First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors.

BACKGROUND: Preclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer comprising physiologically active IL-15 and IL-15 receptor α, as monotherapy and in combination with spartalizumab, an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody, in patients with advanced solid tumors. METHODS: This phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W in patients with anti-PD-1-sensitive or anti-PD-1-resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase. RESULTS: As of February 17, 2020, 83 patients (median age: 63 years; range: 28-85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1-2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3-4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1-sensitive and 20% (5/25) in the anti-PD-1-resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments. CONCLUSIONS: NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs. TRIAL REGISTRATION NUMBER: NCT02452268.

A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors.

BACKGROUND: Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. METHODS: Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. RESULTS: Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. CONCLUSIONS: At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. TRIAL REGISTRATION: NCT02325739 .

Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing.

Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

Study design with staggered sampling times for evaluating sustained unresponsiveness to peanut sublingual immunotherapy.

In this work, we delineate an altered study design of a pre-existing clinical trial that is currently being implemented in the Department of Pediatrics at the University of North Carolina at Chapel Hill. The purpose of the ongoing investigation of the desensitized pediatric cohort is to address the effectiveness of sublingual immunotherapy in achieving sustained unresponsiveness (SU) as assessed by repeated double-blind placebo-controlled food challenges (DBPCFC). With scarce published literature characterizing SU, the length of time off-therapy that would represent clinically meaningful benefit remains undefined. We use the new design features to assess time to loss of SU, an important efficacy endpoint, that to our knowledge, no prior study has investigated. Our work has two-fold objectives: first is to propose and discuss aspects of the altered design that would allow us to study SU and second is to explore methodology to evaluate the time to loss of SU and its association with risk factors in the context of the data originating from the trial. The salient feature of the new design is the allocation scheme of study subjects to staggered sampling timepoints when a subsequent DBPCFC is administered. Due to this feature, the time to loss of SU is either left or right censored. Additionally, some participants at study entry fail the DBPCFC, leading to what can be construed as an instantaneous failure. Through in-depth numerical studies, we examine the performance and power of a recently proposed mixture proportional hazards model specifically designed for the analysis of interval-censored data subject to instantaneous failures.

Side effects from use of one or more psychiatric medications in a population-based sample of children and adolescents.

OBJECTIVE: The purpose of this study was to investigate the side effect risks from using one or more psychiatric medications (including antipsychotics, antidepressants, α-2 agonists, benzodiazepines, mood stabilizers, and stimulants) among a national cohort of children and adolescents. METHODS: A questionnaire survey was administered to parents who filled a prescription for a psychiatric medication for their child at a large national retail pharmacy chain. Primary outcome variables were the total count of side effects from a list of 12 problem areas, as well as parent-reported side effect intensity (mild/moderate/severe). Modifiers investigated included specific medication and number of medications utilized, demographics, and difficulties with access to care. RESULTS: A total of 1347 parents of study subjects ages 3-17 years from 30 U.S. states who were taking psychiatric medications for any indication purchased at one retail pharmacy chain enrolled following a single mail invitation (7.5% response). Of the study subjects, 80% were white/non-Hispanic, 64% were male, 63% had private health insurance, and 67% had used a current medication for >1year. Most (84%) had one or more parent-reported side effect. After adjusting for covariates, subjects with two medications reported 17% (p<0.001) and with three or more medications reported 38% (p=0.002) increases in their average number of side effects than did children taking one medication. Parental reporting of difficulties in accessing care also predicted a 42% (p<0.001) greater number of side effects than for those who had no access difficulties. Side effects were particularly more common in medication combinations including either selective serotonin reuptake inhibitors (SSRIs) (77% higher odds, p<0.001) or antipsychotics (99% higher odds, p<0.001). CONCLUSIONS: Side effects from psychiatric medications appear to be both more common and more severe overall with increasing numbers of medications utilized, and with perceived difficulty in accessing care. Polypharmacy regimens including either SSRIs or antipsychotics were especially associated with experiencing side effects, within this study sample.

Evaluating components of dental care utilization among adults with diabetes and matched controls via hurdle models.

BACKGROUND: About one-third of adults with diabetes have severe oral complications. However, limited previous research has investigated dental care utilization associated with diabetes. This project had two purposes: to develop a methodology to estimate dental care utilization using claims data and to use this methodology to compare utilization of dental care between adults with and without diabetes. METHODS: Data included secondary enrollment and demographic data from Washington Dental Service (WDS) and Group Health Cooperative (GH), clinical data from GH, and dental-utilization data from WDS claims during 2002-2006. Dental and medical records from WDS and GH were linked for enrollees continuously and dually insured during the study. We employed hurdle models in a quasi-experimental setting to assess differences between adults with and without diabetes in 5-year cumulative utilization of dental services. Propensity score matching adjusted for differences in baseline covariates between the two groups. RESULTS: We found that adults with diabetes had lower odds of visiting a dentist (OR = 0.74, p < 0.001). Among those with a dental visit, diabetes patients had lower odds of receiving prophylaxis (OR = 0.77), fillings (OR = 0.80) and crowns (OR = 0.84) (p < 0.005 for all) and higher odds of receiving periodontal maintenance (OR = 1.24), non-surgical periodontal procedures (OR = 1.30), extractions (OR = 1.38) and removable prosthetics (OR = 1.36) (p < 0.001 for all). CONCLUSIONS: Patients with diabetes are less likely to use dental services. Those who do are less likely to use preventive care and more likely to receive periodontal care and tooth-extractions. Future research should address the possible effectiveness of additional prevention in reducing subsequent severe oral disease in patients with diabetes.

A population-based study of periodontal care among those with and without diabetes.

BACKGROUND: Our objectives were to describe the prevalence of periodontal care (a marker of periodontitis) among persons with and without diabetes and to examine the association between periodontal care and diabetes. METHODS: We conducted a cross-sectional analysis, using 5 years of electronic data from a population-based cohort (N = 46,132), aged 40 to 70 years, with dental and medical insurance, and ≥ 1 dental and ≥ 1 medical visit. Periodontal care (yes/no) was defined by dental claims codes for procedures used to manage periodontitis. The association between periodontal care and diabetes was determined using logistic regression adjusted for and stratified by age, sex, insurance type, smoking status, body mass index (BMI) (in kilograms per square meter), and resource utilization band (RUB) (a measure of expected health care utilization attributable to comorbidity). RESULTS: Overall, 11.2% (5,153 of 46,132) met diabetes criteria. The age-adjusted prevalence of periodontal care among those with and without diabetes was 39.1% and 32.5%, respectively (P <0.0001). The association between diabetes and periodontal care decreased with increasing age (interaction, P <0.0001), adjusting for BMI and RUB. The aged-stratified, adjusted odds ratio (OR) for periodontal care associated with diabetes was highest among those aged 40 to 44 years [OR, 1.6; confidence interval (CI), 1.30 to 1.97] and lowest among those aged 60 to 64 years (OR, 0.97; CI, 0.81 to 1.15) and was significant only among those aged 40 to 54 years. CONCLUSION: We found that the prevalence of periodontal care was significantly higher among those with diabetes compared to those without diabetes and that the magnitude of this association decreased with increasing age.

Cross-sectional study of periodontal care and Glycosylated Hemoglobin in an insured population.

OBJECTIVE: Compare GHb among people with diabetes who have and have not received periodontal care. RESEARCH DESIGN AND METHODS: This cross-sectional study linked 5 years of electronic medical record and dental insurance data for dually insured patients with diabetes, ages 40-70 years (n = 5,103). We assessed the association between annual mean GHb (%) and periodontal care (a proxy for periodontitis) defined using claim codes. Among patients who received periodontal care, we assessed the association between GHb and periodontal treatment intensity. We determined associations using linear regression adjusted for potential confounders and tested for effect modification by age, sex, insulin use, diabetes severity, BMI, and smoking. RESULTS: Mean GHb was 7.66%; 38% of participants received periodontal care during the 5 years. After multivariate adjustment, patients who received periodontal care had a GHb level 0.08 percentage points higher than patients who did not (P = 0.02). In stratified analyses, the association was present for women (0.18 percentage points higher GHb with periodontal care, P < 0.001) but not significant for men (0.008 percentage points lower, P = 0.86). In patients who received periodontal care, those with one, and with two or more, surgical treatments had GHb 0.25 (P = 0.04) and 0.36 (P = 0.002) percentage points lower, respectively, than patients without periodontal surgeries. CONCLUSIONS: This population-based cross-sectional study showed small associations between periodontal care (a proxy for periodontitis) and higher GHb. Well-controlled longitudinal studies or clinical trials are needed to evaluate causality and temporal trends. Sub-analyses suggest that further investigation of this association among women, and by intensity of periodontal treatment, may be of interest.

Case study of linking dental and medical healthcare records.

OBJECTIVE: To link the administrative data of a large dental carrier and an integrated health plan in Washington State to conduct an observational study of diabetes and periodontal disease. STUDY DESIGN: Evaluation of variable suitability, testing of linkage variables, and performing an n - 1 deterministic linkage strategy. METHODS: We examined a variety of administrative data variables for their consistency over time and their information richness to use as matching variables. After choosing social security number, date of birth, first name, and last name, we tested their reliability as linking variables among a population with dual dental and medical insurance. Lastly, we performed four n - 1 deterministic linkage steps to obtain our study population. RESULTS: With a success match rate of more than 96% with the 4 test variables, we extracted the entire population who met the study criteria with the understanding that only a subset would successfully link. We linked 78,230 individuals (55.2% of the Group Health Cooperative population). Of these matches more than 50% occurred within a last name-first name-birth date deterministic match. CONCLUSIONS: Employer groups who provide dental-medical benefits for their employees send identical administrative data to dental and healthcare plans. The n - 1 deterministic linkage was accomplished by using a relatively straightforward approach because these data were fairly homogeneous and of high quality. Until medical care and dental care are integrated, it is possible to link these data to assess the impact of oral disease on overall health.