Citations

300 Background: Current methods to assess site feasibility for industry-funded clinical trials are onerous and delay patient access to novel treatment options and high-quality clinical trials. Industry sponsors and contract research organizations (CROs) often probe for unnecessary and/or duplicative information. These burdens prolong trial start-up times and are a barrier to site participation in oncology trials. The American Society of Clinical Oncology (ASCO) Research Community Forum convened a task force to identify ways to improve the site feasibility assessment process. Methods: Data were collected in 3 steps: 1) survey to assess site burdens, 2) collation of sample feasibility questionnaires (FQs), and 3) stakeholder meeting to discuss potential solutions. The task force then developed recommendations for process improvements and obtained stakeholder feedback through a survey. Results: 113 oncology practices (66 community, 47 academic) reported completing a median 5 FQs and 2 pre-study site visits (PSSVs) per month. FQs took a median 2 hours to complete whereas PSSVs took a median 4 hours to complete. Most considered FQ (81%) and PSSV (91%) content redundant to information previously provided, and FQs similar between different sponsors (86%). The median time from first contact to first patient enrolled was 6 months. The 40 respondents to the stakeholder survey represented 19 academic- and 9 community-based sites, 8 industry sponsors, and 4 CROs. Most preferred a model with a short FQ plus a PSSV when there was not a prior relationship. If there was a prior relationship, either a PSSV or teleconference was preferred. All stakeholders identified time savings, expedited start-up, fewer staff resources, and cost savings as the greatest benefits. The greatest barriers to adoption were buy-in from sponsors and CROs, and insufficient information about site capabilities. Conclusions: Site feasibility assessments for industry-sponsored trials are important to ensure patient safety and access to high quality clinical trials. However, current methods are inefficient and time and resource intensive. This initiative provided insights about challenges for sites and the viability of a fundamental change to site feasibility assessments. ASCO recommendations are forthcoming on improving processes, standardizing and minimizing questions, and using portals that are effective across all trials and clinical research scenarios.

Abstract BackgroundMethods for assessing bone metabolism which can replace the gold standard bone biopsy are sorely needed in the clinical setting in patients with chronic kidney disease - mineral and bone disorder (CKD-MBD). The aim of the present study was implementation, validation and comparison of non-invasive dynamic and static whole-body (WB) [18F]NaF PET/CT scan methods to replace invasive bone biopsy, used for quantitative analysis of bone clearance in CKD-MBD patients.MethodsSeventeen patients with CKD-MBD underwent a 60-minute dynamic scan followed by a 30-minute static WB scan. Tracer kinetics in four thoracic vertebrae were analyzed using non-linear regression with the Hawkins model and two different Patlak-analysis methods using image-derived arterial input functions obtained from the left myocardial ventricle and the thoracic aorta. For future use in WB PET/CT scans, we validated the use of a semi-population input function. The resulting kinetic parameters (Ki, K1, k2, k3, k4, V0) were compared between the different methods of analysis using the various derived input functions.ResultsDynamic kinetic results from both standard and single-point Patlak analyses correlate well with non-linear regression analysis, but Ki results using Patlak analysis are generally lower for all tested input functions compared to regression analysis. Single-point Patlak analysis on WB scans correlates well with standard Patlak analysis on dynamic scans but show 13-21% higher Ki-values. ConclusionsOur results show good correlation between dynamic and static analysis of skeletal plasma clearance but different Ki-values depending on the analysis method and choice of input function used. Thus, WB [18F]NaF PET/CT scans can be applied in future studies, but the results should not be compared uncritically with results obtained using non-linear regression analysis.

SummaryIntroductionTo better inform the field of obesity medicine, we set out to describe the current use of pharmacotherapy meant to improve patient weight status among a group of clinicians connected through the Paediatric Obesity Weight Evaluation Registry (POWER), as well as reasons behind clinicians' use or non‐use of the medications.MethodsPaediatric weight management (PWM) programs participating in POWER were asked to complete a program profile survey in 2014 (n = 30) and 2017 (n = 33); questions about pharmacotherapy use were included. Descriptive statistics were used to identify: (a) the proportion of PWM programs offering obesity pharmacotherapy; (b) the medications most commonly prescribed; and (c) reasons among non‐prescribers for not offering pharmacotherapy.ResultsThe 2014 and 2017 surveys were completed by 29 PWM programs (97%) and 30 PWM programs (91%), respectively. Twenty‐one programs completed both surveys. In 2014, 10 (34%) programs reported offering pharmacologic agents specifically for weight control, whereas in 2017, 16 (53%) reported offering pharmacotherapy for a primary indication of weight loss. Metformin was reported as the most commonly used agent in 2014, and topiramate in 2017. Largest reported increases in use over time were for topiramate and phentermine.DiscussionOur survey results demonstrate that a majority of this group of PWM programs offered pharmacotherapy to promote weight loss in patients with complications or associated medical conditions. There was a trend indicating increasing use over time, despite the significant gap regarding pharmacotherapy use in the literature.ConclusionsThese data suggest the need for (a) additional robust paediatric drug trials to further develop the evidence base guiding use or non‐use of pharmacotherapy in paediatric weight management, and (b) increased understanding of both facilitators and barriers to prescribing anti‐obesity pharmacotherapy for youth with obesity.

Background: Donor site morbidity after anterior cruciate ligament (ACL) reconstruction with a bone–patellar tendon–bone (BTB) autograft is clinically significant, but evidence with contemporary techniques is lacking. Purpose: To (1) evaluate donor site morbidity at a single institution using modern techniques of BTB autograft harvest at 2-year follow-up, (2) develop a 10-question donor site morbidity instrument, and (3) compare this instrument against traditional outcome tools. Study Design: Case series; Level of evidence, 4. Methods: We analyzed the 2-year follow-up outcomes of 200 consecutive patients who underwent ACL reconstruction with a BTB autograft performed by 2 surgeons at a single institution. The surgical technique utilized modern and consistent BTB autograft harvest, including graft sizing, patellar tendon and peritenon closure, and patellar and tibial donor site bone grafting. There were 187 patients included, with 13 patients undergoing revision ACL reconstruction excluded. An original 10-question scoring instrument evaluating donor site morbidity was administered to each patient (score, 0-100) and compared against each patient’s International Knee Documentation Committee (IKDC) and Lysholm scores. Results: Overall, 13.9% of patients were noted to have anterior knee pain with activity at 2-year follow-up. Moreover, 3.7% of patients reported an inability to kneel on hard surfaces but had no problems on soft surfaces; 5.9% of patients reported mild discomfort but were able to kneel on all surfaces. Additionally, 75.4% of patients had a perfect (100/100) donor site morbidity score. The mean donor site morbidity score at 2-year follow-up was 98.3 ± 3.4. There was a very strong correlation between the IKDC and Lysholm scores but only a strong and moderate correlation when the donor site morbidity score was compared with the IKDC and Lysholm scores, respectively. Conclusion: Donor site morbidity after ACL reconstruction with a BTB autograft was less frequent than reported in the existing literature. Some patients developed anterior knee pain; therefore, an informed discussion is advised. IKDC and Lysholm scores may not capture donor site symptoms after surgery. The 10-question donor site morbidity instrument may provide a more accurate assessment.

e14092 Background: Current methods to assess trial sites for clinical trial participation are onerous, with unnecessary redundancies and no-value steps that impact research site resources and clinical trial participation. This project sought stakeholder feedback on recommendations to transform industry sponsor and contract research organization (CRO) processes for evaluating sites for trials. Methods: An ASCO task force developed recommendations to improve the feasibility assessment process and standardize and centralize questions and forms. A survey was conducted with sites, industry trial sponsors, and CROs to obtain feedback and assess buy-in for the recommendations. Results: Respondents were from 28 oncology research sites (19 academic, 9 community-based), 8 sponsors, and 4 CROs. All stakeholders agreed that the current process is burdensome (93% sites, 90% sponsors, 100% CROs), standardization will improve the process (86% sites, 87% sponsors, 75% CROs). All agreed a centralized portal will reduce burdens (93% sites, 100% sponsors, 75% CROs) and expedite trial start-up (89% sites, 100% sponsors, 75% CROs). Site certification was a viable option for sites (86%) and CROs (75%), but less so for sponsors (57%). Most respondents preferred a two-tier model: 1) a short site questionnaire followed by a pre-study visit for new interactions, and 2) only a pre-study site visit or a teleconference if there is an existing relationship. The greatest benefits were time savings, expedited start-up, reduction in personnel resources, and cost savings. The greatest barriers to adoption were buy-in and alignment from sponsors/CROs and insufficient information about site or protocol. Top predictors of a site’s success on a trial were physician engagement, available patients, and site experience. Conclusions: Site feasibility assessments are important for all stakeholders to establish trial suitability. However, current methods impose tremendous burdens on site resources (reported by authors elsewhere). While this sample is limited, the proposed process and standardization changes show promise to reduce burdens and costs for all stakeholders and expedite patient enrollment onto clinical trials.

Abstract Objective: Nonresponse to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is common in patients with major depressive disorder (MDD), particularly in women, occurring in about 70% of patients despite adequate dosing. Well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Low-dose testosterone has been shown to improve depression symptom severity, fatigue and sexual function in small studies of women not formally diagnosed with MDD. We sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with treatment-resistant MDD. A functional MRI (fMRI) substudy examined effects of testosterone on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: Randomized, double-blind, placebo-controlled, 8-week trial of adjunctive testosterone cream (AndroFeme® 1, Lawley Pharmaceuticals, Australia) in 101 women, ages 21–70, with treatment-resistant MDD. Testosterone was titrated to achieve blood levels near the upper normal reference limit. Primary outcome measure was depression severity by Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. fMRI substudy (n=20) primary outcome was change in ACC activity. Results: Mean age was 47±14 (SD) years and mean baseline MADRS score was 26.6±5.9. Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS depression scores decreased in both arms [testosterone: 26.8±6.3 to 15.3±9.6; placebo: 26.3±5.4 to 14.4±9.3 (baseline to 8 weeks, respectively)], with no difference between groups (p=0.91). Fatigue and sexual function improved without differences between groups. There were no group differences in side effects. fMRI results demonstrated a relationship between ACC activation and androgen levels pretreatment but no difference in ACC activation with treatment. Conclusions: This rigorously designed, double-blinded clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant MDD and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially impact overall depressive symptom severity, fatigue, or sexual dysfunction. Testosterone did not result in greater activity in a brain region (ACC) implicated in MDD etiopathology compared to placebo. Thus, the addition of low-dose testosterone to ineffective antidepressant treatment should not be recommended for women with MDD. Further studies using strategies designed to reduce placebo effects may be warranted.

Abstract Background: Active cancer is an independent predictor of recurrent venous thromboembolism (VTE; hazard ratio=2.2–4.2). However, whether the risk of VTE recurrence among active cancer patients can be further stratified by tumor site or presence of metastases is uncertain. Objectives: To estimate and compare the cumulative incidence of VTE recurrence by tumor site and presence of metastases among active cancer patients with incident VTE. Study Design and Population: Retrospective cohort study of Olmsted County, MN residents with active cancer who lived >1 day after a first-lifetime deep vein thrombosis or pulmonary embolism over the 35-year period, 1966–2000 (n=418). 25 patients with oral (6), bone (1), skin (4), soft tissue (3), eye (1) and other/unknown (10) were excluded, leaving 393 remaining patients. Measurements: Baseline demographic and clinical characteristics, tumor site, presence and location of tumor metastases, and date of first recurrent VTE. Tumor site and metastases were tested as potential predictors of time-to-recurrent VTE using the Cox proportional hazards model. Results: 114 of 393 patients with active cancer developed recurrent VTE over 764 person-years of follow-up. The cumulative incidence of recurrent VTE at seven, 30, 90, and 180 days, 1, 5, and 10 years was 1.9%, 10.3%, 18.3%, 22.3%, 28.7%, 44.5%, and 53.5%, respectively. After adjusting for age and gender, tumor site was an independent predictor of first VTE recurrence (p<0.01). The hazard of VTE recurrence was over 2-fold higher for lung cancer patients compared to the lowest recurrence group (kidney, bladder and other genitourinary cancer; HR=2.04, 95% CI: 0.88, 4.70, p=0.096), and the hazard for brain and pancreatic cancer was nearly 2-fold higher (HR=1.9 for each, p=0.22, 0.24, respectively). The hazard of recurrence among hematological; breast and ovarian; gastric, colon, and liver; and prostate cancer patients did not differ significantly from the lowest recurrence group. Univariately, the presence of metastases at cancer diagnosis was not associated with recurrent VTE (HR=1.16; 95% CI: 0.79, 1.69, p=0.45). Conclusions: Tumor site is an independent predictor of VTE recurrence after adjusting for age and gender. In particular, lung, brain and pancreatic cancer patients have the highest risk for recurrence and these patients should be considered for secondary prophylaxis. Disease severity, as reflected by metastatic disease at cancer diagnosis, is not a predictor of recurrence.

Abstract The IgVH mutation status is an independent predictor of time to treatment and survival in CLL. However, the biological basis of this difference is unknown. Clinical use of the IgVH mutation status as a prognostic marker is limited due to the technical difficulties of assessing this feature. As such, we probed for differences in protein expression by CLL cells with unmutated (UM) vs mutated (M) IgVH using phage peptide display libraries (PDPL). Methods: PDPL consists of phages engineered to express random peptides (7-mer) on the coat protein. From approximately 2x1011 phages displaying all possible permutations of 7-mer peptide, we selected phages binding to UM cells by incubation with 106 UM cells and elution of bound phages. Then, from numerous phages initially binding to UM cells, we subtracted phages binding to M cells by multiple incubations with M cells (106). Thus, the phages that bound only to UM cells were selected. The procedure was repeated multiple times to increase selection specificity. The peptide sequences displayed by selected phages were evaluated. We identified phage targets on UM cells by immunoprecipitation (IP) of CLL protein with specific phage and by sequencing of precipitated protein. The expression of target protein in CLL cells was confirmed by immunobloting and flow cytometry. Results: Sequencing of phages from the 3rd round of selection (UM v. M) revealed several peptides, with the most predominant being FPSAHFL. IP identified the cellular target for FPSAHFL as vimentin, an intermediate filament protein involved in cell motility and activation. The level of vimentin expressed by CLL cells varied between patient samples (n=15). UM CLL cases were found to express higher levels of vimentin (the mean MFI was 1002; SD 381), than cases of M CLL (mean MFI 547; SD 109), p=0.0128. To evaluate the prognostic significance of vimentin, we assessed vimentin expression by flow cytometry in a separate subgroup of 40 CLL patients. Archived cell samples collected between 6/2000 – 6/2001 were used. The median follow up was 81 months (40–233). Vimentin expression (MFI) as a continuous variable was a risk factor for a shortened time to treatment (TTT) with a proportional hazard ratio of 4.152 (95% CI 1.33–15.220, p=0.0317). Using MFI closest to the median (and rounded to 2 decimal places) as a cutoff, we stratified patients in high (n=21) and low (n=19) vimentin expression groups. The median times to treatment (TTT) in patients with high vs low level expression of vimentin were 2.8 and 12.9 years respectively, p=0.0025 (Fig.). Conclusion: Using novel proteomic technology, we found that CLL cells with unmutated IgVH expressed higher levels of vimentin than CLL cells with mutated IgVH. A high-level of vimentin expression defined by flow cytometry appears to be associated with high-risk disease. Validation of these findings could allow for the vimentin level to be used as a surrogate marker for expression of unmutated IgVH in CLL. Figure Figure