bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of the pan-Bcl2 family inhibitor GX15–070, administered as a 3-hour weekly infusion in patients with refractory solid tumors or lymphomas
Authors: Firozvi K. , Hwang J. , Hansen N. , Malik S. , Maclean M. , Siu L. , Marshall J. L. , Mendelson D. , Kuruvilla J. 
Published: March 2020

3081 Background: GX15–070 is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. GX15–070 activates apoptosis in vitro and exhibits clinical activity in chronic lymphocytic leukemia (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. Methods: In a standard titration design, 4 cohorts of 3 patients (pt) were treated with 5mg/m2 - 14 mg/m2 IV infused over 3 hours, weekly. Each cycle of therapy consisted of 4 weekly infusions. Pharmacokinetics (PK) and pharmacodynamic (PD) response based on plasma oligonucleosomal DNA levels were evaluated. Results: N=15 pts were treated. Median age was 58 (range 24–71). Median number of prior regimens was 4 (range 1–11). A total of 105 infusions (26 cycles) was administered. GX15–070 underwent first order elimination kinetics with a short initial distribution phase (α t1/2=0.6 h), followed by a longer elimination γphase (t1/2=43.8 h). At the 14 mg/m2 dose level, median C max and AUC values were 98 ng/ml and 276 ng.hr/ml, respectively. The coefficient of variation was low at 38%. Adverse events have mostly been observed during or shortly after the infusion and have been transient. The most common pertain to the central nervous and gastro-intestinal system (drowsiness, euphoria, ataxia, and abdominal pain). Most toxicities were mild to moderate, with the exception of grade 3 pain experienced by 2/2 pts with Hodgkin’s disease, that resolved rapidly but resulted in treatment discontinuation in 1 patient. One episode of Grade 3 infusional CNS toxicity was reported at 14 mg/m2 requiring the inclusion of 6 patients with no further DLT. No neutropenia, thrombocytopenia or lymphopenia have been reported. The MTD has not been reached. Mean increase in plasma oligonucleosomal DNA was 36 fold (range 0–182 fold) over baseline. Best response to treatment to date : SD ≥ 8 weeks (4); PD (5); too early (6). Conclusion: Weekly GX15–070 as been well tolerated at doses showing biological activity. Dose escalation will be pursued up to 28 mg/m2 weekly. No significant financial relationships to disclose.
Therapeutic implications for acquired resistance and heart toxicity using targeted therapy to erbB2
Authors: Bacus S. S. , Hill J. , Spector N. 
Published: March 2020

3084 Background: ErbB2 overexpression predicts for a poor prognosis in breast cancer making it an attractive therapeutic target. Molecules such as EGFR/ErbB2 tyrosine kinase inhibitors (TKI’s), lapatinib/GW2974 and antibodies such as trastuzumab are currently used in clinical trials. Clinical responses to TKI’s have been observed, but are short-lived. Our data elucidates the pathway of acquired resistance to TKI’s and the underlying pathway associated with cardiac toxicity after trastuzumab treatment. Finally, we show the clinical implications and the therapeutic approaches to overcome this. Methods: Immunostaining and Western Blot were performed for HER2, EGFR, ER, PR, Bcl-2, FOXO3a, ERRα, ERR, PGC-1α, p-AKT and pERK. AU565, MCF7, BT-474, MCF7/HER2 and AU/BCL2 were treated with ß-estradiol, tamoxifen citrate, GW2974 and trastuzumab. Results: We show that upregulation of ERα and ER-regulated genes contribute to the resistance to HER1/HER2 inhibitors. Although the ErbB2 pathway is inhibited by lapatinib, the dependence of tumor cell survival in resistant cancer cells switches from ErbB2 to ER pathway. By inhibiting ErbB2/P13/AKT signaling, the inhibitors upregulate FOXO3a, which upregulates ER and ER-regulated genes, such as BCL2, contributing to cellular resistance. We also show that this occurs in patients with ErbB2/EGFR overexpressing ER positive cancers treated with lapatinib. By combining EGFR/HER2 inhibitors or antibodies with interventions that down regulate ER activity or estrogen deprivation, we were able to delay ER-mediated resistance. In addition, we have shown that the genes associated with the fatty acid metabolic pathway are upregulated by trastuzumab, but not lapatinib. Conclusion: Our results show that activation of ER and ER-regulated genes (BCL2) that contributed to the development of resistance to ErbB inhibitors in AU and BT474 cells also occurred in patients treated by lapatinib whose breast cancers expressed a similar phenotype. Identifying the mechanisms involved in the development of resistance and toxicities to ErbB inhibitors will lead to rational therapeutic strategies and improve their efficacy. In addition, less cardiac toxicity is anticipated in patients treated with lapatinib. No significant financial relationships to disclose.
Alternating versus continuous “FOLFIRI” in advanced colorectal cancer (ACC): A randomized “GISCAD” trial
Authors: Labianca R. , Floriani I. , Cortesi E. , Isa L. , Zaniboni A. , Marangolo M. , Frontini L. , Barni S. , Beretta G. D. , Sobrero A. 
Published: March 2020

3505 Background: In ACC “FOLFIRI” is one of the standard regimens and is able to obtain about 40% response rate (RR) with an overall survival (OS) of 17–18 months. Experimental studies (Sobrero, 2000) indicate that an alternating chemotherapy could delay the appearance of cell resistance and reduce the therapeutic load for patients (pts). Methods: In order to evaluate whether intermittent “FOLFIRI” (CPT-11: 180 mg/sqm d1 + l-folinic acid -FA: 100 mg/sqm in 2 hr + 5fluorouracil-5FU: 400 mg/sqm bolus + 600 mg/sqm 22 hr infusion, d 1 and 2 every 2 weeks, for 2 months on and 2 months off) (arm A) was at least as effective as continuous “FOLFIRI” (same regimen, every month) (arm B), until progression in both arms, 336 pts from 27 Centers were randomised from 7/2001 to 6/2005. The characteristics of pts were: median age 64 years (r 29–75), males 214 (63%), PS 0: 222 (66%), liver mets only 166 (49%), multiple mts including liver 80 (24%). Results: RR was 29% in arm A and 35% in arm B, with a median progression-free survival (PFS) of 8.8 and 7.3 months respectively (HR = 1.00, 95% CI: 0.74 - 1.36). At a median follow-up of 27 months, median overall survival (OS), the primary endpoint of the trial, was 16.9 months in arm A and 17.6 in arm B (HR = 1.11, 95% CI: 0.83 - 1.48). Toxicity was acceptable and similar in the 2 arms (WHO grade 3–4 toxicity: neutropenia in 12% pts, diarrhoea in 11%, nausea/vomiting in 4% and fatigue in 3%). Conclusions: Our results demonstrate that alternating “FOLFIRI” obtains the same survival as a continuous treatment, thus reducing the discomfort to pts and the economic costs. No significant financial relationships to disclose.
Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Cassidy J. , Bjarnason G. A. , Hickish T. , Topham C. , Provencio M. , Bodoky G. , Landherr L. , Koralewski P. , Lopez-Vivanco G. , Said G. 
Published: March 2020

3507 Background: X, an orally administered non-peptide neurotrophic agent developed by sanofi-aventis, was shown in vitro to minimize neuritic damage induced by Ox (co-culture of Schwann cells and dorsal roots ganglia explant). The probability of occurrence of Grade (Gr) 3–4 PSN at a cumulative dose of Ox of 1000 mg/m2, was consistently reported to be of 18–20%. Methods: First line MCRC pts were randomized to receive, in a DB fashion, FOLFOX4 and either Plcb or X 1mg daily. X was administered from the 1st day of chemotherapy till 15 days post last Ox cycle. Co-primary objectives were reduction in the risk of occurrence of Gr 3–4 PSN relative to cumulative dose of Ox (Kaplan-Meier method) and non-inferiority in response rate (RR). Secondary endpoints included evaluation of sensory action potential (SAP) and safety. Results: From July 2002 to May 2004, 649 pts were randomized (324 Plcb, 325 X). Pts characteristics were well balanced across arms, median number of Ox cycles was 12 in both arms, median relative dose intensity (%) was 83.8 (Plcb) and 85.2 (X). A significant risk reduction of 39% in the probability of Grade 3–4 PSN in favor of X was reported (hazard ratio [95% CI] = 0.61 [0.40; 0.93], p= 0.0203). Overall RR [95 % CI] was: Plcb 42.6% [37.1; 48.2] and X 44.9% [39.4; 50.6]. As prospectively defined in the protocol, the lower bound of the CI of the RR ratio above 0.8 confirms noninferiority in RR (1.055 [0.88; 1.26]). In both arms the mean % of change in SAP worsens as a function of PSN severity. 17.3 (Plcb) and 13.5% (X) of the pts discontinued Ox because of PSN. Severe toxicities (% Gr 3–4), reported with a ≥2% difference between arms, were (plcb vs X): diarrhea 10.9 vs 13.0, pulmonary embolism 0.9 vs 3.1, fatigue 3.7 vs 1.5, neutropenia 43.0 vs 37.8. Conclusion: X was shown to be efficient in reducing the risk of Grade 3–4 oxaliplatin-induced PSN without impacting FOLFOX4 antitumor activity. No significant financial relationships to disclose.
Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2)
Authors: Koehne C. , Bajetta E. , Lin E. , Van Cutsem E. , Hecht J. , Douillard J. , Moore M. , Germond C. , Laurent D. , Jacques C. 
Published: March 2020

3508 Background: PTK/ZK is a novel, oral, small molecule, antiangiogenic compound that inhibits tyrosine kinase signaling of all known vascular endothelial growth factor (VEGF) receptors. Methods: 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically or cytologically documented mCRC, pretreatment for metastatic disease with irinotecan/fluoropyrimidine-based chemotherapy, measurable disease by RECIST, PS of 0–2 and adequate organ and bone marrow function. The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (stratifiedbybaseline serum LDH levels > 1.5 × ULN). Results: OS was 12.1 mo in the PTK/ZK arm and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). A pre-planned triangular test suggested a low probability of demonstrating an improvement in OS at the final analysis (4Q 2006). The response rates (CR+PR) were 18.5% in the PTK/ZK arm, 17.5% in the placebo arm. PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, usually a poor prognostic factor in mCRC, is predictive of the outcome in the PTK/ZK arm. Pts with high LDH showed a strong improvement in PFS when treated with PTK/ZK (5.6 mo vs. 3.8 mo; HR: 0.63; p<0.001) and an improved OS (9.6 mo vs. 7.5 mo; HR: 0.78; p=0.10). Adverse events (AE) were similar to that of the CONFIRM 1 trial (ASCO 2005). Most frequent grade 3/4 AE associated with PTK/ZK were hypertension (PTK/ZK: 21%; placebo: 5%), diarrhea (16%; 8%), fatigue (14.5%; 6.9%), nausea (11%; 5%), vomiting (9%; 5%), dizziness (9%; 1%). AEs were generally reversible. Thrombotic and embolic events of all grades occurred in 6% (PTK/ZK) vs. 1% (placebo) and 4% vs. 1%, respectively. There was no increase in bowel perforations, hematological toxicities or peripheral neuropathy in the PTK/ZK arm. Conclusions: While the primary endpoint for OS was not met, PTK/ZK improves PFS significantly in the overall population, and shows strong activity in patients with high baseline serum LDH. [Table: see text]
Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial
Authors: Sebag-Montefiore D. , Steele R. , Quirke P. , Grieve R. , Khanna S. , Monson J. , Holliday A. , Thompson L. , Griffiths G. , Stephens R. 
Published: March 2020

3511 Background: Radiotherapy reduces local recurrence (LR) when combined with surgery in resectable rectal cancer. The Medical Research Council CR07 trial was designed to compare two different radiotherapy policies when combined with mesorectal excision. Methods: Patients with operable non-metastatic adenocarcinoma of the rectum were randomised to either routine pre-op short course radiotherapy [25Gy/5F] (PRE) or selective post-op chemoradiotherapy (POST) for patients with involvement of the circumferential resection margin (CRM) - [45Gy/25F + 5fluorouracil]. Results: A total of 1350 patients were randomised from 52 centres in the UK, Canada, New Zealand and South Africa between March 1998 and August 2005. Median follow-up is 3 years. Patients (73% male, median age 65 years, 79% PS0) were well balanced between the 2 arms. 595 of 674 (88%) of the pre-op group received their allocated treatment. Of the 676 patients allocated to the selective post-op chemoradiotherapy arm, 73 (11%) were CRM +ve and 51 of these (70%) received chemoradiotherapy. Post operative chemotherapy was received by 85% of patients with stage III disease. At the time of analysis 23 PRE and 61 POST patients had confirmed LR, 96 and 106 patients respectively distant metastases, and 115 and 146 respectively had died. The 3 year rates for LR (primary end point) were 4.7% and 11.1% for PRE and POST groups respectively (HR 2.47, 95% CI 1.61–3.79), for disease free survival 79.5% and 74.9% (HR 1.31, 95% CI 1.02–1.67) and for overall survival 80.8% and 78.7% (HR 1.25, 95% CI 0.98–1.59. The LR benefit in favour of PRE was consistent for tumours 0–5,5–10 and >10cm from the anal verge (HR 2.00, 2.14 and 4.97 respectively). Further subset analysis based on TNM stage and operation performed will be presented. Conclusions: These preliminary results indicate that routine short course pre-operative radiotherapy results in a signifcant reduction in local recurrence and improved disease free survival at 3 years when compared with a highly selective post operative approach. No significant financial relationships to disclose.
A genetic signature of relapse in stage II colorectal cancer derived from formalin fixed paraffin embedded tissue (FFPE) tissue using a unique disease specific colorectal array
Authors: Johnston P. G. , Mulligan K. , Kay E. , Black J. , Moore S. , Mc Dermott U. , Wilson R. , Harkin D. 
Published: March 2020

3519 Background: We have developed the first disease specific microarray for colorectal cancer using a transcriptome-based approach. This unique tool has been specially designed and optimised for analysis of gene expression profiles from formalin fixed paraffin embedded tissues (FFPE). To evaluate this tool we are conducting a study in patients with Dukes B (stage II) colorectal cancer (CRC) using FFPE tissues to determine a prognostic genetic signature predicting disease recurrence. Methods: The colorectal array was developed using a high-throughput transcriptome-based approach and encodes over 52,500 transcripts expressed in normal and diseased colorectal tissue. To date, tumours from 32 patients have been selected (mean FFPE tissue block age - 10.4 years) from the stage II CRC cohort of a phase III randomized trial comparing 5-FU/Leucovorin versus no adjuvant treatment (NI240). The patients were from the observation alone arm;19 of whom were disease-free for 5 years post-randomisation, while 13 suffered relapse prior to 3 years. Results: RNA was extracted from all 32 FFPE tissue samples, amplified, labelled and hybridised to the colorectal cancer disease specific array. Raw data was normalised using scalar, median-polish and z-score strategies and scalar was selected as the best strategy in relation to predictive error. Within this data set genes selected by correlation using ANOVA performed best in both KNN and support vector machine algorithms (supervised). Using this approach a gene signature containing 48 genes demonstrated 100% accuracy in the prediction of relapse in stage II CRC (p<0.001). This signature was also able to separate samples at the meta-node level using unsupervised hierarchical clustering. Conclusion: We have developed the first colorectal cancer disease specific microarray and demonstrated its use using FFPE tissues. Using this approach we have derived a gene signature that predicts for a high likelihood of early relapse in stage II CRC. [Table: see text]
Feasibility of metastasectomy in patients treated with bevacizumab in first-line mCRC - Preliminary results from the First Beat-study
Authors: Michael M. , Vancutsem E. , Kretzschmar A. , Berry S. , Rivera F. , Dibartolomeo M. , Mazier M. , Lutiger B. , Cunningham D. 
Published: March 2020

3523 Background: In a phase III pivotal trial in patients (pts) with mCRC, bevacizumab (BEV) increased overall survival by 30% when added to first-line irinotecan, 5FU and leucovorin. The study reported 10% of pts having wound healing complications after major unplanned or elective surgery. The study had limited data on the feasibility and safety of metastastasectomies. First BEAT was opened to evaluate safety events of BEV in a broader pt population using a variety of chemotherapy (CT) regimens. Methods: First BEAT started in June 2004 and aims to enrol up to 2000 mCRC pts in 41 countries. Eligible patients starting with first-line CT are treated until progression with BEV (5mg/kg q2w (5FU based CT) or 7.5mg/kg q3w (Capecitabine (CAP) based CT). In case of major elective surgery, BEV should be stopped 6–8 weeks prior to the planned surgery and could be restarted 28 days after surgery and complete wound healing. At protocol visits, bleeding and wound healing data was collected according to CTC AE grading (v3.0). Results: By Dec 20th, 2005, 31 pts (13 male; median age 55 years; PS 0/1 90%/10%) had undergone metastasectomies. 27 were liver (1 pt had two operations), 3 lung, 1 peritoneal and 1 other resections. 27 were curative, 3 palliative and 2 other resections. 17 reported no residual disease, 5 had residual disease and for 8 resections the outcome was missing or unknown. Median time from first BEV treatment to surgery was 167 days and 54 days from last BEV administration to surgery, respectively. Median follow-up was 12.4 months. One pt died due to disease progression 5.5 months after surgery. CT regimens used with BEV included FOLFOX (N=9), CAPOX (N=9) and FOLFIRI (N=7). No wound healing or bleeding were reported. 21/31 pts reported no complications at all, for 3/31 data was currently missing and 7/31 pts reported the following complications: stomach perforation, right pleural effusion, surgical area infection, thrombosis portal vein/myocardial infarct, bowel-obstruction, ascites, ileus/cornea infection. Updated data will be available in June 06. Conclusions: Preliminary data suggest metastasectomies are feasible after treatment with BEV and CT. Stopping BEV 6–8 weeks before major surgery resulted in no bleeding or wound healing complications. [Table: see text]
Safety of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: Updated results from a large observational registry in the US (BRiTE)
Authors: Hedrick E. , Kozloff M. , Hainsworth J. , Badarinath S. , Cohn A. , Flynn P. , Dong W. , Suzuki S. , Sugrue M. , Grothey A. 
Published: March 2020

3536 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy for patients with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of patients with mCRC receiving BV plus first-line chemotherapy. Safety and efficacy information in unselected patients with mCRC are collected. Chemotherapy regimen choice is at the physician’s discretion. Methods: To facilitate and evaluate enrollment of a typical community-based mCRC population, eligibility criteria were minimized. Cohort demographics were consistent with the NCI Surveillance, Epidemiology, and End Results (SEER) database for mCRC. Patients are followed for up to 3 years, and safety data including targeted BV-associated serious adverse events (SAEs) are updated every 3 months (mo). Results are based on descriptive analyses and are not adjusted for propensity of treatment, baseline characteristics, and treatment effects. Results: 1968 patients were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo by Nov 4, 2005. SAEs were reported in 12.0% of patients including gastrointestinal perforation (GIP) (1.7%), postoperative bleeding/wound healing complications (1.2%), arterial thromboembolic events (ATE) (2.1%), and grade 3–4 bleeding (1.9%). 3.2% of patients discontinued BV due to a BV-related toxicity, most commonly bleeding. For patients with the respective event(s), median time to first event was 2.1 mo for GIP, 3.5 mo for ATE and 4.0 mo for grade 3–4 bleeding. 8.9% of patients with no history of hypertension (HTN) developed HTN requiring medication and 6.2% of patients who had HTN requiring medication at baseline experienced worsening of their HTN while on study treatment. Conclusions: In this unselected population of patients with mCRC, the safety profile of BV plus various chemotherapy regimens appears consistent with that observed in the pivotal BV trial. Overall discontinuation of BV due to a BV-related toxicity was uncommon. In this large community-based observational registry, no new BV associated safety issues have been identified. [Table: see text]
Influence of bevacizumab on the plasma disposition of CPT 11 and its metabolites in advanced colorectal cancer patients
Authors: Schueller J. , Czejka M. , Kiss A. , Krexner E. , Aigner K. , Wirth M. 
Published: March 2020

3540 Background: The monoclonal antibody (mab) bevacizumab (BEV) inhibits VEGF, downregulates angiogenesis and lowers interstitial pressure, by which blood tissue transfer and metabolism of a drug could be modulated. CPT 11 produced survival benefit combined with BEV and undergoes complex biotransformation by different enzymatic routes: carboxylesterase hCE2 (SN 38), UGT1A1 (detoxificition to SN 38 glucuronide) and CYP 3A4 (APC), the latter enzyme has been described to be reversibly inhibited by mabs. Therefore it seems worthwhile to investigate a potential influence of BEV on plasma disposition and pharmacokinetics (PK) of CPT11 and metabolites. Methods: 10 pts with advanced colorectal cancer (5 first line, 5 second line after FOLFOX) were treated by FOLFIRI schedule (with CPT 11 180 mg/m2 1HR infusion) preceeded by BEV 5 mg/kg (90–60–30 min infusion) every 2 weeks. At cycle 1, CPT 11 was applied before BEV to allow baseline PK analysis of CPT 11 and its metabolites, at cycle 4 (i.e. after 8 weeks) determination of CPT 11 plasma conc was repeated after a 30 min infusion of BEV. Plasma samples were collected every 30 min over 4 HR and analysed by HPLC. Results: PK of CPT 11 remained unaffected by BEV, only a small decrease in cmax and AUC was found. Contrary, SN 38 formation seemed to be delayed and formation rate decreased when combined with BEV, resulting in lower cmax (-24%) and AUC (-20%). SN 38 glucuronide levels were generally found to be higher than those of SN 38, cmax and AUC reduced by 35% when BEV was preadministered. A similar effect was also observed in PK parameters of APC (about 30% reduction of cmax and AUC). Conclusion: A changed plasma disposition of all 3 metabolites - generated by 3 different enzymatic pathways - is unlikely to be caused by BEV influencing CPT 11 metabolism. The observed effect could be explained by increased blood tissue transfer, alteration of microvasculature by BEV may favour tissue uptake of the drug. [Table: see text] No significant financial relationships to disclose.