Institute Clinical Trials Research Articles

Comparison of Noninvasive High-Intensity Focused Ultrasound with Radiofrequency Ablation of Osteoid Osteoma

To evaluate clinical feasibility and safety of magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) treatment of symptomatic osteoid osteoma and to compare clinical response with standard of care treatment. Nine subjects with radiologically confirmed, symptomatic osteoid osteoma were treated with MR-HIFU in an institutional review board-approved clinical trial. Treatment feasibility and safety were assessed. Clinical response was evaluated in terms of analgesic requirement, visual analog scale pain score, and sleep quality. Anesthesia, procedure, and recovery times were recorded. This MR-HIFU group was compared with a historical control group of 9 consecutive patients treated with radiofrequency ablation. Nine subjects (7 male, 2 female; 16 ± 6 years) were treated with MR-HIFU without technical difficulties or any serious adverse events. There was significant decrease in their median pain scores 4 weeks within treatment (6 vs 0, P < .01). Total pain resolution and cessation of analgesics were achieved in 8 of 9 patients after 4 weeks. In the radiofrequency ablation group, 9 patients (8 male, 1 female; 10 ± 6 years) were treated in routine clinical practice. All 9 demonstrated complete pain resolution and cessation of medications by 4 weeks with a significant decrease in median pain scores (9 vs 0, P < .001). One developed a second-degree skin burn, but there were no other adverse events. Procedure times and treatment charges were comparable between the 2 groups. This pilot study shows that MR-HIFU treatment of osteoid osteoma refractory to medical therapy is feasible and can be performed safely in pediatric patients. Clinical response is comparable with standard of care treatment but without any incisions or exposure to ionizing radiation. ClinicalTrials.govNCT02349971.

First person: Jimmie Holland, MD

First person: Jimmie Holland, MD

Neurological Outcome at 30 Months of Age after Mild Hypothermia via Selective Head Cooling in Term Neonates with Perinatal Asphyxia Using Low-Cost CoolCap: A Single-Center Randomized Control Pilot Trial in India

AbstractThe objective of this study was to determine the effectiveness and safety of mild systemic hypothermia by selective head cooling in hospital born neonates with hypoxic-ischemic encephalopathy using low-cost CoolCap. The primary outcome was to determine whether selective head cooling reduces neonatal mortality and neurodevelopmental delay (NDD) at &gt; 30 months of age. The secondary outcome was to determine the serious adverse effects during selective head cooling such as thrombocytopenia requiring platelets transfusion, renal and hepatic dysfunction, bradycardia, hypoglycemia, and dyselectrolytemia (hyperkalemia, hyponatremia, and hypocalcemia). This is a single-center randomized control trial. The risk ratios, risk differences, and numbers needed to treat plus 95% confidence interval (CI) were measured. This study was done at the tertiary care perinatal center. Inborn neonates with ≥ 37 completed weeks of gestation with indicators of perinatal asphyxia and moderate to severe clinical encephalopathy were randomly allocated to hypothermia (n = 30) or standard care (n = 30) groups. The neonates were subjected to mild systemic hypothermia via selective head cooling using ice caps, the target rectal temperature being 34 to 35°C for 72 hours. Therapeutic hypothermia reduced the risk of death and NDD at ≥ 30 months of age: 6 of 30 infants (20%) in the hypothermia group and 18 of 30 infants (60%) in the control group died or had a NDD at ≥ 30 months (risk ratio: 0.33 [95% CI: 0.15–0.72]; p = 0 0.0015). The mortality rate decreased, and the survival rate free of any sensorineural disability increased. The benefits were statistically significant in moderately asphyxiated infants. Adverse effects of hypothermia were minimal. Selective head cooling with mild systemic hypothermia in term asphyxiated neonates is safe and inexpensive in low-resource setting. Hypothermia showed statistically significant reduction in mortality and NDD at ≥ 30 months of age when commenced within 6 hours of birth and was not associated with serious adverse effects. The Institutional Clinical Trial Registry number is CNMC/ETHI/317/P.

Formulation, stability testing, and analytical characterization of melatonin-based preparation for clinical trial

A new institutional clinical trial assessed the improvement of sleep disorders in 40 children with autism treated by immediate-release melatonin formulation in different regimens (0.5mg, 2mg, and 6mg daily) for one month. The objectives of present study were to (i) prepare low-dose melatonin hard capsules for pediatric use controlled by two complementary methods and (ii) carry out a stability study in order to determine a use-by-date. Validation of preparation process was claimed as ascertained by mass uniformity of hard capsules. Multicomponent analysis by attenuated total reflectance Fourier transformed infrared (ATR-FTIR) of melatonin/microcrystalline cellulose mixture allowed to identify and quantify relative content of active pharmaceutical ingredients and excipients. Absolute melatonin content analysis by high performance liquid chromatography in 0.5mg and 6mg melatonin capsules was 93.6%±4.1% and 98.7%±6.9% of theoretical value, respectively. Forced degradation study showed a good separation of melatonin and its degradation products. The capability of the method was 15, confirming a risk of false negative <0.01%. Stability test and dissolution test were compliant over 18 months of storage with European Pharmacopoeia. Preparation of melatonin hard capsules was completed manually and melatonin in hard capsules was stable for 18 months, in spite of low doses of active ingredient. ATR-FTIR offers a real alternative to HPLC for quality control of high-dose melatonin hard capsules before the release of clinical batches.

Abstract C81: A systematic review of breast cancer screening strategies for African American women

Abstract BACKGROUND: Breast cancer mortality is higher among African American women (AAW) in comparison to any other racial/ethnic group. This disparity is reflective of multiple factors including health care access, biological factors and participation in screening mammography. Currently there is a scarcity of literature on evidence-based interventional strategies to increase AAW's participation in screening mammography. Our study aims to: 1) Identify the literature from 2009-2015 on interventional strategies to increase the participation of AAW ≥40 years old in screening mammography and 2) Summarize the evidence from this literature including any impact of these interventions on breast cancer outcomes. METHODS: We conducted a systematic review of published and grey literature on breast cancer screening interventions from 2009-2015. The literature search was conducted in PubMed, Embase (Elsevier), CINAHL (Ebsco), PsycINFO (Ebsco) and the Cochrane Central Register of Controlled Trials (Wiley). Grey literature was searched for using ClinicalTrials.gov, National Cancer Institute's clinical trials database and ProQuest Dissertations and Theses database. Queries utilized a combination of keywords and database-specific terminology derived from pre-determined eligibility criteria. The four reviewers were divided into two teams to balance expertise in public health, primary care, cancer disparities, breast oncology and breast cancer basic science research. The review protocol was developed with guidance from PRISMA standards. Methodological quality of the studies will be determined by examination of study design, theoretical framework and quality of data reporting. RESULTS: Our literature search yielded a total of 1,83O studies. After removal of duplicates, 1,274 studies were screened for inclusion. Twenty studies met all criteria and were designated for abstraction and data analysis. Nineteen studies presented original data from a US based intervention and had a population which included AAW ≥ 40 years old. Study designs included: randomized control trials, quasi-experimental, pre/post study, non-randomized with controls, cohort and case-control studies. The common interventional strategies employed were reminder systems; trained volunteers; media campaigns; telephone and DVD coaching; and patient navigation/case management. Reported outcome measures included: demographics, pre- and post-intervention mammography participation, and intervention retention rates. Study limitations stemmed from limited sample size, lack of generalizability, absence of theoretical framework, attrition rate and utilization of self-reported data. CONCLUSION: Despite knowledge of disparities in breast cancer mortality for AAW and the impact of screening mammography on breast cancer mortality, there is a paucity of evidence on interventional strategies to increase the participation of AAW in screening mammography. The limited evidence available suggests that interventional strategies that incorporate mass media communication, family and social support networks, and nurse navigation increased the number of AAW who participate in screening mammography. Citation Format: Shana O. Ntiri, Laundette P. Jones, Gonca Kocoglu, Emilie Ludeman, Paula Y. Rosenblatt. A systematic review of breast cancer screening strategies for African American women. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C81.

General Biomarker Recommendations for Lymphoma.

Lymphoid malignancies are a heterogeneous group of tumors that have distinctive clinical and biological behaviors. The increasing prevalence of disease reflects both treatment advances and the fact that some of these tumors are indolent. The ability to determine treatment needs at diagnosis remains problematic for some of the tumors, such as in follicular lymphomas. Major clinical advances will likely depend on precision oncology that will enable identification of specific disease entities, prognostic determination at diagnosis, and identification of precise therapeutic targets and essential pathways. However, refinement in diagnostic evaluation is an evolving science. The ability to determine prognosis at diagnosis is variable, and for many of the lymphoid malignancies prognosis can only be made after initial treatment. Clinical trials that aim to evaluate specific features of these diseases are required in order to advance clinical practice that meaningfully addresses this important public health challenge. Herein, we describe the process and general recommendation from the National Cancer Institute (NCI) clinical trials planning meeting in November 2014 to address clinical trial design and biomarker proposals in the context of NCI-supported lymphoma clinical trials in the National Clinical Trials Network.

Protective Effect of Astaxanthin on Vocal Fold Injury and Inflammation Due to Vocal Loading: A Clinical Trial

Professional voice users, such as singers and teachers, are at greater risk of developing vocal fold injury from excessive use of voice; thus, protection of the vocal fold is essential. One of the most important factors that aggravates injury is the production of reactive oxygen species at the wound site. The purpose of the current study was to assess the effect of astaxanthin, a strong antioxidant, on the protection of the vocal fold from injury and inflammation due to vocal loading. This study is an institutional review board-approved human clinical trial. Ten male subjects underwent a 60-minute vocal loading session and received vocal assessments prior to, immediately after, and 30 minutes postvocal loading (AST(-) status). All subjects were then prescribed 24 mg/day of astaxanthin for 28 days, after which they received the same vocal task and assessments (AST(+) status). Phonatory parameters were compared between both groups. Aerodynamic assessment, acoustic analysis, and GRBAS scale (grade, roughness, breathiness, asthenia, and strain) were significantly worse in the AST(-) status immediately after vocal loading, but improved by 30 minutes after loading. In contrast, none of the phonatory parameters in the AST(+) status were statistically worse, even when measured immediately after vocal loading. No allergic responses or adverse effects were observed after administration of astaxanthin. The current results suggest that astaxanthin can protect the vocal fold from injury and inflammation caused by vocal loading possibly through the regulation of oxidative stress.

Lung cancer: Stage III NSCLC - is it time to centralize care?

Eaton et al. report a very strong association between institutional clinical trial accrual volume and the survival of patients with stage III NSCLC. The observed volume effect might have been exaggerated by artefact. More work is required to quantify the volume effect and understand its causes, before rushing to centralize care.

A meta-analysis of cardiovascular events in intermittent androgen-deprivation therapy versus continuous androgen-deprivation therapy for prostate cancer patients.

Androgen-deprivation therapy (ADT) is the standard treatment for advanced and recurrent prostate cancer but it has been shown to cause adverse effects on the cardiovascular system. Intermittent androgen deprivation has been studied as an alternative therapy. To conduct a meta-analysis comparing the incidence of cardiovascular events in patients with prostate cancer receiving intermittent (IADT) versus continuous ADT (CADT). We searched Cochrane CENTRAL, PubMed/Medline, Embase, Web of Science, The National Cancer Institute Clinical Trials and The Clinical Trials Register of Trials Central, and Google Scholar from inception of each database through February 2016. References from published guidelines, reviews and other relevant articles were also considered. We selected randomized clinical trials comparing IADT versus CADT in patients with prostate cancer that reported data on cardiovascular events. Two reviewers performed the study selection, data abstraction and risk of bias assessment. We calculated risk ratios with the Mantel-Haenszel method, using random effect models. We assessed heterogeneity using I2 index. The primary outcome was incidence of cardiovascular events. Secondary outcomes were thromboembolic events and cardiovascular-related mortality. Out of 106 references, we included seven articles from six trials (4810 patients) published between 2009 and 2015. We observed no significant difference between intermittent versus continuous androgen deprivation with respect to cardiovascular events (risk ratio (RR): 0.95; confidence interval (CI) 95%=0.83-1.08; seven trials, 4810 patients) and thromboembolic events (RR: 1.05; CI 95%=0.85-1.30; three trials, 1816 patients). There was marginally significant difference with respect to cardiovascular-related mortality (RR: 0.85; CI 95%=0.71-1.00; five trials, 4170 patients). Compared with CADT, IADT shows no difference in terms of cardiovascular events and thromboembolic events. However, there was an association between lower cardiovascular-related mortality and intermittent androgen deprivation.

SU‐F‐P‐13: NRG Oncology Medical Physics Manpower Survey Quantifying Support Demands for Multi Institutional Clinical Trials

Purpose:A survey was taken by NRG Oncology to assess Full Time Equivalent (FTE) contributions to multi institutional clinical trials by medical physicists.No current quantification of physicists’ efforts in FTE units associated with clinical trials is available. The complexity of multi‐institutional trials increases with new technologies and techniques. Proper staffing may directly impact the quality of trial data and outcomes. The demands on physics time supporting clinical trials needs to be assessed.Methods:The NRG Oncology Medical Physicist Subcommittee created a sixteen question survey to obtain this FTE data. IROC Houston distributed the survey to their list of 1802 contact physicists.Results:After three weeks, 363 responded (20.1% response). 187 (51.5%) institutions reporting external beam participation were processed. There was a wide range in number of protocols active and supported at each institution. Of the 187 clinics, 134 (71.7%) participate in 0 to 10 trials, 28 (15%) in 11 to 20 trials, 10 (5.3%) in 21 to 30 trials, 9 (4.8%) had 40 to 75 trials. On average, physicist spent 2.7 hours (SD: 6.0) per week supervising or interacting with clinical trial staff. 1.25 hours (SD: 3.37), 1.83 hours (SD: 4.13), and 0.64 hours(SD: 1.13) per week were spent on patient simulation, reviewing treatment plans, and maintaining a DICOM server, respectively. For all protocol credentialing activities, physicist spent an average of 37.05 hours (SD: 96.94) yearly. To support dosimetrists, clinicians, and therapists, physicist spend on average 2.07 hours (SD: 3.52) per week just reading protocols. Physicist attended clinical trial meetings for on average 1.13 hours (SD: 1.85) per month.Conclusion:Responding physicists spend a nontrivial amount of time: 8.8 hours per week (0.22 FTE) supporting, on average, 9 active multi‐institutional clinical trials.

Social functioning and facial expression recognition in children with neurofibromatosis type 1.

This study examined social functioning and facial expression recognition (FER) in children with neurofibromatosis type 1 (NF1) compared to typically developing peers. Specifically, the current research aimed to identify hypothesised relationships between neurocognitive ability, FER and social functioning. Children, ages 8 to 16, with NF1 (n = 23) and typically developing peers (n = 23) were recruited during regularly scheduled clinic visits and through advertisements on an institutional clinical trials website, respectively. Participants completed a measure of FER, an abbreviated intelligence test and questionnaires regarding their quality of life and behavioural functioning. Parents were also asked to complete questionnaires regarding the social-emotional and cognitive functioning of their child. As expected, there were significant differences between children with NF1 and typically developing peers across domains of social functioning and FER. Within the sample of children with NF1, there were no significant associations observed between cognitive measures, social functioning and facial recognition skills. Children with NF1 exhibited high rates of social impairment and weak FER skills compared to controls. The absence of associations between FER with cognitive and social variables, however, suggests something unique about this skill in children with NF1. Theoretical comparisons are made to children with autism spectrum disorders, as this condition may serve as a potentially useful model in better understanding FER in children with NF1.

Abstract 15: Target next sequencing profiling of pediatric solid tumors: Potential use for the identification of actionable mutations

Abstract The utilization of next generation sequencing for the identification of actionable gene mutations to guide the choice of therapy towards compounds that selectively inhibit specific genomic alterations is increasingly successful in adult oncology. Yet, limited progress has been achieved in pediatric oncology. Certain pediatric tumor types have shown limited, if any, improvement in overall survival, despite the efforts of institutional and cooperative group clinical trials. For most patients with recurrent pediatric malignancy, the outcome remains dismal. It is clear that a better understanding of the basic biology of these tumors is needed, and that through this understanding, novel and targeted therapeutic approaches may prove beneficial. The utility of systematic genetic profiling for individual tumors has not yet been demonstrated. Genetic screening may not only predict actionable targeted therapy, but also may define alterations that predict resistance to certain therapeutic agents, thereby avoiding the toxicity of salvage therapy with limited hope for benefit. To fill this gap, our group has conducted a pilot study to assess the potential utility of a custom targeted next generation sequencing panel for the identification of directly actionable gene mutations in recurrent pediatric malignancies. Using an “in house” custom panel, we sequenced the exomes of 156 genes (for a total of 5,610 amplicons) frequently mutated in solid tumors, including 29 genes with direct therapeutic target agents. As a proof of principle, we retrospectively analyzed five cases. Tissue sections from paraffin embedded blocks of recurrent pediatric tumors and matching tumor free tissue were microdissected and analyzed using the custom Ion Proton gene panel for the identification of potential targetable sequence variants. All cases were associated with the presence of mutations in actionable genes: ABL1, AKT2, ALK, CDKN2A, EGFR, ERBB2, ERB4, FGFR3, JAK3, NOTHC1, NRAS, PI3CA, RET. Interestingly, four of the five analyzed samples contained mutations in more than one actionable target. These observations suggest that clonal evolution analysis may be of particular importance for these specific tumor types. Our pilot study suggests that in recurrent pediatric malignancies, for which the standard of care offers limited hope for cure, targeted gene sequencing for the identification of actionable targets may provide important information to support therapeutic decision making. Note: This abstract was not presented at the conference. Citation Format: Adam S. Levy, Michael Roth, Nicole Patterson, Erwin Scott, Wilber Quispe-Tintaya, Michelle R. Ewart, Alex Maslov, Aaron Golden, Cristina Montagna. Target next sequencing profiling of pediatric solid tumors: Potential use for the identification of actionable mutations. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 15.

Using design methods to provide the care that people want and need.

Kim Erwin is an Assistant Professor at IIT Institute of Design and trained in user-centered design methods, which put people at the center of any problem space so as to develop solutions that better fit their everyday lives, activities and context. Her expertise is in making complex information easier to understand and use. Her research targets communication tools and methods for collaborative knowledge construction built through shared experiences. Her book, Communicating the New: Methods to shape and accelerate innovation focuses on helping teams explore, build and diffuse critical knowledge inside organizations. Jerry Krishnan is a Professor of Medicine and Public Health, and Associate Vice President for Population Health Sciences at the University of Illinois Hospital & Health Sciences System. He pioneered the use of Analytic Hierarchy Process to elicit the expressed needs of stakeholders for research. He previously served as Chair of the US FDA Pulmonary and Allergy Drugs Advisory Committee and is a Principal Investigator in NIH and Patient Centered Outcomes Research Institute (PCORI)-funded research consortia. He chairs the US National Heart, Lung, and Blood Institute (NHLBI) Clinical Trials review committee and the PCORI Improving Healthcare Systems merit review panel.

Pharmacodynamic Profile and Clinical Response in Patients with B-Cell Malignancies of Anti-CD19 CAR T-Cell Therapy

This study is supported in part by funding from the CooperativeResearch and Development Agreement (CRADA) between the National Cancer Institute and Kite PharmaIntroduction: Chimeric antigen receptor (CAR) engineered autologous T-cell therapy has shown promising efficacy in B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Anti-CD19 CAR T-cell product characteristics and potential pharmacodynamic markers from patients in this study were evaluated together with updated clinical responses.Methods: In this National Cancer Institute (NCI) clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by 1-2 x 106/kg anti-CD19 CAR T cells engineered with a CAR expressing CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the serum of patients prior to conditioning and CAR T-cell infusion, and during an interval of 4 weeks post-CAR T-cell infusion. EMD Millipore Luminex® xMAP® multiplex assays were used to measure all analytes. A Luminex 200™ instrument and xPONENT® 3.1 software were used for data acquisition and analysis. Major T-cell phenotypic markers including CD4, CD8, CD45RA and CCR7 were evaluated by multicolor flow cytometry on CAR-expressing T cells prior to and post-infusion, using a BD FACSCanto II. FlowJo software was used for data analysis. T-cell marker expression, as well as cytokine and chemokine levels were analyzed together with the clinical response to anti-CD19 CAR T cells. Maximum fold increase (MFI) was defined as the maximum fold change of measured analytes above baseline (pre-conditioning, day -5) across sampling timepoints.Results: Anti-CD19 CAR T-cell products, PBMCs from 12 patients, and serum samples from 15 patients have been evaluated. In 12 patient lots evaluated to date, the median CD4+/CD8+ CAR T-cell ratio was 0.48 (range 0.02-6.12). In addition, the median ratio between naïve (TN) plus central memory T cells (TCM), and more differentiated effector memory (TEM) plus effector cells (TE), was 0.48 (range 0.1-16.8). Post-hoc analyses adjusted for multiple comparisons showed that the frequency of CD4+ TN and TCM cells in the 6-8 day T-cell lots was significantly greater than that of CD4+ TN and TCM cells in the 10 day T-cell lots. The corresponding frequencies of CD8+ TN and TCM cells in the 6-8 day T-cell lots compared to 10 day T-cell lots approached significance, but did not meet the threshold after multiplicity adjustment. Clinical responses were seen across broad ranges of CD4+/CD8+ and (TN+TCM)/(TEM+TE) ratios in the CAR T-cell product.CAR T cells upregulated T-cell activation and immune modulating markers, as well as released measurable levels of cytokines and chemokines in response to CAR engagement of CD19 in vitro, or post-infusion. Cytokine and chemokine levels achieved their peak 3-10 days post T-cell infusion and returned to baseline generally within 3 weeks. Key pro-inflammatory cytokines and markers were upregulated: IL-6 median fold increase (MFI) at peak of 66 (interquartile range 5-152), IFN-g MFI 57 (13-126), C-reactive protein MFI 6 (4-42); immune homeostatic cytokines IL-15 MFI 19 (7-54), IL-2 MFI 20 (4-22), IL-10 MFI 10 (4-15); chemokines monocyte chemotactic protein (MCP)-1 MFI 7 (5-9), MCP-4 MFI 4 (2-5); and the immune effector molecules granzyme A MFI 7 (6-17) and granzyme B MFI 5 (3-9). Further analyses are ongoing.Conclusion: Clinical responses were observed irrespective of the CD4+/CD8+ ratio in the CAR T cell product. Cytokines and immune effector mediators peaked and cleared within 3 weeks. This pharmacodynamic profile reveals a rapid and coordinated sequence of T cell activation underlying durable responses in patients with B-cell malignancies. DisclosuresPerez:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Bot:Kite Pharma: Employment, Equity Ownership.

Cyclophosphamide and Fludarabine Conditioning Chemotherapy Induces a Key Homeostatic Cytokine Profile in Patients Prior to CAR T Cell Therapy

This study is supported in part by funding from the Cooperative Research and Development Agreement (CRADA) between the National Cancer Institute and Kite PharmaIntroduction: CAR-engineered autologous T-cell therapy has shown promising activity in relapsed/refractory B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Lymphodepleting conditioning chemotherapy is critical for optimal CAR T-cell activity in animal models. We evaluated the effects of conditioning chemotherapy on cytokine and chemokine levels in patients dosed with anti-CD19 CAR T cells.Methods: In this National Cancer Institute clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by anti-CD19 CAR T cells engineered with a CAR comprising CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the blood of patients pre (day -5) and post conditioning (day 0) by using EMD Millipore Luminex® xMAP® multiplex assays. Data acquisition and analysis were performed using a Luminex 200™ instrument and xPONENT® 3.1 data analysis software. Increases in cytokine and chemokine levels were analyzed pre- and post- conditioning, and the fold-changes in cytokine and chemokine levels were analyzed relative to clinical outcome subsequent to infusion with anti-CD19 CAR T cells. Analyses were performed with the Wilcoxon rank sum test adjusted for multiplicity with a Bonferroni correction, using a nominal level of 0.006 for significance.Results: Samples from 15patients have been evaluated. There were significant increases pre- to post-conditioning in the levels of interleukin 15 (IL-15; p=0.001), interleukin 7 (IL-7; p=0.0002), and monocyte chemoattractant protein-1 (MCP-1; p<0.0025) in blood, five days after the initiation of conditioning chemotherapy. Levels of interferon-gamma induced protein 10 (IP-10) were elevated post-conditioning, but did not meet the threshold for significance (p=0.048). Compared with baseline, levels of IL-15 increased on average 13 fold and levels of IL-7, IP-10 and MCP-1, about 2 fold. Comparison of the fold-increases in IL-15 upon conditioning between responders and non-responders approached significance (p=0.01), but did not meet the threshold after multiplicity adjustment. Larger fold-change increases for responders versus non-responders were also observed with placental growth factor (PLGF) (median fold increase 2.6 v. 1.6, average fold increase 32 v 4.2), C-reactive protein (CRP) (median fold increase 3.5 v 2.4, average fold increase 6.6 v. 2.0), IP-10 (median fold increase 2.1 v. 0.7, average fold increase 2.6 v. 2.8), and interleukin 10 (IL-10) (median fold increase 1.8 v. 0.4, average fold increase 3.1 v. 2.0), but did not meet the threshold for significance. In addition to ongoing analysis of conditioning-mediated cytokine induction and clinical response, we are evaluating the impact of conditioning chemotherapy dose on cytokine levels, as well as the relationship between conditioning-related cytokines and CAR T-cell expansion and persistence.Conclusions: The data obtained to date support the hypothesis that cytokines such as IL-15 play a key role in the clinical outcomes to anti-CD19 CAR T-cell therapy. Our results demonstrate that conditioning chemotherapy significantly increases the levels of homeostatic cytokines known to regulate T-cell expansion, as well as specific pro-inflammatory cytokines and chemokines. Optimization of conditioning chemotherapy is critical to the activity of CAR T-cell therapies. DisclosuresBot:Kite Pharma: Employment, Equity Ownership. Rossi:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma.

Quantitative Features of Liver Lesions, Lung Nodules, and Renal Stones at Multi-Detector Row CT Examinations: Dependency on Radiation Dose and Reconstruction Algorithm.

To determine if radiation dose and reconstruction algorithm affect the computer-based extraction and analysis of quantitative imaging features in lung nodules, liver lesions, and renal stones at multi-detector row computed tomography (CT). Retrospective analysis of data from a prospective, multicenter, HIPAA-compliant, institutional review board-approved clinical trial was performed by extracting 23 quantitative imaging features (size, shape, attenuation, edge sharpness, pixel value distribution, and texture) of lesions on multi-detector row CT images of 20 adult patients (14 men, six women; mean age, 63 years; range, 38-72 years) referred for known or suspected focal liver lesions, lung nodules, or kidney stones. Data were acquired between September 2011 and April 2012. All multi-detector row CT scans were performed at two different radiation dose levels; images were reconstructed with filtered back projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction (MBIR) algorithms. A linear mixed-effects model was used to assess the effect of radiation dose and reconstruction algorithm on extracted features. Among the 23 imaging features assessed, radiation dose had a significant effect on five, three, and four of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). Adaptive statistical iterative reconstruction had a significant effect on three, one, and one of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). MBIR reconstruction had a significant effect on nine, 11, and 15 of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). Of note, the measured size of lung nodules and renal stones with MBIR was significantly different than those for the other two algorithms (P < .002 for all comparisons). Although lesion texture was significantly affected by the reconstruction algorithm used (average of 3.33 features affected by MBIR throughout lesion types; P < .002, for all comparisons), no significant effect of the radiation dose setting was observed for all but one of the texture features (P = .002-.998). Radiation dose settings and reconstruction algorithms affect the extraction and analysis of quantitative imaging features in lesions at multi-detector row CT.

EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non–Muscle-invasive Stage Ta–T1 Urothelial Bladder Cancer Patients Treated with 1–3 Years of Maintenance Bacillus Calmette-Guérin

BackgroundThere are no prognostic factor publications on stage Ta–T1 non–muscle-invasive bladder cancer (NMIBC) treated with 1–3 yr of maintenance bacillus Calmette-Guérin (BCG). ObjectiveTo determine prognostic factors in NMIBC patients treated with 1–3 yr of BCG after transurethral resection of the bladder (TURB), to derive nomograms and risk groups, and to identify high-risk patients who should be considered for early cystectomy. Design, setting, and participantsData for 1812 patients were merged from two European Organization for Research and Treatment of Cancer randomized phase 3 trials in intermediate- and high-risk NMIBC. InterventionPatients received 1–3 yr of maintenance BCG after TURB and induction BCG. Outcome measurements and statistical analysisPrognostic factors for risk of early recurrence and times to late recurrence, progression, and death were identified in a training data set using multivariable models and applied to a validation data set. Results and limitationsWith a median follow-up of 7.4 yr, 762 patients recurred; 173 progressed; and 520 died, 83 due to bladder cancer (BCa). Statistically significant prognostic factors identified by multivariable analyses were prior recurrence rate and number of tumors for recurrence, and tumor stage and grade for progression and death due to BCa. T1G3 patients do poorly, with 1- and 5-yr disease-progression rates of 11.4% and 19.8%, respectively, and 1- and 5-yr disease-specific death rates of 4.8% and 11.3%. Limitations include lack of repeat transurethral resection in high-risk patients and exclusion of patients with carcinoma in situ. ConclusionsNMIBC patients treated with 1–3 yr of maintenance BCG have a heterogeneous prognosis. Patients at high risk of recurrence and/or progression do poorly on currently recommended maintenance schedules. Alternative treatments are urgently required. Patient summaryNon–muscle-invasive bladder cancer patients at high risk of recurrence and/or progression do poorly on currently recommended bacillus Calmette-Guérin maintenance schedules, and alternative treatments are urgently required. Trial registrationStudy 30911 was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911). Study 30962 was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

Co-infusion of insulin-secreting adipose tissue-derived mesenchymal stem cells and hematopoietic stem cells: novel approach to management of type 1 diabetes mellitus

Stem cell therapy (SCT) has promising results in regeneration of injured tissues/cells as well as correcting immune dysregulation. We present our experience of co-infusion of human adipose tissue-derived insulin-secreting mesenchymal stem cells (IS-AD-MSC) along with bone marrow-derived hematopoietic stem cells (BM-HSC) in type 1 diabetes mellitus (T1DM). This was an institutional review board-approved prospective non-randomized open-labeled clinical trial after informed consent of 20 patients (15 males and 5 females) with T1DM for SCT, with mean disease duration of 9 ± 5.51 years. Their mean age and weight were 19.95 ± 8.35 years and 49.9 ± 14 kg, respectively. Our study includes T1DM with positive for glutamic acid decarboxylase (GAD) antibody and history of diabetic ketoacidosis (DKA). Generated IS-AD-MSC and BM-HSC were infused via femoral catheterization under local anesthesia into portal + thymic circulation and subcutaneous tissue with conditioning of injection rabbit anti-thymocyte globulin and Bortezomib. Patients were monitored for blood sugar, serum C-peptide, GAD antibodies, and glycosylated hemoglobin (Hb1Ac) at three monthly intervals post-therapy. Mean SC quantum infused 99.45 ± 22.5 mL, with mean 2.38 ± 0.78 × 104 ISC/μL, mean CD34+ 0.57 %, and mean CD45-/90+ and CD45-/73+ were 47.22 and 24.66 %, respectively. Generated ISCs expressed transcription factors ISL-1, PAX-6, and IPF-1. Variable and sustained improvement in mean FBS, PPBS, HbA1c, and serum C-peptide was noted over a mean follow-up of 43.94 ± 19.8 months with mean reduction of GAD antibody from 525.15 to 120.15 IU/mL. Mean insulin requirement decreased from 60.89 to 39.76 IU/day. There was absence of DKA after SCT. No untoward effect/morbidity/mortality was recorded from SCT. Co-infusion of IS-AD-MSC with BM-HSC offers a safe and viable therapy for T1DM.

What's New in Rectal Cancer Research?

IntroductionClinical evidence has a more significant role in medical specialties than in surgery. Rectal cancer (CR) is no exception. This paper explores what CR-related subjects are being investigated at the present time in a quantitative and qualitative way and analyses this information to know what possible answers clinical research could give us in the future. MethodsThe data collection was carried out in April 2014 and was based on 3 sources: 2 institutional clinical trials registries – American (clinicaltrials.gov) and European (EU Clinical Trials Register) – and a survey given to members of the Asociación Española de Coloproctología (AECP). The obtained studies were exported to a database designed especially for this review, which included a number of descriptive elements that would allow the cataloguing of the different studies. The AECP survey results were analysed separately. ResultsThere are currently 216 clinical trials ongoing related to CR. Two-thirds are primarily conducted by oncologists. Nearly a third are surgical. The research focuses on improving preoperative treatment: new drugs, new schemes of chemo-radiotherapy (usually induction or consolidation schemes), or optimisation of radiotherapy and its effects. Surgical clinical trials are related to robotics, laparoscopy, stoma, low colorectal anastomosis, distal CR, and local treatment. ConclusionMost of the current clinical trials ongoing on CR are analysing aspects of chemo-radiotherapy and its effects. A third focus on purely surgical issues.

Clinical evaluation of an endorectal immobilization system for use in prostate hypofractionated Stereotactic Ablative Body Radiotherapy (SABR)

BackgroundThe objective of this study was to evaluate a novel prostate endorectal immobilization system (EIS) for improving the delivery of hypofractionated Stereotactic Ablative Body Radiotherapy (SABR) for prostate cancer.MethodsTwenty patients (n = 20) with low- or intermediate-risk prostate cancer (T1-T2b, Gleason Score < 7, PSA ≤ 20 ng/mL), were treated with an EIS in place using Volumetric Modulated Arc Therapy (VMAT), to a prescription dose of 26 Gy delivered in 2 fractions once per week; the intent of the institutional clinical trial was an attempt to replicate brachytherapy-like dosimetry using SABR. EBT3 radiochromic film embedded within the EIS was used as a quality assurance measure of the delivered dose; additionally, prostate intrafraction motion captured using pre- and post-treatment conebeam computed tomography (CBCT) scans was evaluated. Treatment plans were generated for patients with- and without the EIS to evaluate its effects on target and rectal dosimetry.ResultsNone of the observed 3-dimensional prostate displacements were ≥ 3 mm over the elapsed treatment time. A Gamma passing rate of 95.64 ± 4.28 % was observed between planned and delivered dose profiles on EBT3 film analysis in the low-dose region. No statistically significant differences between treatment plans with- and without-EIS were observed for rectal, bladder, clinical target volume (CTV), and PTV contours (p = 0.477, 0.484, 0.487, and 0.487, respectively). A mean rectal V80% of 1.07 cc was achieved for plans using the EIS.ConclusionsThe EIS enables the safe delivery of brachytherapy-like SABR plans to the prostate while having minimal impact on treatment planning and rectal dosimetry. Consistent and reproducible immobilization of the prostate is possible throughout the duration of these treatments using such a device.