tbuckley/cabot-search huggingface dataset:
ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation.
Authors: Maeve Aine Lowery, Ghassan K. Abou-Alfa, Juan W. Valle, Robin Kate Kelley, Lipika Goyal, Rachna T. Shroff, Milind M. Javle, Mitesh J. Borad, James M. Cleary, Anthony B. El-Khoueiry, Johanna C. Bendell, Teresa Macarulla, Arndt Vogel, Christopher Korth, Liewen Jiang, Camelia Gliser, Bin Wu, Samuel V. Agresta, Shuchi Sumant Pandya, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2017)

TPS4142 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease for which there are limited therapeutic options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 25% of intrahepatic CC cases. mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite, D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme, and is being tested in a phase 1 study that enrolled 73 patients (pts) with mIDH1 CC who had received a median of 2 prior therapies (range 1–5). AG-120 has demonstrated a favorable safety profile and clinical activity in this study. Among the 72 efficacy evaluable pts (≥1 post-baseline response assessment or discontinued prematurely), 6% (n = 4) had a confirmed partial response and 56% (n = 40) had stable disease. Progression-free survival (PFS) rate at 6 months was 40% as of Dec 16, 2016. The 500 mg once daily (QD) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind study randomizing 186 pts with mIDH1 CC in a 2:1 ratio to AG-120 (500 mg QD) or matched placebo (NCT02989857). Key eligibility criteria: nonresectable or metastatic CC; documented mIDH1 based on central laboratory testing; ECOG 0–1; measurable disease (RECIST v1.1); documented disease progression following ≤2 prior systemic therapies in the advanced setting, including at least 1 gemcitabine- or 5-fluorouracil-containing regimen; and no prior mIDH inhibitor therapy. Crossover from the placebo arm to the AG-120 arm will be permitted. The primary endpoint is PFS as assessed by an independent review. Secondary endpoints include safety, tolerability, overall response rate, overall survival, pharmacokinetic and pharmacodynamic analyses on plasma, and quality of life as assessed by the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L instruments. An independent data monitoring committee will monitor the data throughout the study. The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea. Clinical trial information: NCT02989857.
Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer (AEGC).
Authors: Annette Van Zweeden, Cees Van Groeningen, Richard Honeywell, Rita Ruijter, Carolien H. Smorenburg, Giuseppe Giaccone, Henk M.W. Verheul, Godefridus J. Peters, Hans J. Van Der Vliet
Journal: Journal of Clinical Oncology (2016)

e15555 Background: The overall prognosis of patients with AECG is poor. Research suggests enhanced efficacy and reduced toxicity of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first line palliative chemotherapy with cisplatin and gemcitabine in patients with AEGC. Methods: Patients with AEGC (squamous cell/adenocarcinoma) were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without continuous folic acid 450 μg/day p.o. and vitamin B12 1000 μg i.m. q 9 weeks (supplemented vs unsupplemented pts). The primary end point was RR. Secondary end points included OS, PFS, toxicity, and exploratory biomarker analysis. Results: From October 2004 to September 2013, treatment was initiated in 78 of the 82 randomized pts, 39 in each study arm. RR was not statistically different for supplemented pts (42.1%, all PR) vs. unsupplemented pts (32.4%, 28.9% PR, 2.7% CR); p 0.71; HR 0.87 (95% CI 0.41-1.85) and did not meet the prespecified RR goal. Median OS and PFS were 10.0 and 5.7 months for supplemented vs 7.7 and 4.9 months for unsupplemented pts (OS p = 0.90; PFS p = 0.94). Homocysteine was lower in supplemented vs unsupplemented pts (n = 20, average 6.9 ± 1.6 µM; range 6.2 – 7.2 vs. av. 12.5 ± 4.0 µM; range 11.7 – 13.4; p < 0.001). Cmax of gemcitabine was identical (n = 20, dFdC Cmax 53.4 ± 18.6 µM for supplemented vs. 53.2 ± 15.0 µM for unsupplemented pts). Cisplatin levels were similar in both groups. Supplemented pts experienced slightly more grade 3 and 4 adverse events (AEs) (50 vs. 44 events). Leukopenia was the most common grade 3 AE in supplemented pts; n = 9 (22%) vs n = 4 (10%). Fatigue was the most frequent grade 3 AE for unsupplemented pts; n = 10 (24%) vs n = 4 (10%). Grade 4 AEs were thrombocytopenia in 3 supplemented pts (7%) and in 1 unsupplemented pt (2%); neurologic AEs in 2 (5%) supplemented pts and hemorrhage in 1 supplemented pt (2%). Grade 5 cardiac AEs occurred in 2 unsupplemented pts, probably chemotherapy related. Conclusions: Folic acid and vitamin B12 supplementation does not improve the RR, PFS or OS of cisplatin and gemcitabine in patients with AEGC.
Comprehensive genomic profiling of colorectal cancers with and without microsatellite instability (MSI) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST).
Authors: Kien Thiam Tan, Ming Huang Chen, Pei-Ning Yu, Yi-Lin Hsieh, Yen-Ting Liu, Shih-Ching Chang, Jen-Kou Lin, Jeng-Kai Jiang, Shung-Haur Yang, Shu-Jen Chen
Journal: Journal of Clinical Oncology (2018)

e15620 Background: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) represents a different type of genomic instability in colon cancer (CRC) in contrast to mono-, and dinucleotide based instability microsatellite instability (MSI). In this study, we performed comprehensive genomic profiling (CGP) of CRC patients with different EMAST and MSI status to gain insight into understanding of their genomic structure, which may help match them with relevant targeted therapies. Methods: Ninety-nine formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues were grouped into 4 categories based on EMAST and MSI status: (1) EMAST+ and MSI-high (MSI-H), (2) EMAST+ and microsatellite‐stable (MSS), (3) EMAST- and MSI-H, and (4) EMAST- and MSS. Next-generation sequencing (NGS) with a gene panel of 440 cancer-relevant genes was conducted at an average depth of >800x to identify mutation events, which include nucleotide substitutions, insertions and deletions (InDels). For tumor mutational burden (TMB), mutations detected on of exonic regions (1.17 Mb) were quantified. Results: The average TMB was significantly higher in tumors with concomitant EMAST+ and MSI-H signatures (subgroup (1) vs (2), (3) and (4); 54 vs 19, 25 and 16, p<0.0001). Dual positive tumors (EMAST+ and MSI-H) harbored less frequent mutations in TP53 (17.6%; n=3) and APC (23.5%; n=4) than other subgroups. In EMAST+ tumors, frequency of BRAF codon 600 mutations were significantly higher among MSI-H compared to MSS (41.2% vs 0 %, p=0.0072). MSI-H tumors had a higher prevalence of mutations that may confer primary resistance to anti-EGFR treatment, including PTEN inactivating, AKT1 activating (E17K), KRAS (exon 2, 3, 4) and BRAF V600 mutations, than MSS tumors (75.0% vs 47.5%, p=0.007). Conclusions: EMAST+ and MSI-H represents a unique subtype of CRC with distinctive genomic features that give the potential opportunity for targeted therapies and immunotherapies.
ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations.
Authors: Vincenzo Mazzaferro, Bassel F. El-Rayes, Christian Cotsoglou, William Proctor Harris, Nevena Damjanov, Gianluca Masi, Lorenza Rimassa, Nicola Personeni, Fadi S. Braiteh, Vittorina Zagonel, Kyriakos P. Papadopoulos, Terence Hall, Yunxia Wang, Giovanni Abbadessa, Brian E. Schwartz, Julia Kazakin, Michele Droz Dit Busset, Walid Labib Shaib
Journal: Journal of Clinical Oncology (2017)

4017 Background: FGFR genetic aberrations have been implicated in the development and progression of a number of solid tumor types, including iCCA. Pts with unresectable advanced iCCA who relapse after first-line chemotherapy have limited treatment options with poor prognosis. Recently, FGFR2 fusions, observed in up to 20% of pts, have been recognized as a potential therapeutic target. ARQ 087 is a multi-kinase inhibitor with a potent pan-FGFR activity. Methods: 119 cancer pts were enrolled in the phase 1/2, open-label study of ARQ 087. Study design and results of the phase 1were reported previously. Assessments included response by RECIST v1.1 every 8 wks, safety (physical examination, vital signs, ECOG PS, laboratory tests), plasma concentrations of phosphate and FGF19, 21 and 23 (potential biomarkers). Results: As of 1Feb17, 35 iCCA pts with FGFR2 genetic aberrations were treated with ARQ 087 300 (n = 33) or 400 mg (n = 2) daily. FGFR2 status was identified by FISH or NGS, 29/35 pts were FGFR2 fusion positive (FISH n = 15/18; NGS n = 14/17). Pts were all white, female (60%) with ECOG PS 0 (69%) and median age 58 yrs (31-82). Median number of prior systemic therapies was 1(0-6). Drug-related AEs (all grades) were reported in 89% of pts; the most common (≥10%) included nausea (37%), dry mouth (29%), asthenia (26%), fatigue, vomiting (23%, each), abnormal LFTs, dysgeusia (20%, each), alopecia, diarrhea, vision blurred (14%, each), and conjunctivitis (11%). Grade 3/4 AEs occurring in ≥2 pts were asthenia and abnormal LFTs (6%, each). AEs were mostly (71%) of mild to moderate intensity, manageable and reversible. Median time on treatment was 183 days (95%CI: 166-289). 19 pts were on treatment for &gt; 16 wks, nine are ongoing. 30 pts had at least one post-treatment radiographic assessment: 6 (20%) had PR (32-47% tumor reduction, all FGFR2 fusion positive), 17 SD (7 had tumor reduction between 10 to 25%), and 7 had PD. One pt died prior to scheduled assessment and assessment in 4 pts is pending. Conclusions: ARQ 087 demonstrated encouraging antitumor activity and manageable safety profile. Updated data, including safety, efficacy and biomarkers will be presented. Clinical trial information: NCT01752920.
Abstract 11332: Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis
Authors: Michael H Criqui, Matthew A Allison, Kevin P Cohoon, Julie O Denenberg, Alan Guerci, Joachim H Ix, Robyn McClelland, Preethi Srikanthan, Karol E Watson, Nathan D Wong
Journal: Circulation (2012)

We compared abdominal aortic calcium (AAC) with coronary artery calcium (CAC) in predicting cardiovascular disease (CVD) events and mortality in 1974 men and women randomly selected from a multi-et...
Right tumor, right time: Systematic methodology for fiducial marker placement to achieve reliable and reproducible image guided (IG) delivery of intratumoral immunotherapy into deep/visceral (D/V) lesions and target-lesion imaging follow-up.
Authors: Gregory Woodhead, Hani M. Babiker, Christopher Miller, Charles Hennemeyer, Ankit H Shah
Journal: Journal of Clinical Oncology (2018)

e24137 Background: Immunotherapy is revolutionizing the treatment of many malignancies. Trials evaluating the safety and efficacy of image guided (IG) intratumoral injection (ITI) of immunotherapy agents are ongoing in patients with Stage 4 disease. Toll-Like Receptor (TLR) agonists, including IMO-2125, augment the immunogenic response to neoplasms for patients with previously few therapeutic options. Treating D/V neoplasms via sequential IG ITI and following these lesions over time will be a challenge due to (1) multiple metastases within an organ, and (2) evolution of lesions over time. We propose a novel method of systematic fiducial marker placement to address these challenges. Methods: As part of a Phase 1b trial involving ITI of IMO-2125, we developed a method of fiducial marker placement in order to follow drug-treated and control D/V lesions over time. Index and treatment lesions were selected pre-operatively based on evaluation of CT and MR imaging. For each cohort, IMO-2125 is administered as a once-weekly ITI for 3 consecutive weeks in Cycle 1, followed by ITI in weeks 5, 8, 11, 17, 23, and 29 (Day 1 of Cycles 2-7). On Day 1 of Cycle 1, index and treatment lesions were labeled with a fiducial (PolyMark, CIVCO Medical Solution, Orange City, IA) prior to biopsy of both lesions and ITI of IMO-2125 into the treatment lesion. Results: We find that both treatment and control D/V lesions could be reliably and reproducibly indexed over the course of Cycle 1. The visibility of the PolyMark device on both US, CT, and MRI facilitates real-time IG ITI and long-term cross-sectional imaging follow-up, including trans-axial measurements of target and control D/V lesions. Conclusions: We outline a systematic and reproducible methodology for fiducial marker placement to plan D/V ITI of a novel TLR agonist, IMO-2125 during an ongoing Ph 1b trial. Fiducial placement facilitates reliable visualization of target and control tumors over the course of a multiple cycles of D/V ITI. Clinical trial information: NCT03052205.
Comorbidity and survival in locally advanced laryngeal cancer.
Authors: Collin Francis Mulcahy, Abdallah Mohamed, David Ira Rosenthal, Kate A. Hutcheson, Randal S. Weber, Stephen Yenzen Lai, Gary Brandon Gunn, Adam S. Garden, Mark Zafereo, William H. Morrison, Jan S. Lewin, Merrill S. Kies, Adel K. El-Naggar, Clifton David Fuller
Journal: Journal of Clinical Oncology (2016)

6038 Background: We aim to quantify the relationship between pretreatment comorbidity and survival outcomes for patients with locally-advanced larynx cancer. Methods: We retrospectively reviewed records of patients treated for T3 and T4 laryngeal squamous cell cancer at MD Anderson Cancer Center between 1985 and 2011 after institutional review board approval. Baseline pretreatment comorbidity data were collected and age-adjusted Charlson comorbidity index (CCI) was calculated for each case. Kaplan-Meier and Cox proportional hazards modeling were used to determine associations with survival. Results: Among 548 patients with median age of 59 years (range 31-91), 58% were treated with larynx preservation and the rest with total laryngectomy and adjuvant radiotherapy. 19% received induction chemotherapy (54% platinum + taxane, 40% platinum-based). 34% received concurrent therapy (84% platinum-based). 237 patients (43%) suffered at least one comorbid condition prior to therapy. Cardiovascular diseases were the most common comorbidity (43%). Recursive partitioning showed CCI > 3 associated with poorer outcomes (p < 0.001). For all patients, 5-yr and 10-yr overall survival (OS) for patients with CCI ≤ 3 (n = 443, 81%) were superior to CCI > 3 (n = 105, 19%), (P< 0.0001), though 5 and 10-yr disease-specific survival (DSS) were non-different (70% vs. 66% at 5-yr and 60% vs. 66% at 10-yr, P= 0.17). 5-yr and 10-yr non-cancer cause specific survival (NCCSS) improved for age adjusted CCI ≤ 3 (88% vs. 67% at 5-yr and 68% vs. 28% at 10-yr, P< 0.0001). Multivariate analysis revealed that age adjusted CCI > 3 and nodal staging as independent predictors for worse OS after Bonferroni correction (P = 0.0002 and P = 0.0001, respectively). Competing risk analysis showed risk of non-cancer death exceeded death from disease after 3 years for CCI > 3; while non-cancer risk of demise never exceeded cancer-specific risk during follow up for CCI ≤ 3. Conclusions: The age-adjusted Charlson comorbidity index is a significant predictor of NCCSS and OS for locally-advanced larynx cancer patients, but is not associated with DSS. After 3 years, patients with CCI > 3 have non-cancer mortality risk greater than that of cancer-related death.
Survival of patients treated by a Precision Oncology approach is determined by performance status and lines of therapy.
Authors: Bat-Ami Gordon, Jared Cotta, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2018)

12071 Background: Academic Medical Centers (AMC) and community practices are implementing Molecular Tumor Boards (MTB) to interpret next-generation sequencing (NGS) results and develop clinical guidelines for utilizing NGS results. Reports of MTB experiences from cancer centers nationally vary in their abilities to translate molecular test results to actionable recommendations for their patients. In these efforts, there is not yet a definition for parameters of patients who would benefit most from a Precision Oncology approach. Methods: Defining Platforms for Individualized Cancer Treatment (DePICT) is an IRB approved registry trial designed to monitor outcomes of Broward County, FL residents with late-stage refractory cancer (ECOG ≤2) who undergo NGS. After consent, the MTB used NGS results to match patients to targeted clinical trials and therapies. The patients are followed at 12 week intervals. DePICT has consented 141 patients, out of which 111 have had at least one follow up. We analyzed these cases to identify key characteristics of patients that benefit most from NGS testing and MTB review. Groups were defined as those who pursued targeted therapies versus those who pursued standard of care or palliative regimens. Kaplan Meier survival analyses were done in R 3.4.3. Results: Patients with ≤3 previous lines of therapy were more likely to pursue targeted therapy than patients with ≥4 lines of therapy (32% vs. 17%, p = 0.045). Only patients with an ECOG score 0 or 1 pursued targeted therapy. An analysis of this population (ECOG < 2, ≤3 lines of therapy) revealed that patients on targeted therapy performed better than their palliative care counterparts. Median overall survival (mOS) for patients who received targeted therapy is 84 weeks (95% CI 36-Not Reached (NR)) and the mOS for patients who did not undergo targeted therapies was 36 weeks (95% CI 36-NR). Conclusions: This analysis identifies patients who may benefit most from NGS testing. Patients with ECOG scores of 0 or 1 and 3 or fewer lines of therapy were more likely to go on targeted therapy, and have better outcomes. Patients should be evaluated by precision oncology approaches earlier in their cancer care continuum.
Clonal repopulation dynamics in recurrent human papillomavirus-associated head and neck cancer.
Authors: Richard A. Harbison, Mark Kubik, Eric Konnick, Daniel Faden, Chang Xu, Colin Pritchard, Cristina P. Rodriguez, Qing Zhang, Jeffrey J. Delrow, Chu Chen, Eduardo Mendez, Umamaheswar Duvvuri
Journal: Journal of Clinical Oncology (2017)

e17517 Background: Despite the better prognosis for human papillomavirus (HPV)-associated head and neck cancer (HNC) relative to HPV-negative HNC, 10 to 25% of HPV-associated cases recur within 3 years of completing therapy. We sought to investigate clonal repopulation dynamics in recurrent HPV-related oropharyngeal squamous cell carcinoma (OPSCC). Methods: Deep sequencing ( &gt; 500X) using a CLIA-certified, targeted 262-gene multiplexed assay was performed on DNA extracted from 11 pairs of matched FFPE-preserved primary and subsequent recurrent p16-positive OPSCC samples including two pairs from the University of Washington and nine from the University of Pittsburgh. Results: 82% of patients were male with a median (IQR) age of 62 (15) years. Nine of eleven patients presented with advanced stage disease. Five were initially treated with surgery and concurrent chemoradiation, two with surgery, and four with concurrent chemoradiation. Median (IQR) time to recurrence was 10 (10.5) months. Four patients reported a history of tobacco use. The mean (SD) number of somatic nucleotide variants (SNVs) per tumor was 16.4 (12.2). 42% of SNVs occurred in the primary alone while 28% were unique to recurrences. 28% of SNVs were shared between primary-recurrent pairs. Three patients with distant or regional recurrences had different mutational profiles between the primary and recurrence suggesting repopulation by an early-appearing clone vs sampling error. One patient developed two local recurrences with conserved mutations in addition to de novo mutations in each subsequent recurrence suggesting repopulation by early and late evolving clones. Genes with a substantial functional impact that were frequently mutated in primary tumors include IDH2 and FBXW7. Recurrently mutated genes found in recurrent tumors include TET3, PIK3CA, STK11, and HDAC4. Conclusions: In thistargeted exome sequencing study of matched primary-recurrent OPSCC tumor pairs, we observed clonal repopulation with both transmitted and de novo mutations. Intriguingly, we noted a predilection for mutations involving genes regulating metabolism including IDH2 among primary tumors which has potential implications for precision medicine approaches.
Metabolomics signature in serum months to years before thoracic cancer: The HUNT study.
Authors: Oluf D. RÃ¸e, Vincenzo Lagani, Hans Fredrik Kvitvang, Maria Markaki, Ioannis Tsamardinos, Robin Mjelle
Journal: Journal of Clinical Oncology (2017)

e23059 Background: The Cancer-Biomarkers in HUNTinitiative seeks to identify novel biomarkers for the early cancer diagnosis. For lung cancers and mesothelioma clinically useful early markers are not available. In the prospective HUNT study in Norway, pre-diagnostic samples ranging 0-20 years before diagnosis are available for research purposes. Here we present our first results on high-throughput metabolomics analysis in serum two months to 16 years before diagnosis. Methods: LC-MS untargeted (Amide-) metabolites (n = 1042) were profiled in serum samples from 48 future patients (12 each of adeno-, squamous cell carcinoma, small-cell lung cancer and mesothelioma) and from 48 controls that were cancer-free 5 years after blood sampling. All were active smokers. Metabolic features for (a) each cancer and (b) all cancers pooled together were analyzed with moderated t-test (R limma package). Multivariate analyses included (a) OPLS-DA and (b) signature identification through a data-analysis pipeline that includes feature selection (such as the algorithm in [1]), non-linear modelers (e.g., Random Forests) and Cross-Validation with bootstrapping [2] for optimizing algorithms and providing unbiased performance estimation. The pipeline is implemented in the Just Add Data software (Gnosis Data Analysis). Results: Univariate and OPLS-DA analyses did not identify any association between metabolites and cancer. The non-linear data analysis pipeline identified a signature containing five metabolites able to discriminate between cancer and non-cancer patients, statistically significantly better than random (AUC = 0.667, CI = [0.536, 0.784]). Conclusions: Our results indicate that metabolic profiling in serum may help in identifying subjects who are likely to be diagnosed with lung cancer/mesothelioma in a time period of several years before diagnosis. More data will be presented at the annual meeting. Further validation studies are planned for confirming the replicability of these findings. 1) Lagani V et al., 2016. arXiv:1611.03227 2) Greasidou L, 2017. Bias Correction of the Cross-Validation Performance Estimate and Speed Up of its Execution Time, MSc Thesis, University of Crete