bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I dose escalation trial (ARQ 197–111) evaluating combination of selective c-Met inhibitor ARQ 197 and erlotinib
Authors: Laux I. , Goldman J. , Just R. , Brady K. , Li J. , Schwartz B. , Savage R. , Garmey E. , Rosen L. 
Published: August 2020

3549 Background: ARQ197 (A) is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Phase I data for ARQ 197 monotherapy is previously reported. Recent evidence suggests c-Met promotes resistance to EGFR-inhibition by driving ERBB3 (HER3)-dependent PI3K activation. Dual EGFR-Met inhibition is now proposed as a strategy for overcoming resistance to EGFR-inhibition. Methods: Patients (pts) were enrolled in a sequential-cohort dose-escalation trial seeking to define safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of A in combination with 150 mg daily oral erlotinib (E). Oral A was administered at escalating doses of 120, 240, and 360 mg bid. Intra-patient dose escalation was allowed in the absence of dose-limiting toxicity (DLT) through 1 cycle of therapy (21 days). Results: 25 pts (10 F/15 M; mean 60.5 yrs) received EA combination with starting A dose of 120 (8 pts), 240 (4 pts), and 360 (13 pts) mg bid. PK data reveal linear kinetics through 360 bid and no evidence of drug-drug interaction. Adverse events (AEs) considered related to combination therapy were reported in 13 (52%) of pts incl.sinus bradycardia (5 pts), fatigue (5 pts), rash (4 pts), itching (3 pts), and diarrhea (3 pts). 2 pts experienced related serious AEs incl. neutropenia (360 bid) and sinus bradycardia (240 bid). 1 death occurring on-study was considered unrelated to study drug. 9/10 evaluable pts demonstrated disease stabilization (SD) as their best RECIST response (5.9–27.1+ wks). Tumor regressions (2.3%-19.4%) were observed in 4/10 evaluable pts. Of note, 3/3 evaluable pts with NSCLC achieved SD for durations (14–32 wks) exceeding median PFS in BR.21 (9.7 wks). Conclusions: Continuous therapy with EA combination appears well tolerated and without drug-drug interaction. While no formal MTD was identified, a phase 2 combination dose (R2PD) of 360 mg bid A + 150 mg daily E is recommended. This RP2D is currently being investigated in an ongoing randomized trial comparing EA to E monotherapy in 2nd/3rd line NSCLC. [Table: see text]
A single-center, open-label, dose escalation, safety, and pharmacokinetic study of ENMD-1198 administered orally to patients (pts) with advanced cancer
Authors: Nallapareddy S. , Gustafson D. , Leong S. , Messersmith W. , Arnott J. , Eckhardt S. G. , Sidor C. , Camidge D. R. 
Published: August 2020

3562 Background: ENMD-1198 (2-methoxyestra-1, 3, 5, (10) 16-tetraene-3-carboxamide), an analog of 2-methoxyestradiol (2ME2), has both antiangiogenic and antiproliferative effects in various tumor types. ENMD-1198 inhibits MT polymerization by binding to β-tubulin at the colchicine-binding site and inhibits HIF-1alpha. This Phase 1 study is evaluating the safety of ENMD-1198 to determine the maximum tolerated dose. Methods: Eligible pts had advanced cancer for which no effective therapy exists that is either evaluable by RECIST criteria or tumor markers that could be monitored for clinical benefit. Phase 1 dose escalation in 3+3 design for first 5 cohorts; modified to 1 pt cohorts for subsequent cohorts until Grade 2 treatment related toxicity, and then standard 3+3 design. All pts treated with once daily oral ENMD-1198 in 28-day cycles (with post-treatment drug-free observation period of 7–14 days in Cycle 1 only). Pts are treated until the appearance of significant treatment-emergent toxicities or disease progression (PD) occurs. Results: To date, 27 pts have been enrolled in 12 dose cohorts (range 5 to 550 mg/m2/d). Median age/performance status is 61/1. Total # of treatment cycles to date is 68, with a median of 2 cycles (range <1 to 15 cycles). Most frequent toxicities (all grades, n=22) were pain (77%), fatigue (55%), constipation (36%), neuropathy and nausea (both 32%), and anemia (27%). 4 pts have experienced stable disease (SD) for more than 2 cycles. There have been no objective responses to date. 2 pts experienced dose limiting toxicity with Grade 4 neutropenia in the 550 mg/m2/d cohort. Following drug holiday, pts restarted at 425 mg/m2/d and continued for at least 1–2 more cycles before being removed from study for PD. One pt (neuroendocrine ca pancreas) is experiencing prolonged SD at 60 mg/m2/d >14 cycles and a 2nd pt (prostate ca) experienced SD at 30mg/m2/d for 10 cycles. ENMD-1198 was absorbed rapidly after oral administration. There was a linear relationship between dose and drug exposure as measured by AUC across all doses (5 - 550 mg/m2). The elimination half-life of ENMD- 1198 averaged more than 12 hours after a single dose. Conclusions: DLT was identified at 550 mg/m2/d. Cohort expansion at 425mg/m2/d is ongoing. [Table: see text]
A phase I study of the combination of intravenous Reolysin (REO) and gemcitabine (GEM) in patients (pts) with advanced cancer
Authors: Arkenau H. , Evans J. , Lokelma M. , Roxburgh P. , Morisson R. , Coffey M. , Gill G. , Mettinger K. , Thompson B. , de Bono J. 
Published: August 2020

3584 Background: REO (reovirus serotype 3) is a Dearing strain, naturally occurring, non-enveloped virus with limited pathogenecity in humans. REO replicates specifically in transformed Ras-activated cells due to inhibition of the dsRNA-activated protein kinase, resulting in cell-lysis. GEM has shown efficacy in a wide range of tumors commonly driven by activated Ras, and causes cell cycle arrest in S phase. Results from isobologram analysis suggest potential synergies of REO and GEM. Methods: This open-label, dose-escalating, two-centre phase-I trial studied the combination of iv REO, d1–5 and iv GEM, d1 and 8, qw3. The REO starting dose was 3x109 TCID50 over 1-hour, increasing in successive cohorts and GEM was given at a fixed dose of 1,000 mg/m2 over 30-min. Endpoints were the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and safety profile of REOGEM and to establish a RP2D. Secondary endpoints were to evaluate the immune response, to evaluate pharmacokinetics of REOGEM and to describe any antitumor activity. Results: Since July 2007, 15 heavily pre-treated pts with disease progression prior to trial entry (9M/6F, median age 56 years, ECOG 0/1: 3/12) were entered into this trial. After 2 pts had Grade >3 toxicities during the first cycle (1 pt: GGT and Trop-I increase and PD; 1 pt: Trop-I increase and unspecific ST-changes) considered probably related to both agents the protocol was amended and the dose of REO was adjusted to 1x109 TCID50, d1 of each cycle (C-1) and increased in subsequent cohorts to 3x109, 1x1010, and 3x1010 TCID50. In total 45 cycles were administered (median 3) resulting in mild and expected toxicities including fever, headaches, rhinorrhea, fatigue and myelosupression. The MTD was not reached. Of the 10 pts evaluable for response, 2 pts (breast and nasopharyngeal) had PR and/or clinical response and 5 pts had SD for 4–8 cycles, amounting for a total disease control rate (CR+PR+SD) of 70%. Conclusions: The combination of REOGEM was well tolerated and resulted in disease control for a majority of pts. A RP2D, of REO 3x1010, d1 and GEM 1000mg/m2, d1 and 8, qw3, was recommended and phase-2 trials are underway. [Table: see text]
Further evaluation of 11C-PD153035 as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in non-small cell lung cancer patients
Authors: Yu J. , Liu N. , Hu M. , Song X. , Xie L. , Meng X. , Wang X. , Kong L. , Yang G. 
Published: August 2020

3590 Background: Epidermal growth factor receptor (EGFR) plays a key role in tumorgenosis and is therefore an important target for new therapeutic and prognostic strategies. Our pilot study has demonstrated that 11C-PD153035, a highly EGFR selective tracer for positron emission tomography (PET), accumulated in tumor mass of non-small cell lung cancer (NSCLC) and the tracer uptake correlated with EGFR expression. Here, we further evaluate correlation between the intensity of 11C-PD153035 uptake and EGFR protein expression level and gene mutation. Methods: Fourteen patients (45–71y, mean 59.2±9.2 y, Male: Female = 8:6, squamous carcinoma: adenocarcinoma = 9:5) with pathologically proved NSCLC were examined with PET using 11C-PD153035 one week before surgery. Radioactivity concentrations, derived from regions of interest (ROI), were analyzed mathematically to maximum standardized uptake value (SUVmax). The EGFR protein expression of surgical specimen was utilized by immunohistochemistry (IHC) with a three-tier system intensity scored and Western Blot assay. The EGFR genetic alterations in exon 19 and 21 were examined by direct sequencing of polymerase chain reaction (PCR) products. Results: 11C-PD153035 uptake was observed in 9 out of 14 NSCLC patients (mean SUV 3.94±1.06, range 0.8–5.9) and the biodistribution study further demonstrated accumulation of radioactivity in the tumor mass. The SUVmax of 11C-PD153035 molecular images did not correlate with tumor size and injection dose of the tracer. A closely correlation between SUVmax and EGFR protein expression as determined by IHC (r = 0.84, p = 0.005) was observed but not with the protein expression level of Western Blot analysis (r = 0.442, p = 0.114), as well as EGFR exon 19 (r = -0.078, p = 0.790) or exon 21 (r = 0.118, p = 0.689) gene mutation. With ROC analysis according to IHC intensity, the cut-off value of SUVmax was 2.45. Conclusions: PET with 11C-PD153035 might therefore be used to visualize EGFR pattern on tumor in NSCLC patients and for individualized planning of therapeutic strategies with EGFR targeted drugs, especially small-molecule TKIs (gefitinib and erlotinib) which targeting the intracellular EGFR tyrosine kinase domain as PD153035. No significant financial relationships to disclose.
Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database
Authors: Jackson McCleary N. A. , Meyerhardt J. , Green E. , Yothers G. , de Gramont A. , Van Cutsem E. , O’Connell M. , Twelves C. , Saltz L. , Sargent D. ,   The ACCENT Collaborative Group
Published: August 2020

4010 Background: Prior studies suggested that older and younger pts with colon cancer receive similar benefit from IV fluoropyrimidine (FU) adjuvant (adj) therapy (rx). Combination and/or oral FU rx are increasingly given as adj rx. We sought to determine the impact of pts age <70 v ≥70 yrs on colon cancer recurrence and mortality from adj rx with these newer options. Methods: We used data from 10,499 pts <70 yrs and 2,170 pts ≥70 yrs in 6 phase III adj rx trials comparing IV FU to combinations with irinotecan, oxaliplatin or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer from the ACCENT database. Endpoints were overall survival (OS; time to death), disease-free survival (DFS; time to recurrence or death), and time to recurrence (TTR; censoring at last follow-up). Cox models were stratified by age and adjusted for gender and stage; interaction testing was used to explore the differential benefit by age. Results: Approximately 75% of pts had stage III disease (74% age<70, 77% age≥70). OS, DFS, and TTR were statistically significantly improved for those in the experimental v control arms among pts <70 but not those >70 ( table ); the interaction between age and rx was statistically significant for all endpoints (p=0.01 for OS, DFS, and TTR). These results were consistent whether experimental rx was oxaliplatin-based, irinotecan-based or oral FU. Deaths in first 6 month of adj rx were not statistically significantly different between experimental and control arm. Conclusions: Our results show conclusively that pts >70 do not receive the same benefit from combination and/or oral FU as those <70. Any benefit, if present, compared to IV FU/LV would not be clinically meaningful. Outcomes of experimental (combination or oral FU) vs control (IV 5-FU) by treatment and age [Table: see text] [Table: see text]
Postoperative surveillance recommendations for early-stage colon cancer based on results from the clinical outcomes of surgical therapy trial
Authors: Tsikitis V. L. , Malireddy K. , Green E. A. , Christensen B. , Whelan R. , Hyder J. , Lauter D. , Marcello P. , Larach S. , Sargent D. , Nelson H. 
Published: August 2020

4013 Background: Intensive postoperative surveillance is associated with improved survival and recommended for patients with late stage (stage IIB & III) colon cancer. We hypothesized that stage I & IIA colon cancer patients would experience similar benefits. Methods: Secondary analysis of data from the Clinical Outcomes of Surgical Therapy trial was performed by analyzing results according to TNM stage; early (stage I & IIA; 537 patients) and late (stage IIB & III; 254 patients) stage disease. Five-year recurrence rates were higher in patients with late (35.7%) versus early stage disease (9.5%). Early and late stage salvage rates, recurrence patterns and methods of first detection were compared by χ2 test. Results: Salvage rates for early and late stage disease patients with recurrence were the same (35.9% versus 37%, p=0.9 respectively). Median survival following second surgery after recurrence was 35.8 months late stage and 51.2 months for early stage patients respectively. Sites of first recurrence did not significantly differ between late and early stage disease: liver (37.4% vs. 27.2%); lung (29.7% vs.23.6%); intraabdominal (24.2% vs.10.9%); and locoregional (12.1% vs.10.9%). Methods of first detection of recurrence were also not significantly different: CEA (37.4% vs. 29.1%); CT scan (26.4% vs. 23.6%); chest X-ray (12.1% vs. 7.3%); and colonoscopy (8.8% vs. 12.7%), for late versus early stage disease, respectively. Conclusions: Patients with early stage colon cancer have similar sites of recurrence, and receive similar benefit from post-recurrence therapy as later stage patients; implementation of existing surveillance guidelines for early stage patients is appropriate. No significant financial relationships to disclose.
Use of amphiregulin and epiregulin mRNA expression in primary tumors to predict outcome in metastatic colorectal cancer treated with cetuximab
Authors: Prenen H. , Jacobs B. , De Roock W. , Van Oirbeek R. , Biesmans B. , De Schutter J. , Fieuws S. , Laurent-Puig P. , Van Cutsem E. , Tejpar S. 
Published: August 2020

4019 Background: To study the power of two epidermal growth factor receptor (EGFR) ligands, epiregulin (EREG) and amphiregulin (AREG) expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab plus irinotecan. Methods: Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. ROC analysis was performed for response and survival data. Confidence intervals (CI) for the performance indices were obtained with a non-parametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting. Results: In KRAS wild-type (WT) patients, there was a significant association between log-transformed ligand expression and response (EREG: Odds ratio for objective response 1.90 (p=0.0005, 95%CI:1.27–2.83), c-index=0.681; AREG: Odds ratio for objective response: 1.82 (p=0.0017, 95%CI:1.22–2.72), c-index=0.673). In a Cox- regression model log-transformed ligand expression was significantly associated to progression-free survival (PFS) and overall survival (OS) (EREG: hazard ratio (HR) for PFS: 0.61 (p<0.001, 95%CI:0.51–0.73), cτ-index=0.696; AREG: HR for PFS: 0.60 (95%CI:0.50–0.74), cτ-index=0.671; EREG: HR for OS: 0.61 (p<0.001, 95%CI:0.50–0.73), cτ-index=0.667; AREG: HR for OS: 0.65 (p<0.001, 95%CI:0.54–0.78), cτ-index=0.642). There was no predictive power of ligand expression in KRAS mutant patients. Conclusions: Expression of EGFR ligands in primary tumors significantly predicts favorable outcome in KRAS WT cmCRC treated with cetuximab and irinotecan. [Table: see text]
-93G>A polymorphism of hMLH1 associated with prognosis for patients with colorectal cancer
Authors: Kim J. , Chae Y. , Sohn S. , Kang B. , Lee S. , Lim K. , Choi G. , Baek J. 
Published: August 2020

4039 Background: Polymorphisms in the DNA repair genes may contribute to variation in DNA repair capacity, thereby affecting the risk of carcinogenesis and prognosis of colorectal cancer. Accordingly, the present study analyzed polymorphisms of DNA repair genes and their impact on the prognosis for patients with colorectal cancer. Methods: Three hundred and ninety- seven consecutive patients with curatively resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 14 polymorphisms of DNA repair genes (XRCC1, hMLH1, ERCC2, ERCC4, VARS2[rs2074511, rs2249459], XPA, XPC, POLR2A, POLR2B, RFC1, RFC4, XAB2, DNMT3B) determined using a PCR-RFLP assay. Results: The median age of the patients was 63 years (range, 21–85), and 218 (54.9%) patients had colon cancer and 179 (45.1%) patients rectal cancer. Pathologic stages after surgery were as follows: stage 0/I (n=86, 21.7%), stage II (n=146, 36.8%), stage III (n=145, 36.5%), and stage IV (n=20, 5.0%). Multivariate survival analysis including stage, differentiation, age, and CEA level showed that the survival for the patients with the -93AA genotype of hMLH1 was worse than for the patients with the combined -93GG and GA genotype (overall survival: hazard ratio [HR]=2.953, 95% Confidential Interval [CI], 1.273–6.850, P=0.012; disease-free survival: HR=2.299, 95% CI, 1.417–3.730, P=0.001), whereas the other polymorphisms were not associated with survival. Conclusions: The -93G>A polymorphism of hMLH1 was found to be an independent prognostic marker for patients with colorectal cancer. Accordingly, in addition to the pathologic stage, the analysis of -93G>A polymorphism of hMLH1 can help identify patient subgroups at high risk of a poor disease outcome. No significant financial relationships to disclose.
The impact of the number of lymph node metastases on the overall recurrence of colon cancer in the era of sentinel lymph node mapping
Authors: Arora M. L. , Saha S. , Sirop S. , Chakravarty B. , Korant A. , Soni M. , Wiese D. , Desai D. , Ganatra B. , Kaushal S. , Iddings D. 
Published: August 2020

4049 Background: Sentinel Lymph Node Mapping (SLNM) in colon Cancerc (Cca) has been shown to be successful, sensitive and accurate. We aimed to evaluate the recurrence rates in patients(pts) with Cca after SLNM and correlate it to the number of positive(+ve) LNs. Methods: Between 1996 and 2006, pts diagnosed with Cca were enrolled in a prospective trial and underwent SLNM and oncologic resection including regional LNs. The primary outcome was development of recurrence with minimum follow-up (f/u) of 24 months. For recurrence analysis, exclusion criteria included: stage IV disease, benign pathology, lost to follow-up, refusal of indicated chemotherapy, non cancer related death or second cancer. A retrospective matched control (diagnosed with Cca undergoing standard colon resection without SLNM, gp B) from our own institution were analyzed and compared to the SLNM group for the same period. Results: A total of 486 pts with Cca were included. Of these, 272 consecutive pts underwent SLNM between 1996–2006. SLNM was successful in 99.8% of pts, with a sensitivity, negative (-ve) predictive value, and overall accuracy of 85.3%, 91.7% and 94.4% respectively. The nodal positivity was 46.0%; of these, 15.1% had micrometastasis. The average number of LNs resected / pt was 15.0 and the average number of SLNs / pt was 2.4. For recurrence analysis, 153/272 pts with minimum f/u 2 years were included. Of these, 49 had stage I, 46 had stage II and 58 had stage III disease. The recurrence rates were 4.1%, 8.6% and 15.5% in stage I, II, and III disease respectively. The recurrence rates were significantly lower when our 153 pts were compared to 214 matched controls ( table 1 ). The recurrence rates increased from 6.3% in pts with no +ve LNs to 11.5% when one LN was +ve, 16.7% when 2 LNs were +ve and 20% when 3 or more LNs were +ve. Conclusions: SLNM in Cca is associated with decreased rates of recurrence as compared to conventional therapy. The number of positive LNs is an independent risk factor for recurrence. [Table: see text] No significant financial relationships to disclose.
Colorectal cancer susceptibility variants and clinical outcome in adjuvant and metastatic colorectal cancer
Authors: Lenz H. , Lurje G. , Haiman C. A. , Yang D. , Pohl A. , Ning Y. , El-Khoueiry A. , Iqbal S. , Zhang W. 
Published: August 2020

4051 Background: Recent genome-wide association studies had identified colorectal cancer susceptibility loci on chromosomes 8q24 (rs6983267), 15q13(rs4779584), 18q21(rs4939827, rs12953717 and rs4464148), 10p14(rs10795668) and 8q23.3(rs16892766). Although the function role of these germline variants are unclear, given the importance of these variants and colorectal cancer risk, we have carried out the first pilot study to explore the association of these variants and clinical outcome. We used pooled data from two CRC-cohorts (locally advanced and metastatic CRC), and investigated the hypothesis that these germline variants may be associated with clinical outcome in adjuvant and metastatic colorectal cancer patients. Methods: Whole blood was collected from 515 patients with locally advanced (n=197) and metastatic CRC (n=318). After extraction of genomic-DNA, germline variants were genotyped as previously described (Haiman et al, Nat Genet, 2007). The genotype success rate was 98%. Blinded repeat samples (5%) were included for quality control purposes; genotype concordance was ≥ 99%. Results: Our results suggest that rs10795668 at 10p14 and rs719725 are significantly associated with time to tumor recurrence in adjuvant colorectal cancer patients, patients with rs10795668 AA genotype had significantly increased risk of time to tumor recurrence compared with those harboring G allele (TG+GG) patients(p=0.05, log-rank test). In metastatic cancer patients, we found rs4939827 at 18q21.1 were significantly associated with overall survival in female patients and rs10795668 at 10p14 were significantly associated with OS in male patients, respectively (p<0.05). Conclusions: Our preliminary results suggest cancer risk alleles may also associated with clinical outcome in adjuvant and metastatic colorectal cancer. Moreover, this correlation is sex-specific in metastatic colorectal cancer. Further comprehensive trials warranted to confirm our pilot findings. [Table: see text]