Inclusion Criteria For Clinical Trials Research Articles

An enrichment strategy for clinical trials in SPMS

Background: We recently compared clinical outcomes in secondary progressive MS (SPMS) clinical trials and found an association of timed 25 foot walk (T25FW) worsening events and baseline disability scores. It is unclear whether disability worsening in clinical trials is comparable to that seen in clinical practice. Objective: The objective of this study is to compare disability worsening between the IMPACT and ASCEND data sets and data from the Calgary MS clinic and to characterize the association of baseline T25FW and expanded disability status scale (EDSS) scores with disability worsening. Methods: We combined the three data sets and investigated the impact of baseline characteristics on disability worsening with a logistic regression model. We calculated T25FW, EDSS, and ‘EDSS or T25FW’ worsening events as a function of ascending cut-off baseline disability scores. Results: Data source was not associated with T25FW worsening at 12 months. There was a strong association of baseline T25FW and EDSS cut-off scores with T25FW worsening. No such association was present for the EDSS and ‘EDSS or T25FW’. Conclusion: Our results suggest that it is possible to ‘enrich’ a trial cohort for expected T25FW worsening events using specific baseline T25FW and EDSS cut-off scores. These analyses inform the selection of inclusion criteria for clinical trials in SPMS.

Predicting future amyloid biomarkers in dementia patients with machine learning to improve clinical trial patient selection.

IntroductionIn Alzheimer's disease, asymptomatic patients may have amyloid deposition, but predicting their progression rate remains a substantial challenge with implications for clinical trial enrollment. Here, we demonstrate an artificial intelligence approach to use baseline clinical information and images to predict changes in quantitative biomarkers of brain pathology on future images.MethodsPatients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent positron emission tomography (PET) with the amyloid radiotracer 18F‐AV45 (florbetapir) were included. We identified important baseline PET image features using a deep convolutional neural network based on ResNet. These were combined with eight clinical, demographic, and genetic markers using a gradient‐boosted decision tree (GBDT) algorithm to predict future quantitative standardized uptake value ratio (SUVR), an established biomarker of brain amyloid deposition. We used this model to better identify individuals with the highest positive change in amyloid deposition on future images and compared this to typical inclusion criteria for clinical trials. We also compared the model's performance to other methods such as multivariate linear regression and GBDT without imaging features.FindingsUsing 2577 PET scans from 1224 unique individuals, we showed that the GBDT with deep image features was significantly more accurate than the other approaches, reaching a root mean squared error of 0.0339 ± 0.0027 for future SUVR prediction. Using this approach, we could identify individuals with the highest 10% SUVR accumulation at rates 2‐ to 4‐fold higher than by random pick or existing inclusion criteria.DiscussionPredicting quantitative biomarkers on future images using machine learning methods consisting of deep image features combined with clinical data may allow better targeting of treatments or enrollment in clinical trials.

Review of the Terminology Describing Ionizing Radiation-Induced Skin Injury: A Case for Standardization.

Ionizing radiation causes injury to the skin that produces a complex clinical presentation that is managed by various paradigms without clear standards. The situation is further complicated by the fact that clinicians and researchers often use different terms and billing codes to describe the spectrum of cutaneous injury. There is, however, general agreement between the two most commonly-used diagnostic scales, the Radiation Therapy Oncology Group and the Common Terminology Criteria for Adverse Events, and in their use to describe skin injury following radiation therapy. These scales are typically used by radiation oncologists to quantify radiation dermatitis, a component of the radiation-related disorders of the skin and subcutaneous tissue family of diagnoses. In rare cases, patients with severe injury may require treatment by wound care or burn specialists, in which case the disease is described as a “radiation burn” and coded as a burn or corrosion. Further compounding the issue, most US government agencies use the term Cutaneous Radiation Injury to indicate skin damage resulting from large, whole-body exposures. In contrast, the US Food and Drug Administration approves products for radiation dermatitis or “burns caused by radiation oncology procedures.” A review of the literature and comparison of clinical presentations shows that each of these terms represents a similar injury, and can be used interchangeably. Herein we provide a comparative review of the commonly used terminology for radiation-induced skin injury. Further, we recommend standardization across clinicians, providers, and researchers involved in the diagnosis, care, and investigation of radiation-induced skin injury. This will facilitate collaboration and broader inclusion criteria for grant-research and clinical trials and will assist in assessing therapeutic options particularly relevant to patient skin pigmentation response differences.

HPB cancers in older patients | inclusion of older/senior patients in clinical trials

Liver, biliary tract and pancreatic cancers are increasingly diseases of older people and the global population is aging. ‘Older/senior’ patients are a heterogeneous group who vary widely in their general health, physical reserve and degree of dependence on others. Cancer is not the only disease that becomes more prevalent in old age, which means older/senior patients may also have comorbidities and lower resilience. The use of chemotherapy decreases as age increases. Chemotherapy treatment regimens may require modification to reduce toxicity, which is more common in older/senior patients. The effect this has on treatment efficacy is not fully understood.Older/senior patients are not represented well in clinical trials which makes estimating benefit for these patients challenging. Medicine demands that new drugs are rigorously tested and evaluated before use, yet clinicians are treating older/senior patients on the basis of extrapolating from randomised controlled trials which actively exclude comorbidities and older patients. This review considers the current situation and the value of retrospective analyses and real-world evidence to plug the older/senior patient ‘data gaps’.Moving forwards it is essential to broaden clinical trial inclusion criteria to include more older/senior people. The use of appropriate geriatric assessments may help selection of older patients who are fit enough for more rigorous treatment regimens, alongside effective methods of predicting and managing treatment toxicities. The ability to see past the numerical age of a person and offer appropriate therapeutic choices to individual patients in clinic, is an important skill for younger (and not so young) Medical Oncologists to learn.

Gender and sex bias in clinical trial recruitment in Alzheimer's disease: Findings from Fundació ACE

AbstractBackgroundFDA has made great efforts to promote inclusion of women in clinical trials. The aim is to protect specific biological gender and sex issues and encourage drug developers to consider specific clinical outcomes and drug‐safety profiles in terms of gender and sex. Alzheimer’s disease (AD) affects predominantly women, who double men in the number of patients diagnosed with dementia. Therefore, we explored gender and sex bias in the inclusion criteria for clinical trials in AD. Here our aim was to compare main inclusion criteria for clinical trials in MCI and dementia patients in terms of sex.MethodPatients evaluated at FACE from 1996 to 2019 with CDR 0,5 to 2 evaluated from 1996 to 2019 were analyzed. Then, we used the main inclusion criteria for AD clinical trials to compare the sample in terms of sex and syndromic diagnosis. The chosen variables were age, sex, education, comorbidities, treatment and MMSE score. Logistic regression analysis was used accounting for these variables.ResultFrom a total sample of 20,203 MCI and dementia patients, we selected potential candidates for clinical trials with complete information regarding age, years of education, MMSE, comorbidities and treatment. After adjusting for age, years of education, comorbidities and treatment, in the dementia sample only age and years of education showed statistically significant differences. Whereas in the MCI sample: age, years of education, treatment and comorbidities showed statistically significant differences (Table 1 and 2).ConclusionWomen with MCI and dementia are less likely to participate in a clinical trial due to older age and less years of education than men. Another factor that prevent women for participating in clinical trials is their comorbidities when compared to men, whereas men are excluded due to treatment criteria more often than women. These results show that there is a pre‐selection bias against women in AD clinical trials because of demographic characteristics. Therefore, participation of women in clinical trials does not reflect the prevalence of AD among women and is not representative of reality. Efforts should be made to provide equal opportunities to potential clinical trials candidates regardless of gender.

Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease

BackgroundNeurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood–brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease.MethodsWe undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups.ResultsWe confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant.ConclusionsThis striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

PATH-27. CLINICAL, RADIOLOGIC AND PROGNOSTIC PROFILE OF IDH WILD TYPE DIFFUSE ASTROCYTOMA WITH MOLECULAR FEATURES OF GLIOBLASTOMA

Abstract BACKGROUND cIMPACT-NOW-3 recommends that IDH-wildtype diffuse astrocytic glioma Grade II or III with EGFR amplification, or combined whole chromosome 7 gain and whole chromosome 10 loss, or TERT promoter mutation should receive an integrated classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The aims of this study were: Outline the features of a cohort of patients with molecular glioblastoma according to the above criteria; Assess clinical and molecular factors that may inform prognosis; Determine if cIMPACT-NOW-3 recommendation changed clinical practice and clinical trial enrolment. METHODS 61 patients diagnosed with IDH-wildtype diffuse astrocytic glioma Grade II or III and EGFR amp or mTERT or chromosome (+7/-10) between 2011 and 2019 at MGH were included in this single center retrospective cohort study. Data collected: sex, age, extent of surgery, functional status, histological grade, molecular diagnostics and treatment. Progression was defined using RANO criteria, progression was quantified in terms of months from the initial surgery. Survival was defined in terms of months from initial surgery to date of death or last known visit. RESULTS mOS was 16 months, mPFS was 9 months. 14 patients (23%) survived > 24 months, 7 ≥ 36 months (mOS 32 months; 9 deceased). The probability of survival in patients with markedly enhancing tumors was 0.5 at 3 months versus 0.5 at 11 months in non-enhancing tumors. The probability of survival in patients who underwent biopsy only was 0.5 at 5 months compared to 0.5 at 12 months in patients with maximally resected tumors. 1 patient was enrolled in a clinical trial at diagnosis. 6 were enrolled at time of recurrence. CONCLUSIONS mOS and pFS in the deceased patients was comparable to historical data on survival in IDH wild-type glioblastomas. Inclusion criteria in clinical trials have not reflected the cIMPACT-NOW-3 recommendation so far.

Single-Center Experience with Axicabtagene-Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel) for Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Comparable Response Rates and Manageable Toxicity

The CD19 CAR T-cell products Axi-cel and Tisa-cel induce complete responses (CR) in 40-58% of patients (pts) with relapsed/refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL). However, treatment can be associated with significant toxicity, with Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) as the most prominent and specific adverse events of CAR T-cell therapy. Toxicity profiles differ between both commercially available products, mainly due to their divergent co-stimulatory domain (4-1BB in Tisa-cel vs. CD28 in Axi-cel). Here, we report our single-center experience of DLBCL patients treated with Axi-cel or Tisa-cel at the LMU Munich University Hospital between January 2019 and June 2020. Toxicities, response rates and survival of DLBCL patients were retrospectively assessed. As of June 2020, 48 patients were enrolled for CD19-CAR T-cell therapies at our centre, and 37 DLBCL patients (pts) were apheresed. Median time interval between apheresis and CAR T-cell treatment was 39 days. So far, 31 DLBCL pts were transfused (Axi-cel: 18, Tisa-cel: 13). Median age of transfused pts was 60 years (range 19-74, Axi-cel: 60 years, Tisa-cel: 60 years). ECOG was 0-1 in 19 and 2-3 in 12 pts at time of CAR T-cell transfusion (Axi-cel: 0-1 in 13 and 2-3 in 5 pts, Tisa-cel: 0-1 in 6 and 2-3 in 7 pts). 13 pts had undergone prior stem cell transplant (9 autologous, 3 allogeneic, Axi-cel: 4 auto, 2 allo; Tisa-cel: 5 auto, 1 allo). Median number of prior DLBCL therapy lines was four (range 2-9, Axi-cel: 4, Tisa-cel: 4). Only 9/31 pts (29%) met the inclusion criteria of the pivotal clinical trials (due to e.g. infection, CNS disease, thrombocytopenia) at time of enrolment into our CAR T-cell treatment program. 23 pts (74%) received bridging chemotherapy (Axi-cel: 13/18 pts [72%]; Tisa-cel: 10/13 [77%]). Further details on radiographic response and the incidence of toxicities for all treated pts are summarized in the accompanying table. Response assessment after three months using PET/CT was available for 28 pts. Objective response rate (ORR) was 46%, with CR in eight (28%) and partial remission (PR) in five pts (18%). CRS occurred in 29/31 pts (84% CRS °1-2, 10% °3). Tocilizumab was applied in all CRS pts, with a median of four total infusions (range 1-4). 16 pts (52%) developed ICANS (33% °1-2, 16% °3-4, and 3% °5), which was managed with steroids in 9/16 pts. With a median follow-up of seven months, median progression-free survival (PFS) was 2.4 months for all pts. PFS was significantly longer for pts with normal vs. elevated LDH at time of apheresis (not reached vs. 1.5 mo, p=0.031). PFS of patients with two prior lines of therapy (n=7) was comparable with pts with three (n=5) or more (n=15) lines (2 lines: 3.1 mo, ≥3 lines: 1.9 mo, p=0.520). The time interval of ≤ 12 months (n=8 pts) from initial diagnosis of DLBCL to CAR T-cell transfusion was not prognostic and did not identify patients with worse PFS (≤12 mo: 1.7 months, >12 mo: 2.8 mo, p=0.569). In summary, in our cohort of heavily pretreated patients with a median of four prior DLBCL therapy lines, we observed an ORR of 46% (28% CR) at 3 months after CAR T-cell therapy, with no significant differences between patients treated with Axi-cel and Tisa-cel. In line with results of the pivotal clinical trials, treatment with Axi-cel was associated with a moderately higher incidence of ICANS. Overall, CAR T-cell toxicities were well manageable. Normal LDH levels at time of apheresis identified patients with high probability of sustained remission. In contrast, the number of prior therapy lines or the time interval from initial diagnosis of DLBCL to CAR T-cell transfusion had no impact on PFS. These hypothesis-generating findings might be helpful for future clinical decision-making, but need to be confirmed in a larger cohort. Therefore, we have set up a comprehensive patient monitoring program to identify predictive clinical and immunological markers of response and survival in CAR T-cell treated DLBCL patients. We will present updated results with longer follow-up at the annual meeting. Figure Disclosures Buecklein: Celgene: Research Funding; Pfizer: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy. Blumenberg:Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding. Subklewe:Seattle Genetics: Research Funding; Morphosys: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding.

Eligibility of real-world patients with metastatic breast cancer for clinical trials

IntroductionThe results of clinical trials in metastatic breast cancer (MBC) are generalized to real-world patients. This study determines the proportion of real-world patients who would be eligible for clinical trials and compares outcomes in eligible versus ineligible patients. MethodsPatients diagnosed with MBC from 2004 to 2015 in a large Canadian province were included. Patients with one of the following criteria were considered ineligible: the presence of comorbid conditions (anemia, uncontrolled diabetes, heart disease, liver disease, and kidney disease) or a history of immunosuppression or prior malignancy. The likelihood of receiving cancer therapy was analysed using logistic regression models and factors affecting overall survival (OS) were assessed by Cox proportional hazards models. ResultsA total of 1585 patients with MBC were identified. The median age at diagnosis was 63 years. Of these, 512 (32.3%) patients were deemed ineligible in whom the two most common reasons for ineligibility were renal dysfunction (17.2%), and previous immunosuppression (7.8%). In the real world, ineligible patients were less likely to receive chemotherapy (29.5% vs 45.8%; P < 0.001) but not radiation treatment (7.6% vs 9.6%; P = 0.196) or hormonal therapy (57.6% vs 60.6%; P = 0.261). The 5-year OS of ineligible patients who received systemic therapy in the real-world was significantly better than those who did not. ConclusionsDespite being ineligible for clinical trials based on common eligibility criteria, many real-world patients receive systemic treatment and derive possible benefit. Broadening of inclusion criteria in clinical trials will enhance the representation of real-world patients and increase the generalizability of results.

MUSCLE IMAGING – MRI: P.161 Development of clinical trial simulation tools for Duchenne muscular dystrophy using magnetic resonance biomarkers

Clinical trials in DMD face challenges in selecting optimal endpoints and study cohorts to detect therapeutic efficacy. MR muscle biomarkers are objective and have high potential value for use in clinical trials offering excellent sensitivity to disease progression across a wide age range. A disease-drug trial model that describes the dynamics of MR measured fat fraction (FF) may help inform clinical trial design and identify early readouts that predict longer-term disease progression and response to treatment. A collaboration between industry, ImagingDMD and C-Path to accelerate drug development in DMD focuses on the development of statistical model-based clinical trial simulation (CTS) tool based on MR biomarker data acquired in the multicenter ImagingDMD study. The ImagingDMD study is a longitudinal natural history study in which functional outcome measures and MR biomarkers (FF and MRI-T2) have been collected from a large cohort of boys and young men with DMD annually for up to 10 years (>50% for more than 5 years). Non-linear mixed effects modelling was applied to describe the longitudinal increases of vastus lateralis (VL) muscle FF. The data set (N=122 subjects) was randomly divided into training (N=98) and test (N=24) datasets while maintaining balance in covariates. MR spectroscopy measures of VL FF significantly increased over time. The base model structure that best captured the course of the FF increase over time was a sigmoid Emax model. The model is clinically interpretable, with parameters describing maximum increase in VL FF score and the age at which VL FF is 50% of its eventual maximum. The longitudinal trajectory of VL FF in DMD can be captured by a statistical model, providing the opportunity to evaluate the effect of therapeutic interventions against the model-predicted disease trajectory and possibly broaden inclusion criteria for clinical trials in DMD. A CTS tool based on MR biomarkers has the potential to transform therapy development in DMD.

Application of clinical trial inclusion criteria to clinical practice patients to quantify the burden of CNS metastases on health-related quality of life and healthcare resource use in patients with NSCLC

ObjectivesQuantify the burden of central nervous system (CNS) metastases on health-related quality of life (HRQoL) and healthcare resource use (HRU) in patients with advanced non-small-cell lung cancer (NSCLC) from a prospective European study in clinical practice, utilising clinical trial inclusion criteria. Materials and MethodsPatients ≥18 years, with metastatic NSCLC, Eastern Oncology C0operative Group (ECOG) performance status 0–2 and life expectancy ≥12 weeks were enrolled in two cohorts by baseline CNS metastases status. Demographics, clinical characteristics, NSCLC management data, HRQoL and HRU were collected at baseline and two follow-up visits (Visits 2 and 3, 6 weeks apart). HRQoL was assessed using validated questionnaires. Results162 patients were enrolled (n = 80 CNS cohort, n = 82 non-CNS cohort). Baseline characteristics were balanced, but CNS patients were younger (mean ± standard deviation age: 62.1 ± 9.6 vs 65.6 ± 9.7 years, p = 0.021) with a lower body mass index (13.8 % underweight [<18.5kg/m2] vs 3.7 %, p = 0.049). Mean HRQoL scores were similar between cohorts at all visits. Cancer pharmacotherapy, procedures and concomitant treatment were comparable across cohorts, with some exceptions. More CNS patients were hospitalised at baseline (10.3 % vs 2.2 %) for longer (mean 7.2 vs 4.6 days; p < 0.001). By Visit 2, more CNS patients were hospitalised (50.0 % vs 29.3 %; p = 0.009) with emergency room visits (11.8 % vs 2.7 %; p = 0.032). At baseline, more CNS versus non-CNS patients had Magnetic Resonance Imaging (MRI) scans (80.0 % vs 31.7 %; p < 0.001), but fewer had fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) scans (10.0 % vs 28.0 %; p = 0.004). ConclusionThese data from clinical practice show minor differences in HRQoL/HRU between patients with advanced NSCLC with/without CNS metastases when applying selected clinical trial criteria. Although follow-up was short, HRQoL scores were similar between cohorts at all visits, supporting the wider inclusion of selected patients with CNS disease into clinical trials.

Characterizing inclusion and exclusion criteria in clinical trials for chimeric antigen receptor (CAR) T-cell therapy among adults with hematologic malignancies

ObjectiveRestrictive eligibility criteria are a known barrier to patient enrollment into clinical trials. With the introduction of chimeric antigen receptor T-cell (CAR-T) therapy, it is imperative to ensure trials are generalizable to the intended population with appropriate safety guiderails. MethodsUsing the U.S. National Library of Medicine's clinical trial database, we identified 84 clinical trials and characterized inclusion/exclusion criteria for CAR-T therapy in hematologic malignancies with a focus on age, performance status, and comorbidities, and the relationship to sponsorship, disease type, and study phase. ResultsThe overwhelming majority of CAR-T trials imposed restrictions on upper age (n = 54, 64%), performance status (n = 72, 86%), and renal function (n = 76, 90%). Institution-sponsored studies were more likely to have age restrictions (n = 29) than industry-sponsored (n = 20), (83% vs 45%, p < 0.01). There was no relationship between study phase and use of upper age limit restriction or study phase and affiliation with performance status restrictions. Inclusion criteria for renal function was highly variable and ambiguous; creatinine <1.2–3.0 mg/dL, creatinine clearance >20–60 mL/min, and GFR >30–70 mL/min. ConclusionThese results suggest highly variable inclusion/exclusion criteria for early phase CAR-T studies that may limit patient accessibility to therapy and emphasize the need for a standardized, evidence-based approach to patient enrollment.

Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS.

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2‐year natural history data from 187 children aged 3–20 years with a range of CMT genetic subtypes. Subsets based on age (3–8 years), disability level (CMTPedS score 0–14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.

Age-Related Lymphocyte Output During Disease-Modifying Therapies for Multiple Sclerosis.

Patients with multiple sclerosis exhibit the same qualitative and quantitative changes in immune system cells observed in aging. In the last 20 years, multiple sclerosis patients have shown an increase in life expectancy and average age, but clinical trial inclusion criteria typically exclude patients over the age of 55years. Therefore, disease-modifying therapies are likely administered to patients older than those enrolled in clinical trials. In order to investigate whether disease-modifying therapies for multiple sclerosis induce modifications to the immune system that may have (super)additive effects resulting in an acceleration of immunosenescence, we quantified the number of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs). These molecules are contained in new T and B lymphocytes released by the thymus and bone marrow and are considered molecular age-related markers. The markers of aging were measured by a multiplex quantitative real-time PCR assay in 122 patients who had started therapy with interferon-beta (IFN-β), fingolimod, alemtuzumab, or natalizumab. Samples were obtained before the therapy and at 6 and 12 months of treatment. Comparisons between the variables were performed by a non-parametric statistical analysis. In therapy-naive patients, a significant and direct correlation was found between a lower number of newly produced T and B cells and older age. Although disease-modifying therapies induced different changes (both increases and decreases) in the production of new T and B lymphocytes, 12 months of therapy with IFN-β or natalizumab did not affect the correlations found at baseline between the release of lymphocytes containing TRECs or KRECs and age. On the contrary, in patients treated with alemtuzumab, both correlations were lost, while in fingolimod-treated patients, only the correlation between TRECs and age disappeared. This observational study indicated that different age-related changes of the new T and B lymphocyte production could be one of the reasons for the emergence, in the real-world setting, of adverse events not otherwise observed in clinical trials; thus, caution is advised when choosing disease-modifying therapies for multiple sclerosis patients.

150P Eligibility of real-world patients with metastatic breast cancer in clinical trials

The results of clinical trials in metastatic breast cancer (MBC) are often generalized to real-world patients. However, clinical trials have stringent inclusion and exclusion criteria, which can potentially lead to poor generalizability of results and slow accrual. This study was conducted to determine the proportion of real-world patients with MBC who would be eligible for clinical trials based on common eligibility criteria and to compare outcomes in eligible and ineligible patients. Patients diagnosed with MBC in 2004-2015 from the Alberta cancer registry were included. Patients with one of the following criteria were deemed ineligible: age >75 years, comorbid conditions (uncontrolled diabetes, heart disease, liver disease, and kidney disease), anemia, and history of immunosuppression or a prior malignancy. The likelihood of receiving any therapy was analyzed using logistic regression and factors affecting overall survival (OS) were assessed by Cox model. A total of 1585 patients with MBC were identified with median age at diagnosis was 63 years (interquartile range: 53-75 years). Approximately 44% (693) patients were deemed trial-ineligible and the most common reasons for ineligibility were advanced age (24%), renal dysfunction (17%), and cardiac disease (8%), respectively. In the real-world, 87% of eligible patients received hormonal or chemotherapy as compared to 72% of ineligible patients [odds ratio 2.65; 95% confidence interval, 2.04-3.42; P< 0.0001]. The 5-year OS of trial-ineligible patients who received any therapy was significantly better than those who did not (Table).Table 150PGroup5-year OSHazard ratio95% CIP-valueIneligible and no therapy (n=195)2.1%------Ineligible and received therapy (n=498)24.7%0.750.59-0.960.02Eligible (n=892)34.8%0.690.53-0.90.006 Open table in a new tab Despite being ineligible for clinical trials by the common eligibility criteria, most of the patients still derive benefit from treatment. Relaxation of an arbitrary upper limit of age as an inclusion criteria for clinical trials is likely to enhance the representation of real-world patients leading to faster accrual and increase in generalizability of results of such trials.

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada

Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.

Acute severe paediatric asthma: study protocol for the development of a core outcome set, a Pediatric Emergency Research Networks (PERN) study

BackgroundAcute severe childhood asthma is an infrequent, but potentially life-threatening emergency condition. There is a wide range of different approaches to this condition, with very little supporting evidence, leading to significant variation in practice. To improve knowledge in this area, there must first be consensus on how to conduct clinical trials, so that valid comparisons can be made between future studies. We have formed an international working group comprising paediatricians and emergency physicians from North America, Europe, Asia, the Middle East, Africa, South America, Central America, Australasia and the United Kingdom.Methods/designA 5-stage approach will be used: (1) a comprehensive list of outcomes relevant to stakeholders will be compiled through systematic reviews and qualitative interviews with patients, families, and clinicians; (2) Delphi methodology will be applied to reduce the comprehensive list to a core outcome set; (3) we will review current clinical practice guidelines, existing clinical trials, and literature on bedside assessment of asthma severity. We will then identify practice differences in tne clinical assessment of asthma severity, and determine whether further prospective work is needed to achieve agreement on inclusion criteria for clinical trials in acute paediatric asthma in the emergency department (ED) setting; (4) a retrospective chart review in Australia and New Zealand will identify the incidence of serious clinical complications such as intubation, ICU admission, and death in children hospitalized with acute severe asthma. Understanding the incidence of such outcomes will allow us to understand how common (and therefore how feasible) particular outcomes are in asthma in the ED setting; and finally (5) a meeting of the Pediatric Emergency Research Networks (PERN) asthma working group will be held, with invitation of other clinicians interested in acute asthma research, and patients/families. The group will be asked to achieve consensus on a core set of outcomes and to make recommendations for the conduct of clinical trials in acute severe asthma. If this is not possible, the group will agree on a series of prioritized steps to achieve this aim.DiscussionThe development of an international consensus on core outcomes is an important first step towards the development of consensus guidelines and standardised protocols for randomized controlled trials (RCTs) in this population. This will enable us to better interpret and compare future studies, reduce risks of study heterogeneity and outcome reporting bias, and improve the evidence base for the management of this important condition.

Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.

High MYC mRNA Expression Is More Clinically Relevant than MYC DNA Amplification in Triple-Negative Breast Cancer.

DNA abnormalities are used in inclusion criteria of clinical trials for treatments with specific targeted molecules. MYC is one of the most powerful oncogenes and is known to be associated with triple-negative breast cancer (TNBC). Its DNA amplification is often part of the targeted DNA-sequencing panels under the assumption of reflecting upregulated signaling. However, it remains unclear if MYC DNA amplification is a surrogate of its upregulated signaling. Thus, we investigated the difference between MYC DNA amplification and mRNA high expression in TNBCs utilizing publicly available cohorts. MYC DNA amplified tumors were found to have various mRNA expression levels, suggesting that MYC DNA amplification does not always result in elevated MYC mRNA expression. Compared to other subtypes, both MYC DNA amplification and mRNA high expression were more frequent in the TNBCs. MYC mRNA high expression, but not DNA amplification, was significantly associated with worse overall survival in the TNBCs. The TNBCs with MYC mRNA high expression enriched MYC target genes, cell cycle related genes, and WNT/β-catenin gene sets, whereas none of them were enriched in MYC DNA amplified TNBCs. In conclusion, MYC mRNA high expression, but not DNA amplification, reflects not only its upregulated signaling pathway, but also clinical significance in TNBCs.

Characterizing Inclusion and Exclusion Criteria in Clinical Trials for CAR-T Cellular Therapy Among Adults with Hematologic Malignancies

Introduction: Clinical trial development and enrollment are pivotal to advancing cancer outcomes. Novel treatment modalities such as Chimeric Antigen Receptor (CAR) T-cell therapy is an intensive therapy that has altered the landscape of hematologic malignancy therapies, with several FDA approvals based on Phase I-II studies. Strict eligibility criteria are implemented to ensure safety of trial participants; however, these criteria can lead to barriers to patient enrollment, hinder the generalizability of the study, and result in a population of participants not representative of those who would benefit from therapy. The aim of this proposal is to characterize inclusion and exclusion criteria in clinical trials for CAR-T cellular therapy in adults with hematologic malignancies. Methods: The U.S. National Library of Medicine's Clinical Trial database of privately and publicly funded clinical studies was accessed June 2019 to assemble a list of studies with the following filters applied: hematologic, recruiting, not yet recruiting, not recruiting, active, completed, suspended, terminated studies, interventional studies, CAR, CAR T, chimeric antigen receptor, CAR NK, adult, older adult, early phase 1, phase 1, phase 2, phase 3. From this, 95 studies populated, 84 were utilized in this study and 11 studies excluded due to non-hematologic malignancy. Results: We analyzed 84 CAR-T clinical trials targeting multiple diseases (Table 1) including; acute lymphoblastic (n=7) and myeloid leukemia (n=2); lymphoma (n=6); multiple myeloma (n=40); multiple hematologic malignancies (n=27) and other (n=2). The majority of studies were phase 1 (n=47) or phase 1/2 (n=28). Upper age limit restrictions were in place for 53/84 (63%) of trials. Trials included the AYA population (n=5), ≤ age 65 (n=1), ≤ age 70 or 73 (n=26), ≤ age 75 or 78 (n=12), ≤ age 80 or 85 (n=9). Of the 84 trials, 65 (77%) had performance status inclusion criteria, most commonly was status ECOG 0-2 (n=23) and ECOG 0-1 (n=24). Patients were excluded for a history of a separate or concurrent malignancy in 52/84 (62%) trials, CNS disease was excluded in 45/84 (54%) trials and 70/84 (83%) clinical trials excluded infectious diseases; HIV (n=69) and Hepatitis B/C (n=64). Many studies had restrictions for impairment in organ function; renal impairment (n=66), cardiac deficits (n=67), and abnormal pulmonary function (n=44). Unique to CAR-T trials, 27/84 had restrictions in place for neurological disorders: epilepsy (n=15), history of brain injury (n=10), dementia (n=8), coordination/movement disorder (n=6), cerebellar disease (n=8), psychosis (n=7), paresis (n=6), history of stroke/aphasia (n=21), and active autoimmune or inflammatory disease of the central nervous system (n=3). Conclusion: CAR-T cellular therapy is a tremendous therapeutic advancement in the medical community. This study emphasizes, in detail, highly variable cross-study inclusion/exclusion criteria for early phase CAR-T studies. This new and promising therapy is actively being studied in a highly select group of patients and may not be generalizable to the older adult with hematologic malignancies due to non-uniform trial criteria. The applicability of this modality should be tempered by the understanding that CAR-T trials have overt age caps, ambiguous performance and comorbidity exclusions, and neurologic exclusions and play a role in limiting patient accessibility to novel clinical trial therapy. Confirmatory prospective and observational studies of CAR-T therapy in representative populations are a high priority. 1. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. 2016 127:3321-3330. Doi: 10.1182/blood-2016-04-703751 2. Kim ES, Bruinooge SS, Roberts S, et al. Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737-3744. doi:10.1200/JCO.2017.73.7916 3. Unger JM, Cook E, Tai E, and Bleyer A. The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. American Society of Clinical Oncology Educational Book. 2016; 36:185-198. Doi:10.1200/EDBK\_156686 Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Olin:Spectrum: Research Funding; Novartis: Research Funding. Artz:Miltenyi: Research Funding. Jaglowski:Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Rosko:Vyxeos: Other: Travel support.