A Master Protocol for the Multi-Cohort Phase 1/2 Study of DCC-3116 in Combination with Anticancer Therapies in Participants with Advanced Malignancies
This master protocol is a Phase 1/2, multicenter, open-label (unless otherwisespecified in a combination-specific module) study of DCC-3116 in combination with anticancertherapies. Modules within the master protocol are defined according to different combinations ofDCC-3116 with other anticancer agents. Each module will generally be conducted in 2 parts: Part 1(Safety/Dose-finding) and Part 2 (Expansion). Modules may open and close independently of eachother.In Part 1 (Safety/Dose-finding) of each module, dose levels of DCC-3116 in combination withmodule-specific anticancer therapies will be studied. Escalation and de-escalation will be guided bysafety, PK, and pharmacodynamics analyses within the framework of a Bayesian optimal interval(BOIN) design to remain within an expected dose-limiting toxicity (DLT) frequency of no more than30% for the MTD if any DLTs are observed. Details on sample size can be found in thecombination-specific modules.In Part 1, 2-6 participants will initially be enrolled for each new dose level. Toxicity-guided rulesaccording to the BOIN design for escalation and de-escalation will be based on a target DLT toxicityrate for the MTD of 30% and at least 2 participants per dose level having completed the DLT periodof 28 days. Dose-limiting toxicities are defined in each combination-specific module.The BOIN design for establishing the MTD uses the following rule, optimized to minimize theprobability of incorrect dose assignment, to guide dose escalation/de-escalation:• If the observed DLT rate at the current dose is =0.236, escalate the dose to the next higherdose level• If the observed DLT rate at the current dose is >0.359, de-escalate the dose to the nextlower dose level• Otherwise, stay at the current doseFor overdose control, the following rule will be applied: if the probability exceeds 0.95 that the DLTrate for a dose level of DCC-3116 is greater than 30% and at least 3 DLT evaluable participants havebeen treated at that dose level, the respective and any higher dose levels of DCC-3116 will beeliminated from further examination. If the lowest dose of DCC-3116 is eliminated, the module willbe stopped for safety.Dose escalation and de-escalation may continue according to the BOIN design until the maximumsample size for the module is reached or if the number of DLT evaluable participants treated at thecurrent dose reaches 15 and the decision is to stay at the current dose level. Additional participantsmay be enrolled in lower dose levels. To better characterize safety, PK, and pharmacodynamics, up toapproximately 15 participants per dose level may be considered for Phase 2 evaluation.After Part 1 (Safety/Dose-finding) for the module is completed, if any DLTs are observed, the MTDfor DCC-3116 in combination with module-specific anticancer therapies will be computed usingisotonic regression. The recommended dose(s) for Phase 2 evaluation of DCC-3116 in combinationwith module-specific anticancer therapies to be used in Part 2 (Expansion) will be selected based onnot exceeding the MTD and achieving the most targeted overall safety, PK, pharmacodynamics, andpreliminary anticancer activity profile. In Part 2 (Expansion) of each module, a two-stage designbased on the exact binomial distribution with non-binding futility will be used. Details on sample sizeand boundaries for futility can be found in the combination-specific modules.
A MIXED METHODS SINGLE-GROUP SINGLE-CENTER FEASIBILITY STUDY OF A FOOD RESPONSE AND ATTENTION TRAINING TO REDUCE UNHEALTHY DIETARY INTAKE AND PROMOTE WEIGHT LOSS IN RACIALLY AND ETHNICALLY DIVERSE PATIENTS WITH OBESITY
Over 40% of American adults have obesity, with a higher prevalence for racial/ethnic minorities such as Hispanic (47%) and non-Hispanic Black/African American populations (46.8%), increasing their cardiovascular disease risk. Most behavioral interventions do not target attention bias that may be driving food intake, and this may limit their effectiveness. Attention bias to unhealthy foods describes the automatic processes by which these foods capture attention, and activate the brain’s reward system. During computer-based food response training, people can learn to counteract this attention bias by repeatedly inhibiting their responses to unhealthy foods. Afterward, people devalue these foods, experience fewer cravings, and reduce their food intake, binge eating symptoms, and weight. Food response training may be particularly beneficial for people with low inhibitory control who, by definition, demonstrate decreased ability to suppress task-irrelevant behaviors. Food response training has promise as a novel weight-loss treatment, yet most studies to date have taken place in laboratory settings with students. Thus, it is unclear whether findings are generalizable to diverse patient populations and within clinical settings. Using a mixed-methods approach, this study aims to determine the acceptability and feasibility of a food response training intervention among racially and ethnically diverse patients with obesity and elevated cardiovascular disease. We will conduct a single group pre-post study to examine the acceptability and feasibility of the food response training intervention and 12-week outcomes (i.e., dietary intake, weight, and blood pressure). We will also conduct individual interviews with a subset of patients to examine patients’ perceptions of the food response training intervention. We also explore if the effects of the food response training intervention on reduced dietary intake and weight will be stronger for patients who score low on the inhibitory self-control scale. Food response training is a novel and potentially scalable weight-loss intervention that may help diverse patients with obesity to consume healthy foods, lose weight, and improve their cardiovascular health.
A Modular Open-label Phase I/II Study to Evaluate the Safety Tolerability Pharmacokinetics and Efficacy of EP0031 in Patients with Advanced RET-altered Malignancies
EP0031-101 is an interventional, modular, multi-arm, multi-centre, open-label Phase I/II study to investigate the safety, tolerability, PK, and PD of EP0031, to determine the RP2D of EP0031, and todetermine preliminary efficacy of EP0031 in defined patient populations with RET-altered malignancies.The design consists of a core study protocol and individual Modules, as follows:? Module A: Monotherapy dose escalation and RP2D optimisation in patients with RETaltered solid tumours (including a paired biopsy cohort)? Module B: Dose-expansion cohorts will be opened to further explore the safety andtolerability and provide preliminary efficacy data in selected patient populations withRET-altered tumours? Module C: Further dose expansion and initial efficacy investigation in patients who haveprogressed following first-generation SRI therapy
A Multi-Center Observational Study Assessing the Utility of an Immune Cell Function Assay in a Cardiac Sarcoid Population
Sarcoid is an autoimmune disease that can be found in any and every organ system. The greatest degree of morbidity and mortality comes from cardiac involvement where it can lead to sudden cardiac death, heart block, and heart failure. The basics of the treatment for cardiac sarcoid include appropriate preventative treatment for ventricular arrhythmias, guideline directed medical treatment for heart failure, and immunosuppression to decrease active cardiac inflammation. The amount of immunosuppression and with which medication is of expert opinion. Using PET scan, we can help assess for successful suppression of the disease, but often 2nd or 3rd line treatments are required after initial therapy strategy is deemed insufficient. As of now, there are no predictors of who will fail initial treatment. For this study, there are three different hypotheses. First, we suspect the baseline Immuknow tertile (low, medium, high) will correlate with the rate of response to first line immunosuppression with low being more likely than the combined medium/high grouping to be responsive on first clinically indicated PET follow up. Second, that a subsequent decrease in ImmuKnow grade, for those that start in the medium or high range, will be predictive of resolution of inflammation on cardiac PET. Lastly, we would like to assess whether an intermediate ImmuKnow assay, drawn at 1 month, would be predictive of response at 3 month follow up.The study population will include adults with a clinical or histological diagnosis of cardiac sarcoidosis found to have active inflammation on cardiac PET scan who are not currently on immunosuppressive therapy. This should be their first time undergoing treatment for cardiac sarcoid (i.e. not with disease recurrence). This will give us a uniform patient population that will not have effects of prior immunosuppression as to their response to current treatment, and not possibly already have treatment failure. We will also be storing biologic samples for future analysis. We believe that a change in the immunophenotype of an individual in response to treatment will be the hallmark of successful immunosuppression. We will be using these samples to assess this in the future.
A Multi-Center Phase 2/3 Randomized Double-Blind Placebo-Controlled Parallel- Group Safety and Efficacy Study of Dapansutrile Tablets in Subjects with an Acute Gout Flare
This is a multi-center Phase 2/3 randomized, double-blind, placebo-controlled,parallel-group safety and efficacy study with a 7-day period of IMP treatment conducted insubjects with an acute gout flare.
A Multi-Center Prospective Observational Study of Patients with Neuroinflammatory Disease
Patients meeting inclusion criteria for the study will be prospectively enrolled and followed over time to evaluate clinical variables and the natural history of these disorders. Additionally, we will analyze patient electroencephalograms, brain imaging studies, and collect blood, spinal fluid, tissue, and other biospecimens when available, for future biomarker, immunophenotyping, and genetic analyses.
A multi-center randomized blinded controlled study to evaluate the safety and efficacy of the Urocross Expander System and Retrieval System (EXPANDER-2)
The Urocross Expander System is indicated for the treatment of lowerurinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia(BPH) in men = 45 years old, and while implanted in the prostaticurethra.The Urocross Expander Implant is indicated for an indwell duration of 6months, after which it is retrieved under visualization, using the UrocrossRetrieval Sheath and a commercially available compatible grasper usedduring urological procedures.The Urocross Retrieval Sheath is indicated for use to retrieve theUrocross Expander Implant using a compatible flexible cystoscope andcompatible graspers commonly used during urological procedures.
A Multi-center Randomized Control Cross-over Study to Evaluate the Effectiveness of a Novel Portable Non-Pneumatic Active Compression Device vs. an Advanced Pneumatic Compression Device for Treating Lower Extremity Lymphedema (TEAYS)
To evaluate the Non-Pneumatic Active Compression Device (NPCD) in contrast to an advanced pneumatic compression device (APCD)
A multi-cohort randomized Phase 2 open-label study to assess the preliminary efficacy safety and pharmacokinetics of BIVV020 for prevention and treatment of antibody-mediated rejection in adult kidney transplant recipients.
Antibody-mediated rejection (AMR) remains as the most common cause of allograft failure following kidney transplantation (1, 2). The primary mechanism of AMR involves activation of the classical complement pathway (CP) through the interaction of donor-specific antibodies (DSA), pre-existing or de novo, against antigens on the donor organ, leading to complement-induced inflammation and endothelial injury of the allograft (3, 4). There is currently no approved treatment for prevention or treatment of AMR. Current management of AMR primarily relies on avoiding positive crossmatch transplantation, or utilizing off-label DSA-depleting therapies such as plasmapheresis (PP), intravenous immunoglobulin (IVIg), and rituximab for pre- or post-transplant desensitization (5, 6). This study is designed to explore the safety, pharmacokinetics (PK), and efficacy of BIVV020 when given in addition to standard of care (SOC) therapy in renal transplant participants for the prevention and treatment of AMR.
A Multi-Phase Study Examining Hospital to Home Transitions for Children with Medical Complexity
The overarching objective of this study is to make it easier for parents of children with medical complexity (CMC) to take care of their children after discharge home from the hospital and reduce the chance of post-hospitalization morbidity (meaning bad outcomes such as readmissions) after discharge. CMC, or those with multiple chronic conditions, progressive conditions, or technology dependence, are at high risk for post-hospitalization morbidity. This study will take place in 3 phases at 2 sites: Bellevue Hospital Center (BHC) and Hassenfeld Children’s Hospital (HCH). We will recruit parents of CMC with a prior or current admission at these two sites, as well as pediatricians who care for these children in the inpatient setting for the following 3 aims: - In Aim 1, we will interview parents of CMC and pediatricians to understand their views on what makes it challenging, and what can make it easier, for parents to understand and follow the instructions they get from the hospital about how to take care of their CMC after leaving the hospital. We will also ask pediatricians what may make it difficult to provide relevant education to families. We hypothesize that we will identify several contributing factors.- In Aim 2, we will design a tool to make it easier for parents to understand and follow the discharge instructions for their CMC. We will use structure of existing tool, findings from Aim 1, and extensive interviews and testing of the tool with parents and pediatricians as we design the new tool. We hypothesize that we will successfully design a tool that will be usable by both parents and pediatricians.- In Aim 3, we will use a randomized controlled trial (RCT) to study the impact of the tool on parent comprehension and adherence (or how well they can follow) their child's discharge instructions, as well as its impact on post-discharge morbidity (such as readmissions and emergency department visits). Parents will be randomized to either receive usual hospital care and instructions or the intervention/tool (in addition to the usual care and instructions). We will also ask parents who receive the intervention about its usability. We hypothesize that, compared to subjects who receive usual care, subjects in the intervention group will have higher comprehension and adherence, and their children will have lower post discharge morbidity. Parents will find the intervention to be usable.