Confirmatory Phase Research Articles

A qualitative analysis of Finnish RE students’ perceptions of their professional development during their initial teacher education

ABSTRACT This article studies three RE (religious education) student teachers’ perceptions about their professional development from the beginning to the end of their initial teacher education. The focus of study was to investigate via an inductive content analysis if there are the same kind of phases in RE teacher education and how those phases are in relation to their training. Based on their characterisations of professional development, three phases were found: an explorative phase, a confirmatory phase and an induction phase. In the first phase, the typical things were uncertainty about the teaching profession and the importance of managing the content knowledge. In the second phase, it was observed by the interviewees that theory and practice could be combined and the development of different skills were seen as important. In the third phase, the interviewees perceived gaining experience from practice and combining their personal life and career as relevant. Finally, the interviewees believed that their professional development will continuously evolve. RE student teachers saw the various elements of their teacher education as important factors in all the phases.

A Mixed Methods–Grounded Theory Design for Producing More Refined Theoretical Models

Current literature lacks explication of how traditional grounded theory and mixed methods–grounded theory (MM-GT) are similar/different and specific explication of how to construct MM-GT designs—our purpose is to do this. We illustrate the design process using a published study. Exploratory Phase 1 involves creation of a formative–theoretical model based on multiple implicit or explicit models identified in the literature, which are then combined into a single model using meta-modeling integration. Also, in Phase 1, a traditional grounded theory is developed “independently” using interview data. These two models are integrated into a combined/meta-model at the end of Phase 1. Confirmatory Phase 2 involves testing of the final Phase 1 meta-model using a mixed methods experiment. In Phase 3, the Phase 1 and Phase 2 results are integrated, producing the “final” meta-model. This article contributes to the field of mixed methods research by showing how to design an MM-GT study that is focused on theory development and testing.

Combination of monalizumab and cetuximab in recurrent or metastatic head and neck cancer patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.

6516 Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8+T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .

TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).

TPS4666 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC is established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. IDMC last reviewed the trial in October 2019 and suggested the trial continue as planned. Clinical trial information: NCT03665441 .

MicroRNA Profile of Patients with Chronic Limb-Threatening Ischemia.

Chronic limb-threatening ischemia (CLTI) results in devastating complications such as lower-limb amputations. In this study, a genome-wide plasma microRNAs (miRNA) sequencing was performed to identify miRNA(s) associated with CLTI. Blood samples were collected from early stage CLTI patients (ABI < 0.9) and non-PAD controls (ABI ≥ 0.9) for 3 experiments: discovery phase (n = 23), confirmatory phase (n = 52) and validation phase (n = 20). In the discovery phase, next generation sequencing (NGS) was used to identify miRNA circulating in the plasma CLTI (n = 13) patients, compared to non-PAD controls (n = 10). Two down-regulated miRNAs (miRNA-6843-3p and miRNA-6766-5p) and three upregulated miRNAs (miRNA-1827, miRNA-320 and miRNA-98-3p) were identified (≥2-fold change). In the confirmatory phase, these 5 deregulated miRNAs were further investigated in non-PAD (n = 21) and CTLI (n = 31) patients using qRT-PCR. Only miRNA-1827 was found to be significantly upregulated (≥3-fold, p-value < 0. 001) in the CLTI group. Lastly, to minimize the influence of confounding factors, miRNA-1827 plasma levels were validated in a third cohort of CLTI patients (n = 10) matched to non-PAD controls (n = 10). Our analysis demonstrated that miRNA-1827 expression was increased in the CLTI cohort (≥2-folds, p-value < 0.001). In summary, circulating miRNA-1827 is significantly elevated in patients with CLTI.

Children’s occupational knowledge: a conceptual framework and measure

We describe a conceptual framework for and introduce a measure to examine children’s knowledge about occupations and the world of work. The framework comprises three aspects of occupational knowledge: identifying occupations from pictures (occupational picture naming), naming and explaining occupations (occupational vocabulary), and explaining the essence of work (occupational comprehension). Scale development included exploratory and confirmatory phases. The Cronbach alpha for the subscales ranged between 0.70 and 0.90. Age differences on scales were compared between 3- and 8-year-old children (N = 101). The older children demonstrated greater occupational knowledge than the youngest in all aspects. Theoretical and practical implications are discussed.

Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer

Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up). When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. ClinicalTrials.gov Identifier: NCT01042379.

Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan.

Two issues in clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, the relationship between rare events and endpoints, and the differences in multiplicity adjustment between regions, and (2) the current practice on multiplicity adjustment and sample size calculation. This article summarizes the results of the survey on the second issue. Eligible trials for this survey fulfilled the following conditions: (1) confirmatory phase 3 trial; (2) use of multiple primary endpoints, co-primary endpoints, key secondary endpoint(s) or composite endpoint(s); (3) inclusion of Japanese participants; and (4) protocols created in 2010 or later. The survey was conducted at member companies of the Japan Pharmaceutical Manufacturers Association from October 2017 to November 2017. Useable responses were obtained from 78 trials in 13 companies based in Japan and 9 companies based in other countries. The Bonferroni procedure was mostly used in clinical trials with multiple primary endpoints, while multiple testing procedures that consider a hierarchy of endpoints or a structure of hypotheses were used in clinical trials with key secondary endpoint(s). In sample size calculation, we can consider the probability of study success, such as the probability of statistical significance in at least one comparison of primary endpoints; however, other probabilities were also considered. This survey reveals that multiplicity adjustment and the correlation of endpoints were not always considered in sample size calculation. In clinical trials with multiple endpoints, clinical importance was considered when determining multiple testing procedures. Challenges remain with the definition of power, the consideration of multiple testing procedures and the correlation between endpoints in sample size calculation.

TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).

TPS783 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.

Optimal Designs for Multi-Arm Phase II/III Drug Development Programs

In drug development programs, phase II studies may be carried out as multi-arm trials aiming to identify treatment(s) with the optimal benefit-to-risk profile(s). Succeeding confirmatory phase III trials then attempt to demonstrate efficacy and safety of the designated treatment(s). While upmost important to consider multi-arm phase II/III study(ies) holistically to optimize drug development, sample size allocation with sound go/no-go decision rules has become more complex to handle but critical to guide decision making. For example, one has to decide whether to conduct the phase III trial with a single (the most promising) treatment only, or with multiple treatments (if sufficiently promising). We propose a framework for program-wise phase II/III drug development planning aiming to optimize the sample size allocation and go/no-go decision rule with respect to the maximal expected utility for time-to-event endpoints. The approach is based on a utility function taking into account, for example, fixed and variable costs of the program, expected benefits after successful market launch, assumed true treatment effects, and event rates. We illustrate our method by application to practical examples. Our results show that program-wise drug development planning is indispensable. This can be done by using a user-friendly R Shiny application. Supplementary materials for this article are available online.

Psychosocial Factors Related to Adverse Outcomes in Heart Failure Caregivers: A Structural Equation Modeling Analysis.

Heart failure (HF) caregivers experience increased demands and burden. Social support and problem solving may influence the effect of these variables on caregiver outcomes. The aim of this study was to examine whether social support and problem solving mediate relationships among caregiver demands and burden, self-care, depression, and life changes in heart failure caregivers. Using a cross-sectional, exploratory design, heart failure caregivers (n = 530) completed online questionnaires on caregiver demands and burden, social support, problem solving, depression, self-care, and life changes. Path analysis examined a hypothesized mediating role of social support and problem solving in the relationships among caregiver demands and burden and caregiver outcomes. The analysis included (1) a model-development phase (n = 329) to make data-based decisions on measurement indicators and model structure and (2) a confirmatory phase (n = 201) to provide unbiased inference on the model structure resulting from the initial phase. Participants were 41.39 (±10.38) years old and primarily white (78.3%) men (50.9%) caring for a spouse (44.9%). Per the magnitudes of the estimated path coefficients, social support mediated the relationship between caregiver burden and depression but did not relevantly mediate the relationship between caregiver burden and self-care or caregiver life changes. In the presence of social support as a parallel mediator, problem solving was not a relevant mediator between caregiver burden and demands and caregiver outcomes. Social support mediates the effects of caregiver burden on depression but has little effect on self-care or life changes. In the presence of social support, problem solving does not mediate the effects of caregiver demands and burden on caregiver outcomes.

Reasons for Premature Conclusion of Late Phase Clinical Trials: An Analysis of ClinicalTrials.gov Registered Phase III Trials.

Confirmatory phase III trials aim to provide decisive evidence about a medical product's safety and efficacy. Although these trials are planned and conducted based on accumulated knowledge, they are not without risk or uncertainty. A trial prematurely concluding contributes to great loss in both financial and human research resources. We categorized and evaluated trials concluded prematurely after recruitment had begun, as registered in Clinical Trials.gov between January 2013 and August 2017. We found 9828 registered interventional phase III trials; of those, 320 were concluded prematurely. Many clinical trials were concluded prematurely for reasons related to reducing participant risk, such as interim stopping for safety, efficacy, or futility. Yet, 70% trials were halted for other reasons, such as insufficient recruitment (the most often cited reason) or unspecified business decisions. Of all prematurely concluded trials, 102 trials evaluated 72 different novel therapeutics; in 66.7% of these trials, the clinical development program was stopped entirely. Most of the prematurely concluded trials (78%) had not provided results to ClinicalTrials.gov at the time of this analysis. Evaluation of the factors that influence premature conclusion could inform solutions for improving research participation and help ensure trial completion. Registering and reporting results acknowledges the voluntary contribution and consent expectations of research participants.

Zanubrutinib: a new BTK inhibitor for treatment of relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) has historically been an aggressive disease with poor long-term survival. In the last decade, Bruton tyrosine kinase (BTK) inhibition has emerged as a new treatment strategy for MCL, especially in the relapsed/refractory (r/r) setting. Zanubrutinib, a second-generation BTK inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in late 2019 for r/r MCL on the basis of combined overall response rate of 84% in a total of 118 patients from two multicenter clinical trials, BGB-3111-AU-003 and BGB-3111-206. Duration of response was 14-18 months. Although 57% of patients developed grade 3 and 4 adverse side effects including anemia, pneumonia and neutropenia, only 8% discontinued treatment suggesting zanubrutinib monotherapy was fairly well tolerated. As compared to first-generation ibrutinib, zanubrutinib has higher BTK selectivity which may result in fewer off-target effects and improved potential for combination with other targeted therapies. In addition to a confirmatory phase III trial, there are multiple ongoing studies evaluating zanubrutinib as part of two- and three-drug regimens in MCL and other B-cell malignancies. These current results and areas of further interest indicate an exciting future for zanubrutinib in the treatment of MCL.

Viewpoint: Futility Analyses in Alzheimer's Disease (AD) Clinical Trials: A Risky Business.

In the standard, orderly progression of drug development trials, a moderately-sized Phase 2 trial demonstrates safety and efficacy of one or more doses of the investigational product, followed by large confirmatory Phase 3 trials of one or two doses leading to regulatory approval. The large and lengthy Phase 3 trials often include interim futility analyses using statistical methods to assess lack of benefit, so that programs “fail early” by identifying ineffective treatments early if evidence points toward lack of efficacy, in part to limit financial loss and redirect resources. For disease-modifying drug development programs in Alzheimer’s disease (AD), finding an optimal strategy is particularly challenging. A slowing of decline rather than symptomatic improvement indicates disease-modification, and primary outcomes for such trials are noisy and sometimes subjective. As a result, very large, lengthy trials are required to see efficacy signals, so Phase 2 trials may look like Phase 3 programs or Phase 3 trials may directly follow Phase 1 trials. In other words, enormous trials may be launched without sufficient evidence of preliminary efficacy of the doses studied, dramatically increasing the financial risk to sponsors. In such instances, futility analyses embedded in trials would seem to be particularly important.

Pharmacological properties and clinical efficacy of dotinurad (URECE® tablets), a novel hypouricemic agent

In Jan 2020, dotinurad (URECE® tablets) was approved for gout and hyperuricemia therapy in Japan. We developed a novel hypouricemic agent because benzbromarone, a commercially available uricosuric agent, has several problems, such as drug-induced liver injury or drug-drug interaction caused by CYP2C9 inhibition. In transporter-overexpressing cells, dotinurad potently inhibited URAT1 which is localized in the renal proximal tubules and functions as a urate reabsorption. On the contrary, dotinurad hardly inhibited urate secretion transporters, ABCG2 or OAT1/3. In Cebus monkeys, dotinurad dose-dependently decreased plasma urate levels at low doses compared with benzbromarone. Inhibitory effect of dotinurad on mitochondria was weaker than that of benzbromarone and there was no observation suggesting a risk of drug-induced liver injury taking into consideration the clinical dose or exposure. Dotinurad weakly inhibited CYPs and further analysis indicated there was no drug-drug interaction risk in the clinical dose. In clinical pharmacology studies, there was no difference among sex and age. Furthermore, dosage and administration are equal even in hepatic impairment patients (mild to severe) and renal impairment patients (mild to moderate). In confirmatory phase II and long-term studies, dotinurad decreased serum urate levels at low doses and almost patients using maintenance dose (2 or 4 mg) achieved a serum urate level ≤ 6.0 mg/dL. Moreover, there was no finding to raise safety concern including liver injury. In conclusion, dotinurad, a selective urate reabsorption inhibitor (SURI) could be a therapeutic option because of its more effective hypouricemic action at low doses than those of commercially available uricosuric agents.

Abstract B22: Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)

Abstract Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized phase 2b study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression-free survival (PFS). The safety profile of eryaspase was acceptable. The results of this phase 2b study provided a rationale for initiating this confirmatory phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label phase 3 trial (N= ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anticancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1, stage IV disease, documented evidence of disease progression, available tumor tissue, and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted, which represents a conservative estimate based on the phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Citation Format: Pascal Hammel, Rosanna Berardi, Eric Van Cutsem, Jaime Feliu, Richard Greil, Harpreet Wasan, Jean-Philippe Metges, Peter Nygren, Pia Österlund, Marcus Noel, Thomas Seufferlein, Geert-Jan Creemers, Anu Gupta, Sophie Salesse, Nigel Biswas-Baldwin, Hedy Dion, Hagop Youssoufian, Iman El-Hariry, Manuel Hidalgo. Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B22.

Clinical efficacy and safety of dotinurad, a novel selective urate reabsorption inhibitor, in Japanese hyperuricemic patients with or without gout: randomized, multicenter, double-blind, placebo-controlled, parallel-group, confirmatory phase 2 study

BackgroundDotinurad, a novel selective urate reabsorption inhibitor (SURI), reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1) for the treatment of hyperuricemia with or without gout. We confirmed the serum uric acid lowering effect and safety of dotinurad.MethodsThis was a confirmatory, 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose escalation, late phase 2 study. The study arms were dotinurad 0.5, 1, 2, or 4 mg and placebo. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. The secondary endpoint was the percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit.ResultsThe study drugs were administered to 200 Japanese hyperuricemic patients with or without gout. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad 0.5, 1, 2, and 4 mg groups and the placebo group was 21.81%, 33.77%, 42.66%, 61.09%, and − 2.83%, respectively. The percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit in each group was 23.1%, 65.9%, 74.4%, 100%, and none, respectively. Regarding safety, the incidence of adverse events did not increase with dose escalation in the dotinurad groups. No significant differences were observed in the incidence of gouty arthritis in each group.ConclusionThe serum uric acid lowering effect and safety of dotinurad were confirmed in hyperuricemic patients with or without gout.ClinicalTrials.gov IdentifierNCT02416167

Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.

A Randomized Phase 3 Clinical Trial of the Combination of Plinabulin (plin) + Pegfilgrastim (peg) Versus (vs) Peg Alone for Tac (docetaxel, doxorubicin, cyclophosphamide) Induced Neutropenia (cin)

Trial in Progress: Granulocyte colony stimulating factors (G-CSFs) (including Peg) reduce, but do not completely ameliorate CIN. Plinabulin is a novel, small molecule, single-dose-per cycle therapy, with equal activity against docetaxel CIN vs. Peg, but with several advantages: Plin has 1. Less bone pain, 2. Anticancer effects, and 3. Dosing 30 min after chemotherapy (chemo). The CIN nadir with Plin occurs in week 2 and with Peg in week 1 of the chemo cycle. All these features suggest a mechanism of action (MoA) with Plin that is different from Peg (Blayney, ASCO 2018; IASLC 2018). Neutrophil demargination with Plin and a reduced neutrophil transit time consistent with IL-6 signaling, and reversal of a LSK block in bone marrow, suggest protective rather than a stimulatory MoA for Plin in CIN (Blayney, SLB 2018; Ghosh, AACR 2018, Suwa, Am J Physiol 2000). Due to their differences in MoA, there is a strong rationale to combine Plin and Peg, as this offers the potential of better protection against CIN in both week 1 and 2 in the chemo cycle. In the Phase II portion of study BPI2358-106 (Study 106., NCT03294577), we evaluated the effects of the Plin combined with Peg on CIN and Bone Pain. Study 106 treated breast cancer (BC) patients with TAC with 6 mg Peg alone (Peg6), or Peg6+Plin. Plin dose was 20 mg/m2. Grade (Gr) 3 and 4 neutropenia frequency, duration of Gr 3 and 4 neutropenia (DSMN), and neutrophil nadir was based on absolute neutrophil counts, obtained on days 0, 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 15. Bone pain was assessed by a validated questionnaire on days 1, 2, 3, 4, 6, 7, 8, 9, and expressed as % of patients reporting bone pain. Phase II Results. The confirmatory phase 3 portion of study 106 will test addition of Plin to Peg6, which may offer superior protection against TAC CIN vs Peg alone without bone pain. The Plin/Peg combination is a novel CIN approach with the potential to optimize chemotherapy, by minimizing chemotherapy dose modifications due to CIN or bone pain.*p&amp;lt;0.05; **p&amp;lt;0.001; ***P&amp;lt;0.01 Peg+Plin vs Peg 6mg Table Disclosures Blayney: BeyondSpring Pharmaceuticals: Research Funding. Huang:BeyondSpring Pharmaceuticals: Employment. Mohanlal:BeyondSpring Pharmaceuticals: Employment.

PNS150 CONDITIONAL MARKETING AUTHORISATION FOR NOVEL TREATMENTS: A LANDSCAPE ASSESSMENT OF EXPEDITED PATHWAYS OUTSIDE US AND EU

Approval of pharmaceuticals based on promising early efficacy results using conditional marketing authorisation (CMA) pathways is one of the tools used by EMA and FDA to expedite patient access to life-saving treatments. A targeted search of HTA agency documents was conducted to categorise policies in other regions, where use of CMA has been poorly documented. Two researchers extracted information on CMA pathways from official websites of countries with a national HTA agency, unit or committee: this included eligibility criteria, requirements and time frame for post-authorisation data collection. Hand searches of published/grey literature were conducted to find additional insights on the CMA process. CMA policies were found in 8 of the 40 countries included in the search: Argentina, Australia, Canada, China, Japan, Serbia, South Korea and Taiwan. Eligibility for orphan drugs was specified in 4 countries. In 6 countries, requirements included unmet need and a major therapeutic advance. Pathways aimed at innovative drugs were identified in the Asia Pacific region: Japan’s Sakigake for regenerative medicine and cell and gene therapy in South Korea. China and Serbia leverage approval decisions in the US and EU to minimise risk from early approvals. In terms of post-approval clinical data requirements, Canada and Taiwan require confirmatory phase III data, whilst others specify longer term phase II studies. Taiwan, Australia and Japan set explicit time limits for additional data (5,6 and 7 years, respectively), although it is unclear how agencies ensure compliance. CMA pathways have been established in a number of emerging healthcare markets, although policies differ across countries. Whilst all 8 agencies specified serious and rare conditions are eligible for CMA, some focused on innovative drugs or on products already in use in established markets. Additional research is needed to describe how CMA impacts on reimbursement and patient outcomes.