Clinical Trial Eligibility Criteria Research Articles

Comparison of Drug Discontinuation, Effectiveness, and Safety Between Clinical Trial Eligible and Ineligible Patients in BADBIR

Patients with psoriasis enrolled in clinical trials of biologics may not be representative of the real-world population. There is evidence that patients ineligible for such trials have a greater risk of serious adverse events (SAEs), but the effect on drug discontinuation and effectiveness are unknown. To determine whether (1) drug discontinuation, (2) effectiveness, and (3) rates of SAEs differ in patients with psoriasis categorized as eligible or ineligible for clinical trials. An observational study using 157 dermatology centers in the United Kingdom and Republic of Ireland was carried out wherein we applied the eligibility criteria of clinical trials of biologic therapies for psoriasis to patients who were being followed up in the British Association of Dermatologists Biologic Interventions Register (BADBIR) and being prescribed biologics as part of standard clinical care. Patients with psoriasis registered to BADBIR who were taking etanercept (enbrel only; n = 1509), adalimumab (n = 4000), and ustekinumab (n = 1627) with at least 1 follow-up visit. Eligibility criteria were extracted from phase 3 licensing trials for etanercept, adalimumab, and ustekinumab for the treatment of moderate to severe psoriasis. Patients in BADBIR with a missing baseline Psoriasis Area and Severity Index (PASI) or baseline PASI value less than 10 (etanercept) or less than 12 (adalimumab; ustekinumab) but who would otherwise be eligible were investigated separately. Eligibility categories applied to BADBIR included: eligible, ineligible, insufficient baseline PASI only, and missing baseline PASI only. (1) Drug discontinuation: cumulative incidence at 12 months by stop reason per eligibility category and drug; (2) effectiveness: linear regression of absolute change in PASI from baseline to 6 and 12 months; and (3) SAEs: incidence rate ratio (IRR) at 12 months between eligibility categories per drug. The mean (SD) age of the 7136 patients included in the analysis was 45 (13) years and 2924 (41%) were women and 4212 (59%) were men. Of 7136 patients, 839 (56%) etanercept, 2219 (56%) adalimumab, and 754 (46%) ustekinumab registrations were categorized as eligible. The most common reasons for ineligibility were diabetes (etanercept, 143 [9%]; ustekinumab, 201 [12%]) and nonchronic plaque psoriasis (adalimumab, 157 [4%]). Patients categorized as ineligible (etanercept, 367 [24%]; adalimumab, 282 [7%]; ustekinumab, 394 [24%]) achieved a smaller absolute change in PASI after 6 and 12 months (adalimumab, ustekinumab), and had significantly higher rates of SAEs compared with the eligible category (etanercept: IRR, 1.9; 95% CI, 1.4-2.6; adalimumab: IRR, 2.0; 95% CI, 1.5-2.6; ustekinumab: IRR, 2.8; 95% CI, 2.1-3.8). No significant differences in drug discontinuation were observed between categories. Clinical trial effectiveness and safety outcomes are not representative of real-world patients in BADBIR patients categorized as ineligible for such trials.

An observational study profiling biospecimens from 10,000 metastatic prostate cancer (mPCa) patients to screen for molecular alterations.

TPS402 Background: Despite recent success in development and use of targeted agents in patients with solid tumors, there is a paucity of such therapies approved for use in prostate cancer. This observational study provides next-generation sequencing (NGS) to men with mPCa to evaluate the proportion of patients available for targeted therapy clinical trials in mPCa and to assess the feasibility of using a large-scale NGS screening program to match patients for eligibility criteria in clinical trials. Methods: Using a virtual clinical trial model to maximize patient access and enrollment, this study is providing next-generation sequencing (NGS) to 10,000 men with mPCa. Patients with histologically-documented mPCa and surplus formalin-fixed paraffin-embedded tumor tissue are eligible for enrollment. Leftover archival tissue is submitted for NGS to Strata Oncology, a clinical laboratory improvement amendments (CLIA)-certified lab. The StrataNGS assay sequences DNA and RNA, and simultaneously detects a range of actionable genomic alterations including gene mutations, small insertions and deletions, copy number changes, and gene fusions in 87 cancer-related genes. Microsatellite instability status is determined via the number of length variant alleles observed in NGS sequencing data at several microsatellite loci. Test reports presented to the clinician include all positive and negative variants detected, and information about potential matching therapeutic protocols. Clinical trial information: NCT03061305.

Mesopic and Dark-Adapted Two-Color Fundus-Controlled Perimetry in Choroidal Neovascularization Secondary to Age-Related Macular Degeneration.

PurposeTo determine the retest variability of mesopic and two-color dark-adapted (DA) fundus-controlled perimetry (FCP), to evaluate the predictive value of patient reliability indices, and to analyze the extent of impairment of rod- and cone function in neovascular age-related macular degeneration (nAMD).MethodsA total of 50 eyes of 50 patients with nAMD (mean age, 76.1 years) and 70 eyes of 70 age-similar normal subjects underwent multimodal imaging as well as mesopic and DA two-color perimetry using the S-MAIA device. A subset of patients (n = 28) underwent duplicate testing for retest reliability assessment. Mixed models were used for analysis of the hierarchical data.ResultsIn eyes with nAMD, the coefficient of repeatability was (mean ± standard deviation [SD]) 5.99 ± 1.55 dB for mesopic, 6.14 ± 2.19 dB for DA cyan, and 6.06 ± 1.09 dB for DA red testing. “Patient reliability indices” explained 55%, 54.2%, and 64.2% of the variance in retest variability. The mean sensitivity loss was greater for DA cyan compared to DA red testing (cyan-red differences [mean ± SD] −2.63 ± 3.87 dB, P < 0.001).ConclusionsThe relatively greater degree of DA cyan versus DA red sensitivity loss indicates preferential rod vulnerability in nAMD, and qualifies rod function-based outcomes measures as potential sensitive and early markers of treatment response in nAMD.Translational RelevanceThe S-MAIA allows reliable testing of mesopic, DA cyan, and DA red sensitivity in patients with nAMD. Patient reliability indices may serve as eligibility criteria for clinical trials to identify patients with adequate retest reliability.

Efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer not meeting trial eligibility criteria: a retrospective study

BackgroundThe efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer has been demonstrated in phase III trials. However, as patients receiving eribulin in daily practice do not necessarily meet all the eligibility criteria of clinical trials, data for such patients are limited.MethodsWe identified patients with locally advanced or metastatic breast cancer, treated with eribulin monotherapy between July 2011 and December 2015 at the National Cancer Center Hospital, Tokyo, Japan. Patients who would have met the following eligibility criteria from the EMBRACE trial were included in the eligible group, and the rest were included in the ineligible group: 1) Eastern Cooperative Oncology Group Performance status 0–2; 2) adequate function of principal organs; and 3) absence of active infection. We compared the relative dose intensity (RDI), tumor response, progression-free survival (PFS), overall survival (OS), and adverse events between the groups. Nominal and continuous values were compared using the Fisher’s exact test and Mann-Whitney U test, respectively. Survival outcomes were determined using Kaplan-Meier estimation, and between-group differences were assessed using the log-rank test.ResultsOf the 203 patients included, 34 were classified into the ineligible group and 169 into the eligible group. Initial dose reduction and treatment discontinuation due to adverse events (AEs) were more common in the ineligible group (initial dose reduction: 23.5% in the ineligible group vs. 7.7% in the eligible group, p = 0.011; treatment discontinuation due to AEs: 11.8% vs. 3.0%, p = 0.045). However, RDI (66% vs. 71%, p = 0.130), response rate (15.6% vs. 18.1%, p = 1.000), PFS (3.7 months vs. 4.0 months, p = 0.913), OS (11.5 months vs. 16.1 months, p = 0.743), AEs requiring hospitalization (5.9% vs. 6.5%, p = 1.000), and grade 3/4 AEs were similar in both groups. PFS, OS, AEs requiring hospitalization, and discontinuation due to AEs in the eligible group were comparable to those found in previous phase III trials.ConclusionThe safety and efficacy of eribulin monotherapy was demonstrated in a broader patient population than that eligible for clinical trials. Eribulin may be a treatment option in these patients with locally advanced or metastatic breast cancer, considering dose reduction and pre-existing dysfunctions.

Generalizability of Clinical Trial Results for Adolescent Major Depressive Disorder.

Although there have been a number of clinical trials evaluating treatments for adolescents with major depressive disorder (MDD), the generalizability of those trials to samples of depressed adolescents who present for routine clinical care is unknown. Examining the generalizability of clinical trials of pharmacological and psychotherapy interventions for adolescent depression can help administrators and frontline practitioners determine the relevance of these studies for their patients and may also guide eligibility criteria for future clinical trials in this clinical population. Data on nationally representative adolescents were derived from the National Comorbidity Survey: Adolescent Supplement. To assess the generalizability of adolescent clinical trials for MDD, we applied a standard set of eligibility criteria representative of clinical trials to all adolescents in the National Comorbidity Survey: Adolescent Supplement with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD (N = 592). From the overall MDD sample, 61.9% would have been excluded from a typical pharmacological trial, whereas 42.2% would have been excluded from a psychotherapy trial. Among those who sought treatment (n = 412), the corresponding exclusion rates were 72.7% for a pharmacological trial and 52.2% for a psychotherapy trial. The criterion leading to the largest number of exclusions was "significant risk of suicide" in both pharmacological and psychotherapy trials. Pharmacological and, to a lesser extent, psychotherapy clinical trials likely exclude most adolescents with MDD. Careful consideration should be given to balancing eligibility criteria and internal validity with applicability in routine clinical care while ensuring patient safety.

Re-Evaluating Eligibility Criteria for Oncology Clinical Trials: Analysis of Investigational New Drug Applications in 2015.

Clinical trial eligibility criteria are necessary to define the patient population under study and improve trial safety. However, there are concerns that eligibility criteria for cancer clinical trials are too restrictive and limit patient enrollment in clinical trials. Recently, there have been initiatives to re-examine and modernize eligibility criteria for oncology clinical trials. To assess current eligibility requirements for cancer clinical trials, we have conducted a comprehensive review of eligibility criteria for commercial investigational new drug clinical trial applications submitted to the US Food and Drug Administration Office of Hematology and Oncology Products in 2015. Our findings suggest that eligibility criteria for current cancer clinical trials tend to narrowly define the study population and limit the study to lower-risk patients, which may not be reflective of the greater patient population outside of the study. We discuss potential areas for expanding eligibility criteria to include more patients in clinical trials and design options for clinical trials incorporating expanded eligibility criteria. The broadening of clinical trial eligibility criteria can be considered to better reflect the real-world patient population, improve clinical trial participation, and increase patient access to new investigational treatments.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group.

Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute-sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute-sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group.

Purpose Patients with organ dysfunction, prior or concurrent malignancies, and comorbidities are often excluded from clinical trials. Excluding patients on the basis of these factors results in clinical trial participants who are healthier and younger than the overall population of patients with cancer. Methods ASCO and Friends of Cancer Research established a multidisciplinary working group that included experts in trial design and conduct to examine how eligibility criteria could be more inclusive. The group analyzed current eligibility criteria; conducted original data analysis; considered safety concerns, potential benefits, research, and potential hurdles of this approach through discussion; and reached consensus on recommendations regarding updated eligibility criteria that prioritize inclusiveness without compromising patient safety. Results If renal toxicity and clearance are not of direct treatment-related concern, then patients with lower creatinine clearance values of > 30 mL/min should be included in trials. Inclusion of patients with mild to moderate hepatic dysfunction may be possible when the totality of the available nonclinical and clinical data indicates that inclusion is safe. Ejection fraction values should be used with investigator assessment of a patient's risk for heart failure to determine eligibility. Patients with laboratory parameters out of normal range as a result of hematologic disease should be included in trials. Measures of patient functional status should be included in trials to better assess fit versus frail patients. Conclusion Expanding inclusion of these patients will increase the number and diversity of patients in clinical trials and result in a more appropriate population of patients.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group.

Purpose Broadening trial eligibility to improve accrual and access and to better reflect intended-to-treat populations has been recognized as a priority. Historically, patients with brain metastases have been understudied, because of restrictive eligibility across all phases of clinical trials. Methods In 2016, after a literature search and series of teleconferences, a multistakeholder workshop was convened. Our working group focused on developing consensus recommendations regarding the inclusion of patients with brain metastases in clinical trials, as part of a broader effort that encompassed minimum age, HIV status, and organ dysfunction. The working group attempted to balance the needs of protecting patient safety, facilitating access to investigational therapies, and ensuring trial integrity. On the basis of input at the workshop, guidelines were further refined and finalized. Results The working group identified three key populations: those with treated/stable brain metastases, defined as patients who have received prior therapy for their brain metastases and whose CNS disease is radiographically stable at study entry; those with active brain metastases, defined as new and/or progressive brain metastases at the time of study entry; and those with leptomeningeal disease. In most circumstances, the working group encourages the inclusion of patients with treated/stable brain metastases in clinical trials. A framework of key considerations for patients with active brain metastases was developed. For patients with leptomeningeal disease, inclusion of a separate cohort in both early-phase and later-phase trials is recommended, if CNS activity is anticipated and when relevant to the specific disease type. Conclusion Expanding eligibility to be more inclusive of patients with brain metastasis is justified in many cases and may speed the development of effective therapies in this area of high clinical need.

How Do Patients With Idiopathic Pulmonary Fibrosis in the Real World Compare With Eligibility Criteria for Clinical Trials?

SESSION TITLE: Diffuse Lung Disease 2 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Few data are available describing how the characteristics of patients with idiopathic pulmonary fibrosis (IPF) in the real world compare with those eligible for participation in clinical trials. We compared the characteristics of patients with IPF enrolled in the ongoing Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry with eligibility criteria for recent clinical trials in IPF. METHODS: The IPF-PRO Registry includes patients recently diagnosed with IPF at the enrolling site. We compared the characteristics of patients in the IPF-PRO Registry (regardless of whether they were treated with antifibrotic drugs) with eligibility criteria for clinical trials. Data were analyzed from patients enrolled at 18 ILD centers in the US from 5 June 2014 to 24 October 2016 who had complete information on treatment status at baseline defined as status of nintedanib or pirfenidone use prior to, at the time of, or within 30 days after enrollment into the registry. The proportions of patients who met the key eligibility criteria for participation in the INPULSIS trials of nintedanib or the ASCEND trial of pirfenidone at enrollment were analyzed descriptively. RESULTS: Of 419 patients analyzed, 73.9% were male, median age was 70 years, 55.4% were treated with nintedanib or pirfenidone at baseline. At enrollment, median FVC was 69.8% predicted and median DLco was 41.6% predicted. All patients met the inclusion criteria for diagnosis of IPF within the previous 5 or 4 years as required in INPULSIS or ASCEND, respectively. All patients met the age criterion of ≥40 years and 92.8% met the age criteria of 40-80 years as required in INPULSIS and ASCEND, respectively. Of patients with available values at enrollment for FVC (n=371) and DLco (n=360), most patients met the trials’ eligibility criteria for lung function impairment. As required in INPULSIS, 90.3% of patients had FVC ≥50% predicted and 78.1% had DLco between 30% and 79% predicted. As required in ASCEND, 76.5% had FVC between 50% and 90% predicted and 78.6% had DLco between 30% and 90% predicted. Of patients with HRCT data available (n=412), 92.2% had an HRCT performed in the previous 12 months (as required in INPULSIS). Of patients with data available on 6-minute walk test (6MWT) at enrollment (n=281), 94.3% of patients had a 6MWT distance of ≥150 m (as required in ASCEND). CONCLUSIONS: While the designs of registries and randomized controlled trials differ, comparison of registry-enrolled patients to eligibility criteria for clinical trials may provide insights for evaluation of antifibrotic drug prescribing patterns or treatment response in a real-world setting. Although there are similarities in the patient population enrolled in clinical trials and in the IPF-PRO Registry, the IPF-PRO Registry includes a broader population. CLINICAL IMPLICATIONS: The ongoing IPF-PRO Registry will provide insights into the characteristics of patients with IPF, current practice in diagnosis and treatment, and the clinical course of the disease. Assessing the characteristics and the journey for patients with IPF enrolled in the IPF-PRO Registry will provide more information on the real-world population. Primary source of funding: Boehringer Ingelheim Pharmaceuticals, Inc. DISCLOSURE: Victoria Gamerman: Employee: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Daniel Culver: Consultant fee, speaker bureau, advisory committee, etc.: Advisory board for steering commitee (Boehringer Ingelheim) Thomas Leonard: Employee: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Craig Conoscenti: Employee: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Scott Palmer: Grant monies (from industry related sources): Grant paid by Boehringer Ingelheim to Duke Clinical Research Institute (DCRI) The following authors have nothing to disclose: Margaret Salisbury, Megan Neely, Eric Yow No Product/Research Disclosure Information

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OBJECTIVES/SPECIFIC AIMS: This poster presents a detailed characterization of the distribution of semantic concepts used in the text describing eligibility criteria of clinical trials reported to ClincalTrials.gov and patient notes from MIMIC-III. The final goal of this study is to find a minimal set of semantic concepts that can describe clinical trials and patients for efficient computational matching of clinical trial descriptions to potential participants at large scale. METHODS/STUDY POPULATION: We downloaded the free text describing the eligibility criteria of all clinical trials reported to ClinicalTrials.gov as of July 28, 2015, ~195,000 trials and ~2,000,000 clinical notes from MIMIC-III. Using MetaMap 2014 we extracted UMLS concepts (CUIs) from the collected text. We calculated the frequency of presence of the semantic concepts in the texts describing the clinical trials eligibility criteria and patient notes. RESULTS/ANTICIPATED RESULTS: The results show a classical power distribution, Y=210X(−2.043), R2=0.9599, for clinical trial eligibility criteria and Y=513X(−2.684), R2=0.9477 for MIMIC patient notes, where Y represents the number of documents in which a concept appears and X is the cardinal order the concept ordered from more to less frequent. From this distribution, it is possible to realize that from the over, 100,000 concepts in UMLS, there are only ~60,000 and 50,000 concepts that appear in less than 10 clinical trial eligibility descriptions and MIMIC-III patient clinical notes, respectively. This indicates that it would be possible to describe clinical trials and patient notes with a relatively small number of concepts, making the search space for matching patients to clinical trials a relatively small sub-space of the overall UMLS search space. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results showing that the concepts used to describe clinical trial eligibility criteria and patient clinical notes follow a power distribution can lead to tractable computational approaches to automatically match patients to clinical trials at large scale by considerably reducing the search space. While automatic patient matching is not the panacea for improving clinical trial recruitment, better low cost computational preselection processes can allow the limited human resources assigned to patient recruitment to be redirected to the most promising targets for recruitment.

Impact of prior malignancies on the outcome of colorectal cancer: Revisiting clinical trial eligibility criteria

Impact of prior malignancies on the outcome of colorectal cancer: Revisiting clinical trial eligibility criteria

Thoracic Oncology Clinical Trial Eligibility Criteria and Requirements Continue to Increase in Number and Complexity

IntroductionEligibility criteria and screening procedures are designed to optimize the scientific yield and maximize the safety of clinical trials. However, they may also heighten trial complexity, hinder enrollment, decrease generalizability, and increase costs. We analyzed the types and number of eligibility criteria and screening procedures among thoracic oncology clinical trials sponsored or endorsed by the Eastern Cooperative Oncology Group. MethodsWe identified trials and obtained protocols from the Eastern Cooperative Oncology Group website. Eligibility criteria were grouped and categorized as comorbidity (classified by organ system), administrative requirements, prior treatment, and measurable disease requirements. Associations between trial characteristics and eligibility criteria were analyzed by using the Kruskal-Wallis and Wilcoxon tests. ResultsA total of 74 lung cancer trials activated in 1986–2016 were identified. The total number of eligibility criteria was associated with trial principal therapy (a median of nine for surgical, 18 for radiation, and 20 for medical therapy [p = 0.02]), trial primary end point (a median of 20 for overall survival, 28 for progression-free survival, and 17 for other [p = 0.001]), number of therapies (p = 0.05), and year of activation (a median of 16 for 1986–1995, 19 for 1996–2005, and 27 for 2006–2016 [P < 0.001]). The increase in trial eligibility requirements over time was limited to medical therapy trials. Over time, there was also an increase in blood test screening procedures (p = 0.05) but not in imaging, cardiac assessment, or pulmonary function screening procedures. ConclusionsThe number of eligibility criteria and screening procedures in medical therapy lung cancer clinical trials continues to rise. Continued efforts to simplify protocol eligibility and procedures are warranted to promote trial adherence, enrollment, completion, and generalizability.

Algorithmic matching of genomic profiles to precision cancer medicine clinical trials at DFCI.

6620 Background: Genomic profiling and access to precision medicine clinical trials are now standard at leading cancer institutes and many community practices. Interpreting patient-specific genomic information and tracking the complex criteria for precision medicine trials requires specialized computational tools, especially for multi-institutional basket studies such as NCI-MATCH and TAPUR. Methods: To address this challenge we have developed an open source computational platform for patient-specific clinical trial matching at Dana-Farber Cancer Institute (DFCI) called MatchMiner, which aides in both patient recruitment to precision medicine trials, as well as decision support for oncologists. Trial matches are computed based on genomic criteria, including mutations, CNAs, and SVs, as well as clinical and demographic information, including cancer type, age, and gender. A formal standard called clinical trial markup language (CTML) to encode complex clinical trial eligibility criteria has also been created. Results: MatchMiner is now available at DFCI. Currently 123 precision medicine clinical trials have been transformed into CTML and 13,000 patient records are available, with over 88% of current patients having at least 1 match (average 2.6). A total of 103 genes are specified as criteria for at least 1 trial. KRAS, TP53, PTEN, PIK3CA and BRAF are the genes driving the most number of matches. General usage statistics and trial enrollment rates are currently being monitored to determine the system effectiveness. As this is an open source initiative, the software is also now publically available at https://github.com/dfci/matchminer. Conclusions: We have developed an open source computational platform that enables patient-specific matching and recruitment to precision medicine clinical trials at DFCI. We are actively seeking collaborators and plan to make CTML a multi-institution standard for encoding complex clinical trial eligibility in a computable form.

EliIE: An open-source information extraction system for clinical trial eligibility criteria.

To develop an open-source information extraction system called Eligibility Criteria Information Extraction (EliIE) for parsing and formalizing free-text clinical research eligibility criteria (EC) following Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) version 5.0. EliIE parses EC in 4 steps: (1) clinical entity and attribute recognition, (2) negation detection, (3) relation extraction, and (4) concept normalization and output structuring. Informaticians and domain experts were recruited to design an annotation guideline and generate a training corpus of annotated EC for 230 Alzheimer's clinical trials, which were represented as queries against the OMOP CDM and included 8008 entities, 3550 attributes, and 3529 relations. A sequence labeling-based method was developed for automatic entity and attribute recognition. Negation detection was supported by NegEx and a set of predefined rules. Relation extraction was achieved by a support vector machine classifier. We further performed terminology-based concept normalization and output structuring. In task-specific evaluations, the best F1 score for entity recognition was 0.79, and for relation extraction was 0.89. The accuracy of negation detection was 0.94. The overall accuracy for query formalization was 0.71 in an end-to-end evaluation. This study presents EliIE, an OMOP CDM-based information extraction system for automatic structuring and formalization of free-text EC. According to our evaluation, machine learning-based EliIE outperforms existing systems and shows promise to improve.

A novel semantic representation for eligibility criteria in clinical trials

Eligibility Criteria (EC) comprise an important part of a clinical study, being determinant of its cost, duration and overall success. Their formal, computer-processable description can significantly improve clinical trial design and conduction by enabling their intelligent processing, replicability and linkability with other data. For EC representation purposes, related standards were investigated, along with published literature. Moreover, a considerable number of clinicaltrials.gov studies was analyzed in collaboration with clinical experts for the determination and classification of parameters of clinical research importance. The outcome of this process was the EC Representation; a CDISC-compliant schema for organizing criteria along with a patient-centric model for their formal expression, properly linked with international classifications and codifications. Its evaluation against 200 randomly selected EC indicated that it can adequately serve its purpose, while it can be also combined with existing tools and components developed for both EC specification and especially application to Electronic Health Records.

Use of the Total Cancer Care System to Enrich Screening for CD30-Positive Solid Tumors for Patient Enrollment Into a Brentuximab Vedotin Clinical Trial: A Pilot Study to Evaluate Feasibility.

BackgroundOne approach to identify patients who meet specific eligibility criteria for target-based clinical trials is to use patient and tumor registries to prescreen patient populations.ObjectiveHere we demonstrate that the Total Cancer Care (TCC) Protocol, an ongoing, observational study, may provide a solution for rapidly identifying patients with CD30-positive tumors eligible for CD30-targeted therapies such as brentuximab vedotin.MethodsThe TCC patient gene expression profiling database was retrospectively screened for CD30 gene expression determined using HuRSTA-2a520709 Affymetrix arrays (GPL15048). Banked tumor tissue samples were used to determine CD30 protein expression by semiquantitative immunohistochemistry. Statistical comparisons of Z- and H-scores were performed using R statistical software (The R Foundation), and the predictive value, accuracy, sensitivity, and specificity of CD30 gene expression versus protein expression was estimated.ResultsAs of March 2015, 120,887 patients have consented to the institutional review board–approved TCC Protocol. A total of 39,157 fresh frozen tumor specimens have been collected, from which over 14,000 samples have gene expression data available. CD30 RNA was expressed in a number of solid tumors; the highest median CD30 RNA expression was observed in primary tumors from lymph node, soft tissue (many sarcomas), lung, skin, and esophagus (median Z-scores 1.011, 0.399, 0.202, 0.152, and 1.011, respectively). High level CD30 gene expression significantly enriches for CD30-positive protein expression in breast, lung, skin, and ovarian cancer; accuracy ranged from 72% to 79%, sensitivity from 75% to 100%, specificity from 70% to 76%, positive predictive value from 20% to 40%, and negative predictive value from 95% to 100%.ConclusionsThe TCC gene expression profiling database guided tissue selection that enriched for CD30 protein expression in a number of solid tumor types. Such an approach may improve screening efficiency for enrolling patients into biomarker-based clinical trials.

Incidence and characterization of antiandrogen withdrawal syndrome (AAWS) after enzalutamide (ENZA) in patients (pts) with metastatic castration-refractory prostate cancer (mCRPC).

228 Background: AAWS manifested as PSA decline after discontinuation of first generation AAs, like bicalutamide, has been well characterized and reported. Objective of this study was to assess the incidence and characterize AAWS after ENZA in pts with mCRPC. Methods: From a single institution cohort, pts with mCRPC who discontinued ENZA after documented disease progression per PCWG2 criteria were included. AAWS after ENZA was defined as any degree of PSA decline after discontinuation of ENZA. Baseline pts, disease, and treatment characteristics were compared between Òpts with AAWS after ENZAÓ vs. Òpts without AAWS after ENZAÓ treated during the similar time period: median values were compared with the Wilcoxon rank sum test; proportions were compared with FisherÕs Exact test; and the log rank test was used to compare PFS (Table). Results: 5 pts of 72 eligible pts (~7%) experienced AAWS after discontinuation of ENZA. The levels of PSA decline were as follows: 84%, 32%, 17%, 15% and 15%, respectively. Median AAWS response time, until subsequent PSA progression, was 6 weeks. None of the pts, disease or treatment characteristics (such as prior duration of response to ENZA) were different among Òpts with AAWS after ENZAÓ vs. Òpts without AAWS after ENZAÓ. Conclusions: This is the largest study reporting on the incidence and characterization of AAWS after ENZA. AAWS after ENZA is infrequent (~7%), of short duration (6 weeks), and not predicted by pts, disease or treatment related characteristics. Unlike AAWS after first generation AR inhibitors, like bicalutamide, the AAWS after ENZA is not clinically meaningful and should not have any bearing on the eligibility criteria of clinical trials conducted in the post ENZA setting. [Table: see text]

Patients Followed in an Addiction Medicine Clinic Are Less Likely to Be Eligible to Hepatitis C Drug Studies Regardless of Drug Use

Background Phase 3 trials evaluating direct-acting antivirals (DAA) consistently report high sustained virologic responses (SVR). The strict eligibility criteria applied to these studies may affect the reproducibility in clinical practice. It has been demonstrated that drug use generally does not affect SVR. This retrospective cohort study sought to estimate the proportion of patients followed in a tertiary addiction clinic that would meet eligibility criteria for clinical trials, if drug use was not considered as a rejection criteria.Methods The sample population consists of patients with active HCV genotypes (GT) 1-3, seen at the clinic between 01/2013 and 09/2015. Information from clinical charts was retrieved to examine how participants would meet the eligibility criteria of 14 studies. Individual patient’s data were compared with the studies’ eligibility criteria.ResultsA total of 234 patients met the inclusion criteria (GT 1: 58.1%; GT 2: 8.5%, GT 3: 34.2%; experienced: 16.2%; cirrhotic: 14.5%) and 53% (124/234) of patients could have been included in at least one study. Table shows individual study results. The most inclusive study was COSMOS (31/49; 63%). The most frequent exclusion criteria were the presence of significant diseases (cardiac, pulmonary, hepatic, porphyria or other), contraindicated medication and haemoglobin level.Conclusion Even without considering drug use, only half of the patients of the addiction clinic would have been eligible for at least one study. This under-representation stems from strict eligibility criteria that promote a healthier population. Our study suggests that the DAA might prove less effective when administered to infected populations followed in specialized clinics for drug.StudyGenotypeTreatment historyCirrhosisEligibilityION-11Naivew/wo37/119 (31%)ION-21Experiencedw/wo4/19 (21%)ION-31Naivewo34/108 (32%)SAPPHIRE-I1Naivewo17/108 (16%)SAPPHIRE-II1Experiencedwo1/15 (7%)PEARL-II1bExperiencedwo0/1 (0%)PEARL-III1bNaivewo2/14 (14%)PEARL-IV1aNaivewo15/95 (16%)TURQUOISE-II1Naive Experiencedw6/37 (16%)COSMOS1Naive Experiencedw/wo31/49 (63%)FISSION2-3Naivew/wo30/81 (37%)POSITRON2-3Naive Experiencedw/wo24/100 (24%)FUSION2-3Experiencedw/wo5/19 (26%)ALLY-III3Naive Experiencedw/wo31/78 (40%)Disclosures J. Bruneau, Gilead: Consultant, Consulting fee. Merck: Consultant, Consulting fee. V. Martel-Laferrière, Gilead Inc.: Consultant and Grant Investigator, Consulting fee and Research grant. Abbvie: Grant Investigator, Research grantMerck: Consultant, Consulting fee

Immune Therapy for Sarcomas.

Absolute lymphocyte count (ALC) recovery rapidly occurring at 14 days after start of chemotherapy for osteosarcoma and Ewing sarcoma is a good prognostic factor. Conversely, lymphopenia is associated with significantly decreased sarcoma survival. Clearly, the immune system can contribute towards better survival from sarcoma. This chapter will describe treatment and host factors that influence immune function and how effective local control and systemic interventions of sarcoma therapy can cause inflammation and/or immune suppression but are currently the standard of care. Preclinical and clinical efforts to enhance immune function against sarcoma will be reviewed. Interventions to enhance immune function against sarcoma have included regional therapy (surgery, cryoablation, radiofrequency ablation, electroporation, and radiotherapy), cytokines, macrophage activators (mifamurtide), vaccines, natural killer (NK) cells, T cell receptor (TCR) and chimeric antigen receptor (CAR) T cells, and efforts to decrease inflammation. The latter is particularly important because of new knowledge about factors influencing expression of checkpoint inhibitory molecules, PD1 and CTLA-4, in the tumor microenvironment. Since these molecules can now be blocked using anti-PD1 and anti-CTLA-4 antibodies, how to translate this knowledge into more effective immune therapies in the future as well as how to augment effectiveness of current interventions (e.g., radiotherapy) is a challenge. Barriers to implementing this knowledge include cost of agents that release immune checkpoint blockade and coordination of cost-effective outpatient sarcoma treatment. Information on how to research clinical trial eligibility criteria and how to access current immune therapy trials against sarcoma are shared, too.