Citations

PURPOSE: Feasibility assessments (FAs) are important to establish site capabilities to conduct clinical trials and their suitability for specific trials. However, current FA methods used by biotechnology and pharmaceutical (biotech-pharma) trial sponsors and contract research organizations (CROs) are costly, inefficient, unnecessarily burdensome, and resource intensive. These methods delay trial start-up, act as a barrier to site participation, and ultimately reduce timely patient access to clinical trials and novel treatments. METHODS: An ASCO Task Force was convened to assess the specific burdens and challenges with FAs and to develop recommendations to improve their efficiencies and effectiveness. Stakeholders (including trial sites, biotech-pharma sponsors, and CROs) provided insights into challenges and offered solutions through two surveys and an in-person meeting. The Task Force used the feedback to formulate consensus recommendations to improve FAs for oncology clinical trials. RESULTS: Three key recommendations were identified for application across all biotech-pharma sponsored trials: (1) implement a streamlined and uniform FA process across trials and sponsors; (2) minimize and standardize questions; and (3) leverage technology to centralize FAs, facilitate communications, and reduce redundancies. CONCLUSION: There is an urgency to improve the current FA process, which is costly, inconsistent, inefficient, labor intensive, and of uncertain effectiveness. All stakeholders stand to benefit from implementing these recommendations, which aim to minimize burdens and ensure that more trial sites and patients have timely access to oncology clinical trials. To have meaningful impact, adoption and consistent execution of these recommendations across all trials, sponsors, CROs, and sites are essential.

Purpose: molecular testing is often indicated for recently transfused patients. However, there are no guidelines regarding the potential interference from donor DNA or whether it is necessary to wait for a period of time post-transfusion prior to genetic testing. While the majority of patients are transfused in the non-trauma setting using leukoreduced (LR) red blood cell products, the degree of leukoreduction varies among centers and is not universally practiced. Methods: whole blood units collected from anonymous donors were used in an in vitro transfusion model. One unit was split: half being leukoreduced simulating a leukopenic recipient and half left untreated. Donors were simulated by leukoreduced, partially leukoreduced (PLR), or non-leukoreduced units, transfused in 2, 5, or 16 unit equivalents. DNA from the combinations were subjected to short tandem repeat (STR) analysis for chimerism detection. Results: donor DNA was not detectable in any of the LR combinations, but detected in the PLR combinations, ranging from 0.1 to 1.5% donor DNA in the immunocompetent recipient and 6.3–27.8% in the leukopenic recipient. Non-LR donor DNA was also detected (13–95%). Conclusion: donor-derived DNA from leukoreduced blood products is unlikely to interfere with the interpretation of germline genetic testing in immunocompetent recipients but may interfere in immunocompromised recipients.

AbstractBackgroundThe need exists for a device that can rapidly and accurately assess mild cognitive impairment (MCI). Because the link between oculometrics and cognition is well‐documented, the Oculo‐Cognitive Addition Test (OCAT) was developed which tracks users’ eye movements as they complete a simple mental addition test.MethodOCAT consisted of 12 trials of summing three consecutive single‐digit numbers, shown separately on three consecutive screens (Figure 1). The first, second, and third screen in each trial corresponded to low, medium, and high cognitive workload. Using an infinity‐loop pattern of 24 symmetrical positions, eye movements were captured systematically in horizontal, vertical, and diagonal directions (Figure 2).MCI was simulated by exposing subjects to 5 minutes of hypoxic gas mixture (8% O2 + balance N2). 20 subjects completed OCAT in baseline (i.e. normal room air), hypoxic, and post‐baseline (i.e. 20 minutes of room air) conditions. Raw scan‐paths were collected with an eye‐tracking device. Oculometrics pertaining to fixations and saccades were extracted. Statistical significance was assessed using repeated measures ANOVA. Effect size and clinical significance was evaluated using computed Cohen’s d.ResultOCAT completion time significantly increased from baseline to hypoxia, which corresponded to a significant decrease in cerebral oxygenation from baseline to hypoxia (Figure 3). From baseline to hypoxia, saccadic latency significantly increased while saccadic velocity significantly decreased in the diagonal direction, however, results in the horizontal and vertical directions were not significant (Figure 4). Fixation time significantly increased from baseline to hypoxia in medium and high cognitive workload, but did not significantly change in low cognitive workload (Figure 5). From baseline to hypoxia, fixation size did not significantly change in any cognitive workload, however, the fluctuation in fixation size significantly increased in medium cognitive workload. From baseline to hypoxia, fixation area significantly increased in low and high cognitive workload, but did not significantly change in medium cognitive workload.ConclusionOCAT can detect subtle changes in oculometrics that correlate with MCI. This study provides rationale for providing varying degrees of cognitive load to elucidate subtle changes in oculometrics that may otherwise go undetected in neurocognitive tests that do not increase cognitive load.

Abstract BACKGROUND With increasing studies reporting on the molecular profiling of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a final set of core and supplemental meningioma-specific Common Data Elements (CDEs) to facilitate comparative and pooled analyses. METHODS The generation of CDEs followed the four-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: development/discovery based on data from published and ongoing meningioma trials, internal validation, external validation including presentation of our data form at the Society for Neuro-Oncology previously, and distribution. RESULTS We developed a set of CDEs organized into patient- and tumor-level modules. In total, the Consortium identified 16 core CDEs (9 patient-level and 7-tumour-level) e.g. age at index surgery, diagnosis of neurofibromatosis, prior chemotherapy or radiation, tumor location, extent of resection, recurrence, etc. An additional 15 supplemental CDEs were defined and described (8 patient-level and 7 tumour-level) e.g. race, cause of death, multiple tumors, tumor size, Simpson grade, second intervention, etc. These CDES are now made publicly available for dissemination and adoption. We also present a narrative review and analysis of recent and ongoing meningioma trials. CONCLUSIONS These CDEs provide a framework for discussion in the neuro-oncology community that will facilitating data sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The CDEs are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.

Abstract Introduction: CLR 131 (I-131-CLR1404) is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on preclinical and clinical experience and the radiosensitivity of MM, CLR 131 is being examined in relapsed or refractory B-cell malignancies through an open-label, phase 2 trial, CLOVER-1 (NCT02952508); initial results in pts with LPL/WM are reported here. Procedures: The primary objective of this study is to determine the efficacy and safety of CLR 131 in select B-cell malignancies. Eligibility criteria include adult pts with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL)/Wadenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or diffuse large B-cell lymphoma (DLBCL). Pts with LPL/WM must have received at least two prior treatment regimens unless ineligible to receive standard agents and have measurable disease: either a nodal lesion > 15 mm, an extranodal lesion > 10 mm, or measurable IgM. Prior external beam radiation therapy is allowed (< 20% of total marrow irradiated). CLR 131 is administered intravenously up to 30 minutes at total body doses (TBD) of <50 mCi, ~50 mCi, and ~75 mCi. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the 2012 WM Criteria for Response Assessment. Results: Four pts with LPL/WM have been enrolled in the study with data presented as of 1 Mar 2020. The median age was 70 (range 54-81) and included 2 females and 2 males who had a median of two prior regimens (range 1-5). The overall response rate was 100%, including one pt with a complete response, one pt with a partial response, and one pt with a minimal response; one pt remains under evaluation. The primary treatment-emergent AEs across all doses in pts with LPL/WM included neutropenia, thrombocytopenia, nausea, fatigue, anemia, and decreased white blood cell count, in line with experience to date with CLR 131 in other B-cell malignancies. Median time to resolution of cytopenias was 21 days. One pt received two cycles of CLR 131 with a TBD of ~100 mCi. The pt was determined to be a partial response 43 days post initial dose and a complete response at approximately 200 days; this was confirmed radiologically 406 days post initial dose. The duration of response for this pt is currently at 25 months and is ongoing. One pt received ~ 50 mCi CLR 131 and saw an 89% decrease in IgM at 64 days post infusion. One pt received ~ 75 mCi CLR 131 and had a 45% decrease in IgM at 64 days post infusion. One pt received two cycles of CLR 131 with a TBD of ~150 mCi, experiencing a 48% reduction in IgM to date and has not yet completed the evaluation period. Conclusions: CLR 131 is a unique, first-in-class targeted radiotherapeutic in development for multiple B-cell hematologic malignancies. The observed positive signals of efficacy and safety from this preliminary data in relapsed or refractory LPL/WM pts is encouraging and will be further explored. Citation Format: Sikander Ailawadhi, Jarrod Longcor, Kate Oliver, Igor D. Grachev. CLR 131 demonstrates 100% overall response rate in relapsed or refractory lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM): initial results from ongoing phase 2 trial, CLOVER-1 study [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-25.

Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF βPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of βPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of βPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover βPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with βPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF βPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.

Abstract Background: Obesity is a well established risk factor not only for increased prostate cancer incidence, but for poorer survival from prostate cancer. However, there is limited knowledge on the role of the circulating lipidome in prostate cancer. In order to target lipid metabolism optimally, it is critical to understand the spectrum of changes in circulating lipid profiles and the association with clinical outcome across the natural history of prostate cancer. Aim: To assess the relationship between the plasma lipidome and clinical outcome in localized and metastatic prostate cancer. Methods: Liquid chromatography-tandem mass spectrometry was used to quantitate over 500 lipid species in plasma samples from 3 cohorts (1) 389 men with localized prostate cancer, (2) 44 men with metastatic hormone-sensitive prostate cancer (mHSPC), and (3) 137 men with metastatic castration-resistant prostate cancer (CRPC). Associations between circulating lipids with metastatic relapse, androgen-deprivation therapy (ADT) failure or overall survival for each relevant disease stage were examined by latent class analysis and cox regression. Results: Circulating lipid profiles displaying elevated levels of ceramides were associated with metastatic relapse in localized prostate cancer (HR 5.8, 95% CI 3.0-11, P 1 × 10−6), early ADT failure in mHSPC (HR 2.4, 95% CI 1.1-5.3, P 0.03), and shorter overall survival in CRPC (HR 2.5, 95% CI 1.7-3.7, P 2 × 10−6). ADT failure in mHSPC and shorter overall survival in CRPC were also associated with elevated levels of other sphingolipids (sphingomyelins, hexosylceramides). The prognostic significance of the high risk lipid profiles in localized prostate cancer was independent of clinicopathological characteristics (lipid profile HR 4.7, 95%CI 2.4-9.3, P 7 × 10−6) when modeled with Gleason score (P<0.0001) and pathological stage (P<0.0001). Furthermore, the circulating lipid profiles were independent of metabolic factors (localized prostate cancer lipid profile HR 8.2, 95% CI 2.6-25, P 0.0003 when modeled with diabetes, statin, hypertension, body mass index [BMI]; CRPC lipid profile HR 2.6, 95% CI 1.7-3.8, P x10−6 when modeled with BMI). Conclusion: Elevated circulating ceramides are associated with poorer clinical outcomes across the natural history of prostate cancer (from localized to metastatic hormone-sensitive to metastatic castration resistant prostate cancer). This demonstrates that aberrant lipid metabolism in the patients occurs early in prostate cancer and could be therapeutically targeted in prospective clinical trials to improve prostate cancer outcomes. Citation Format: Lisa Glen Horvath, Hui-Ming Lin, Blossom Mak, Kate Mahon, Nicole Yeung, Maria Docanto, Peter Sutherland, andrew Shepherd, Winston Tan, Arun Azad, Manish Kohli, Peter Meikle, Lisa Butler. Lipidomic analysis of circulating lipids across the natural history of prostate cancer identifies aberrant ceramide metabolism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4761.

Abstract Copy number alterations and loss of heterozygosity (LOH) are common in ovarian tumors, including those on the X chromosome. In females, one of the two copies of the X chromosome is transcriptionally silenced during embryonic development in the epigenetic process of X chromosome inactivation. Specifically, the long non-coding RNA XIST is expressed from the inactive X (Xi) and triggers chromosome-wide DNA methylation. In breast and ovarian cancer cell line studies, Xi deletion with concomitant duplication of the active X (Xa) has been observed. We sought to examine which copy of the X chromosome, Xi or Xa, was gained or lost in a set of primary ovarian tumors, using levels of XIST expression as a marker of X chromosome inactivation. To determine which copy of the X chromosome harbors the alterations, we compared local copy number and LOH in Xq13.2 to the levels of XIST expression in a set of N=134 primary tumors from Mayo Clinic ovarian cancer patients. Associations with XIST expression were examined using ANOVA, with copy number of two and absence of LOH as the reference level. Associations between expression of XIST and expression of other genes were examined with a mixed effects model, to account for the repeated observations across patients, after adjusting for local copy number and LOH. Associations with XIST expression and overall survival were performed with Cox regression. Additional analyses were performed in a subset of 24 patient tumors with X chromosome-wide alterations to simplify interpretation, including a visual examination of chromosome-wide DNA methylation patterns. Analyses were replicated in N=106 ovarian tumors from TCGA with X chromosome-wide alterations. Across N=134 ovarian tumors from Mayo Clinic, abnormal copy number (not equal to two) was associated with reduced XIST expression (p=0.0016). Levels of XIST expression were similar for tumors with one copy and tumors with three or more copies. Similarly, levels of XIST expression were also lower for tumors with LOH (p=5.2E-5). Reduced XIST expression was also associated with poorer survival, after adjusting for age (p=0.02). Results were consistent in the subset of tumors with whole chromosome alterations (pCN=0.0013, pLOH=0.0019). For these tumors, when LOH was present, XIST expression was low and the DNA methylation distribution is bi-modal, suggesting that the inactive X was lost and the active X was gained. Furthermore, after adjusting for copy number and LOH, XIST expression was weakly positively correlated with the median expression of other genes (R2=0.04, p=0.026). In N=106 TCGA tumors with whole X chromosome alterations, XIST expression was also reduced in tumors with abnormal copy number (p=0.006) and with LOH (p=1.5E-10). Taken together, because XIST is expressed from Xi and not Xa, associations of reduced XIST expression with abnormal copy number and presence of LOH suggest that Xi is frequently lost and Xa is gained in ovarian tumors, consistent with cell line studies. These results should be further validated in larger sample sets and examined for association with clinical outcome. Citation Format: Yilin Song, Bryan M. McCauley, Melissa C. Larson, Sebastian M. Armasu, Kate Lawrenson, Ellen L. Goode, Nicholas B. Larson, Stacey J. Winham. Evidence of decreased X chromosome inactivation in primary ovarian tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2452.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.