scholarly journals Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials

2021 ◽  
Vol 151 ◽  
pp. 115-125
Author(s):  
Chun L. Gan ◽  
Igor Stukalin ◽  
Daniel E. Meyers ◽  
Shaan Dudani ◽  
Heidi A.I. Grosjean ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Solid Tumour ◽  
First Line ◽  
Eligibility Criteria

scholarly journals Modernizing Eligibility Criteria in First-Line Clinical Trials for Diffuse Large B-Cell Lymphoma: Consensus Recommendations Using a Modified Delphi-Method Survey

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-50
Author(s):  
Robert Andrew Harkins ◽  
Christopher Flowers
Keyword(s):  
Clinical Trials ◽  
Cohort Study ◽  
Delphi Method ◽  
Research Funding ◽  
Study Group ◽  
First Line ◽  
Eligibility Criteria ◽  
Modified Delphi Method ◽  
Consensus Recommendations ◽  
Modified Delphi

PURPOSE: First-line randomized clinical trials (RCTs) for patients with diffuse large B-cell lymphoma (DLBCL) comparing R-CHOP versus R-CHOP plus targeted therapy have consistently exhibited negative results in part due to eligibility criteria that limit rapid enrollment of poorest-risk groups. Observational studies indicate that longer diagnosis to treatment interval (DTI) is associated with improved event-free survival (Maurer et al. 2018), and recent trials have shown DTI of ~30 days suggesting enrollment of DLBCL patients with the best expected outcomes. We conducted a modified Delphi-method survey with investigators in the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study group to modernize eligibility criteria to help shorten DTI for first-line DLBCL RCTs. METHODS: We catalogued eligibility criteria from 19 first-line DLBCL RCTs spanning the R-CHOP era. We developed a modified Delphi-method survey to define Consensus Essential and Consensus Unnecessary criteria from among eligibility criteria included in ≥ 1/3 of the 19 analyzed studies. The survey consisted of two rounds and was administered via email to clinical investigators in the LEO Cohort Study group. In each round, survey participants were asked to rate each criterion on a 1-9 Likert-style scale (1 = unnecessary, 9 = essential) for the importance of inclusion of each criterion in modern DLBCL RCTs and to provide comments explaining each rating selection. Eligibility criteria with median Likert-style value ≥ 7 were deemed Consensus Essential, while criteria with median value ≤ 3 were considered Consensus Unnecessary. Criteria with median value > 3 and < 7 were deemed either Unresolved or in Disagreement depending on the distribution of responses. Survey participants received summaries of round-one results including the rating distribution for each criterion and anonymized comments from the survey group prior to starting round two. Additionally, the round-two survey requested appropriate threshold ranges for quantitative eligibility criteria. Based on round-one and round-two results and in collaboration with survey participants, we finalized consensus recommendations for modern eligibility criteria in first-line clinical trials for DLBCL. RESULTS: We enumerated 52 eligibility criterion categories across 19 DLBCL RCTs spanning the R-CHOP era, with 31 criterion categories meeting criteria for inclusion in the Delphi-method survey. Seventeen out of 29 invited members of the LEO Cohort Study group participated in round one (59% participation rate; median number of years' experience as a hematologist/oncologist: 17 years; range: 3-30 years). After round one, 12 criteria were deemed Consensus Essential, nine criteria were Consensus Unnecessary, and 10 criteria were Unresolved or showed Disagreement (Figure 1-A). Fifteen out of 17 round-one respondents participated in round two (response rate 88%). After round two, one additional criterion was deemed Consensus Essential (Figure 1-B). Final Consensus Essential criteria and Consensus Unnecessary criteria with median and interquartile range values for ratings are shown in Table 1. In total, we defined consensus recommendations for 31 eligibility criteria including quantitative threshold values for 10 eligibility criteria for first-line DLBCL RCTs. CONCLUSION: Using a modified Delphi-method survey, we developed consensus recommendations for eligibility criteria in DLBCL RCTs comparing R-CHOP versus R-CHOP + X. Our methods identified multiple criteria that were commonly included in prior DLBCL RCTs that are now deemed unnecessary according to consensus expert opinion. In addition, our results modernize enrollment by defining quantitative threshold values for eligibility criteria based on current clinical judgment, enabling enrollment of a more clinically diverse patient population. Application of our streamlined eligibility criteria in future RCTs will increase generalizability of study results while maintaining patient safety in DLBCL clinical trials comparing R-CHOP versus R-CHOP + X. Disclosures Flowers: AbbVie: Consultancy, Research Funding; Kite: Research Funding; Karyopharm: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; BeiGene: Consultancy.

Evaluation of factors associated with recruitment in hematological clinical trials: A retrospective study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6567-6567
Author(s):  
C. Amireault ◽  
S. Camden ◽  
J. Poulin ◽  
J. Lemieux
Keyword(s):  
Clinical Trials ◽  
Stage Iv ◽  
Quebec City ◽  
Cancer Clinical Trials ◽  
First Line ◽  
Exclusion Criteria ◽  
Eligibility Criteria ◽  
Factors Associated ◽  
Study Population ◽  
Few Data

6567 Background: Recruitment of patients in cancer clinical trials has been reported to be between 3%–5%. Very few data come from Canada. Methods: The objective was to measure the recruitment and its associated characteristics in hematology clinical trials for malignant diseases. This was a retrospective cohort study using charts review in a tertiary hematology centre in Québec City, Canada. Clinical trials opened between 2002 and 2008 were selected. For each protocol, main criteria were used to define the population under study (e.g., stage IV Hodgkin lymphomas first-line). If the patient filled the main criteria, all eligibility criteria (inclusion and exclusion criteria) of the protocol were assessed. Results: Among all charts reviewed, 697 patients were identified in 17 protocols. However, as a patient could be assessed for more than one protocol if applicable, this population reached 1,394 observations. The study population filling the main criteria of a protocol included 195 observations in 17 protocols (186 different patients). Only 9.7% (8.2–11.4) filled all the eligibility criteria and 3.3% (2.5–4.4) were recruited among all charts reviewed (1394 observations). However, theses rates reached 68.2 % (61.2–75.1) and 23.1 % (17.9–29.8), respectively, among patients meeting the main criteria of a protocol (195 observations). Recruitment in the population who filled all eligibility criteria (inclusion and exclusion criteria) was 33.8% (26.7–42.5). Patient's sex, age, comorbidities, doctor's sex, doctor's age and protocol characteristics were not associated with recruitment in the population filling the main criteria, but having a note in the chart about the protocol appears to be associated with higher recruitment (p < 0.0001). The most common reasons for not being recruited were as follow (could have more than one reason): 40.7% not fulfilling all eligibility criteria, 31.3% protocol not being proposed and 22.7% patients’ refusal. Patients reasons for refusals were (could have more than one reason): 50% unknown, 26.5% fear of side effects, 20.6% too many visits, 14.7 % already enough anxious about disease, other. Conclusions: The largest barriers about recruitment were protocol ineligibility and protocol not being proposed by the medical team. No significant financial relationships to disclose.

Outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first-line Immuno-oncology (IO) agents who do not meet eligibility criteria for clinical trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5070-5070
Author(s):  
Chun Loo Gan ◽  
Shaan Dudani ◽  
Connor Wells ◽  
Ziad Bakouny ◽  
Nazli Dizman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Neutrophil Count ◽  
Clear Cell ◽  
Karnofsky Performance Status ◽  
Cell Component ◽  
First Line ◽  
Eligibility Criteria ◽  
Patient Counselling ◽  
Number Of Patients

5070 Background: IO combination therapies [including IOIO and IO/vascular endothelial growth factor inhibitor (IOVE) combinations] in mRCC have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of trial ineligible patients who are treated with first-line IOIO or IOVE combinations are unknown. Methods: Metastatic RCC patients treated with first-line IOIO or IOVE were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria in IO trials) if they had a Karnofsky performance status (KPS) < 70%, no clear-cell component, brain metastases, hemoglobin (Hb) < 9 g/dL, eGFR < 40 mL/min, platelet count of < 100,000/mm3, and/or neutrophil count < 1500/mm3. Time to treatment failure (TTF) and overall survival (OS) were calculated from time of starting first-line IO therapy. Results: Overall, 26% (155/592) of patients in the International mRCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Baseline characteristics are listed in Table. The reasons for ineligibility were: no clear-cell component (34%, 53/155), Hb < 9g/dL (28%, 44/155), eGFR < 40 mL/min (19%, 30/155), brain metastases (19%, 29/155), KPS < 70% (14%, 21/155), platelet < 100,000/mm3 (3%, 4/155) and neutrophil count < 1500/mm3 (0%, 0/155). Between ineligible versus eligible patients, the response rate, median TTF and median OS of first-line IOIO or IOVE was 34% vs 46% (p = 0.02), 4.2 vs 9.7 months (p < 0.01), and 25.3 vs 44.4 months (p < 0.01), respectively. When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.50 (95% CI 1.05-2.14). Conclusions: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. These data may guide patient counselling and specific trials addressing the unmet needs of protocol ineligible patients are warranted. [Table: see text]

Assessing real-world survival outcomes of patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line FOLFIRINOX compared to patients from a phase 1/2 trial treated with NALIRIFOX.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16252-e16252
Author(s):  
Xuelian Zhu ◽  
Paul Cockrum ◽  
Bonny Shah ◽  
Craig Parzynski ◽  
Tamer Garawin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Renal Function ◽  
Real World ◽  
Missing Values ◽  
Randomized Clinical Trials ◽  
Phase 1 ◽  
Locally Advanced ◽  
Survival Outcomes ◽  
First Line ◽  
Eligibility Criteria

e16252 Background: Treatment options remain limited for pts newly diagnosed with mPDAC. NCCN and ASCO guidelines both recommend treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel in the first line (1L) setting for pts with mPDAC and good performance status. Over 80% of randomized clinical trials (RCTs) studying treatments for mPDAC have failed to meet their primary endpoints. Recently published analyses have utilized real-world (RW) data to compare outcomes between pts enrolled in clinical trials and RW pts. This study sought to identify the eligible population of pts with mPDAC treated with FOLFIRINOX in the 1L setting who would meet RCT eligibility criteria for the phase 1/2 study (NCT02551991) evaluating NALIRIFOX for pts with previously untreated locally advanced or mPDAC, and to assess their survival outcomes. Methods: This retrospective observational study utilized the Flatiron Health EHR database. Data were analyzed for adult pts diagnosed with mPDAC between January 2016 and February 2020 who initiated treatment with FOLFIRNOX in 1L within 90 days of their diagnosis for metastatic disease. Eligibility criteria from the phase 1/2 trial were applied to select a population of RW pts who may have been eligible to enter the RCT. Pts meeting the following criteria were included: good performance scores (ECOG 0-1), adequate hematological, hepatic, and renal function, were recovered from the effects of surgery, were untreated in the year prior to initiating 1L, and had no evidence of a different cancer in the last three years. Kaplan-Meier analyses were used to assess the median overall survival (mOS) from the start of 1L FOLFIRNOX treatment. Results: Of the 1,210 pts treated with 1L FOLFIRINOX, 652 pts (53.8%) met less stringent versions of the RCT eligibility criteria in which missing values were deemed to indicate normal function/performance; 244 pts (20.2%) met the more stringent criteria and had complete data. The most restrictive selection criteria were the requirements for adequate hematological, hepatic, and renal function and having received prior therapy. The median age at treatment initiation among the 244 pts was 64 years (IQR: 58 – 70). 153 pts were male (62.7%), 158 were White (64.8%), and ECOG scores of 0 and 1 were split among the cohort 50%/50%. The mOS observed for the 244 pts was 10.1 months (95% CI: 9.1 – 11.3). The reported mOS from the phase 1/2 trial of NALIRIFOX was 12.6 months (8.7 – 18.7). Conclusions: This study demonstrates that RW data may be used to select a comparator cohort for a clinical trial. Initial estimates suggest NALIRIFOX pts from the RCT experienced longer survival than those receiving 1L FOLFIRINOX in the RW setting. Further analysis is necessary to minimize the effects of confounding and the differences in data collection between the RW and the RCT settings.

scholarly journals Real-World Data for Planning Eligibility Criteria and Enhancing Recruitment: Recommendations from the Clinical Trials Transformation Initiative

2021 ◽  
Author(s):  
Scott R. Evans ◽  
Dianne Paraoan ◽  
Jane Perlmutter ◽  
Sudha R. Raman ◽  
John J. Sheehan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Real World Data ◽  
Eligibility Criteria ◽  
World Data ◽  
Study Planning ◽  
Efficiency And Effectiveness ◽  
Multi Stakeholder ◽  
Functional Teams ◽  
Data Driven Decisions

AbstractThe growing availability of real-world data (RWD) creates opportunities for new evidence generation and improved efficiency across the research enterprise. To varying degrees, sponsors now regularly use RWD to make data-driven decisions about trial feasibility, based on assessment of eligibility criteria for planned clinical trials. Increasingly, RWD are being used to support targeted, timely, and personalized outreach to potential trial participants that may improve the efficiency and effectiveness of the recruitment process. This paper highlights recommendations and resources, including specific case studies, developed by the Clinical Trials Transformation Initiative (CTTI) for applying RWD to planning eligibility criteria and recruiting for clinical trials. Developed through a multi-stakeholder, consensus- and evidence-driven process, these actionable tools support researchers in (1) determining whether RWD are fit for purpose with respect to study planning and recruitment, (2) engaging cross-functional teams in the use of RWD for study planning and recruitment, and (3) understanding patient and site needs to develop successful and patient-centric approaches to RWD-supported recruitment. Future considerations for the use of RWD are explored, including ensuring full patient understanding of data use and developing global datasets.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

scholarly journals Effect of first-line biologic initiation on glucocorticoid exposure in children hospitalized with new-onset systemic juvenile idiopathic arthritis: emulation of a pragmatic trial using observational data

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rosemary G. Peterson ◽  
Rui Xiao ◽  
Hannah Katcoff ◽  
Brian T. Fisher ◽  
Pamela F. Weiss
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Biologic Therapy ◽  
Tertiary Care ◽  
Pragmatic Trial ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Source Population ◽  
First Line ◽  
Eligibility Criteria ◽  
Over Time ◽  
New Onset

Abstract Background Glucocorticoid exposure is a significant driver of morbidity in children with systemic juvenile idiopathic arthritis (sJIA). We determined the effect of early initiation of biologic therapy (IL-1 or IL-6 inhibition) on glucocorticoid exposure in hospitalized patients with new-onset sJIA. Methods We emulated a pragmatic sequence of trials (“pseudo-trials”) of biologic initiation in children (≤ 18 years) hospitalized with new-onset sJIA utilizing retrospective data from an administrative database from 52 tertiary care children’s hospitals from 2008 to 2019. Eligibility window, treatment assignment and start of follow-up between biologic and non-biologic study arms were aligned for each pseudo-trial. Patients in the source population could meet eligibility criteria at several timepoints. Mixed-effects logistic regression was used to determine the effect of biologic initiation on in-hospital glucocorticoid exposure. Results Four hundred sixty-eight children met eligibility criteria, of which 19% received biologic therapy without preceding or concomitant initiation of immunomodulatory medications. This proportion significantly increased over time during the study period (p <  0.01). 1451 trial subjects were included across 4 pseudo-trials with 71 assigned to the biologic arm and 1380 assigned to the non-biologic arm. After adjustment, there was a trend toward decreased odds of glucocorticoid initiation in the biologic arm compared to the non-biologic arm (OR 0.39, 95% CI [0.13, 1.15]). Conclusion Biologic initiation in children hospitalized with new-onset sJIA significantly increased over time and may be associated with reduced glucocorticoid exposure. The increasing use of first-line biologic therapy may lead to clinically relevant reductions in treatment-related adverse effects of glucocorticoid-reliant therapeutic approaches.

scholarly journals First-Line Maintenance Treatment in Metastatic Colorectal Cancer (mCRC): Quality and Clinical Benefit Overview

2021 ◽  
Vol 10 (3) ◽  
pp. 470
Author(s):  
Marta Martín-Richard ◽  
Maria Tobeña
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Clinical Benefit ◽  
Maintenance Treatment ◽  
Randomized Clinical Trials ◽  
Line Treatment ◽  
First Line ◽  
Design Quality ◽  
Primary Endpoints ◽  
First Line Treatment

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.

scholarly journals Efficacy and Safety of Intravenous rtPA in Ischemic Strokes Due to Small-Vessel Occlusion: Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Bartosz Karaszewski ◽  
Adam Wyszomirski ◽  
Bartosz Jabłoński ◽  
David J. Werring ◽  
Dominika Tomaka
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Randomized Clinical Trials ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
Efficacy And Safety ◽  
Eligibility Criteria ◽  
Vessel Occlusion ◽  
Excellent Outcome ◽  
Symptomatic Intracerebral Hemorrhage

AbstractIntravenous recombinant tissue plasminogen activator (iv-rtPA) has been routinely used to treat ischemic stroke for 25 years, following large clinical trials. However, there are few prospective studies on the efficacy and safety of this therapy in strokes attributed to cerebral small vessel disease (SVD). We evaluated functional outcome (modified Rankin scale, mRS) and symptomatic intracerebral hemorrhage (sICH) using all available data on the effects of iv-rtPA in SVD-related ischemic stroke (defined either using neuroimaging, clinical features, or both). Using fixed-effect and random-effects models, we calculated the pooled effect estimates with regard to excellent and favorable outcomes (mRS=0–1 and 0–2 respectively, at 3 months), and the rate of sICH. Twenty-three studies fulfilled the eligibility criteria, 11 of which were comparative, and there were only 3 randomized clinical trials. In adjusted analyses, there was an increased odds of excellent outcome (adjusted OR=1.53, 95% CI: 1.29–1.82, I2: 0%) or favorable outcome (adjusted OR=1.68, 95% CI: 1.31–2.15,I2: 0%) in patients who received iv-rtPA compared with placebo. Across the six studies which reported it, the incidence of sICH was higher in the treatment group (M-H RR = 8.83, 95% CI: 2.76–28.27). The pooled rate of sICH in patients with SVD administered iv-rtPA was only 0.72% (95% CI: 0.12%–1.64%). We conclude that when ischemic stroke attributed to SVD is considered separately, available data on the effects of iv-rtPA therapy are insufficient for the highest level of recommendation, but it seems to be safe. Although further therapeutic trials in SVD-related ischemic stroke appear to be justified, our findings should not prevent its continued use for this group of patients in clinical practice.

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