (C) + 5-fluoruracil (F) or capecitabine (X)) is a reference chemotherapy (CT) regimen in metastatic GC. Trastuzumab with CF/X prolonged survival (OS) of metastatic HER2+ gastric or esophagogastric junction cancer (GC) patients (pts). Lapatinib (LAP) inhibits both, EGFR1 and HER2, and showed activity in phase II GC trials. This double-blind Phase II study prospectively addressed efficacy and safety of LAP with ECF/X in GC pts with discordant FISH or IHC HER2 status or EGFR1+. Methods: Pts without prior palliative CT, screened centrally for HER2/EGFR1 (by FISH and IHC) were enrolled into 3 strata: 1) HER2 FISH+ and IHC 2/3+, 2) HER2 FISH- and IHC 2/3+, or 3) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts without HER2 + or EGFR1+, by FISH or IHC, were excluded. Pts were randomized to LAP 1250mg (arm 1) or placebo (arm 2), with ECF or ECX (investigator-selected) for 6 cycles. Primary endpoint was progression free survival (PFS). Secondary endpoints were toxicity, response rates, OS, HER2 concordance and correlation of HER2/EGFR. Results: The trial was prematurely closed to patient accrual given the LOGIC trial results at ASCO 2013. A total of 69 pts were tested in central lab of whom 9 (13%), 5 (7.2%) and 25 (36.2%) were in stratum 1, 2 and 3. Of these, 28 patients (6/4/18) were randomized (14 in arm 1, 14 in arm 2) and followed up. Due to the low number of pts accrued, no formal statistical tests were carried out. No safety concerns were found in arm 1. No complete responses were seen. 6 pts had partial responses in arm 1 vs. 3 pts in arm 2. Median PFS was 7.1 months in arm 1 vs. 5.9 months in arm 2 (HR=0.94, 95% CI: 0.41-2.14) for all pts, and 6.2 months in arm 1 vs. 6.3 months in arm 2 (HR=0.99, 95% CI: 0.36-2.75) for stratum 3 pts, respectively. Median overall survival was 13.8 months in arm 1 vs. 10.1 months in arm 2 (HR=0.90, 95% CI: 0.35-2.27) for all pts. Conclusions: Lapatinib with ECF/X did not show appealing activity in EGFR+ metastatic GC patients in this small phase 2 trial. The combination was well tolerated. Clinical trial information: NCT01123473.
Association of AKT expression with degree of pathologic response in patients with esophageal cancer undergoing neoadjuvant therapy.
Authors: Saeed Nadia , Doepker Matthew , Shridhar Ravi , Weber Jill , Hoffe Sarah E. , Almhanna Khaldoun , Meredith Kenneth L. 
Published: February 2017

89 Background: Neoadjuvant therapy (NCRT) has become standard in the treatment of locally advanced esophageal adenocarcinoma (EAC) with survival correlated to degree of pathologic response. The activation of the PI3K/Akt/mTOR pathway plays an important role in tumorgenesis and resistance to anticancer drugs. The aim of this study was to elucidate the role of AKT in chemoresistance in patients with esophageal adenocarcinoma (AC) who received NCRT. Methods: After IRB approval, a prospective trial was initiated in which patients with EAC requiring NCRT were consented for endoscopic biopsies of normal and tumor tissue prior to instituting therapy. After completion of NCRT patients then proceeded to esophagectomy. The tissues obtained preoperatively underwent gene expression profiling using the Affymetrix 133 Plus 2.0 Gene chip. SAM method was used to analyze significant differentially expression of AKT within normal and tumor tissue. Expression was then correlated to degree of pathologic response. Results: One-hundred patients were consented for the study, of which 67 met final eligibility. Nineteen patient’s tumors ultimately underwent gene expression profiling via microarray. The differential expression of all AKT probesets in tumor tissue was markedly overexpressed compared to normal tissue (p=6x10-5). There were 3 patients designated as pNR, 5 as pPR, and 11 as pCR. Investigating the relationship between the degree of expression of AKT and pathologic response demonstrated a linear correlation between over-expression of AKT and degree of pathologic response. Partial and non-responders had higher expressions of AKT compared to pCR with the non-responders consistently illustrated the highest expression of AKT (p=0.02). There was a significant correlation between individual probesets AKT1, AKT2, and AKT3 and degree of pathologic response (p=0.002, 0.04, and 0.04 respectively). Conclusions: AKT is overexpressed in patients with AC of the esophagus. Moreover, pathologic response to NCRT may be correlated with degree of AKT expression. Additional data is needed to clarify this relationship further and add potential targeted therapies.