Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study.

Purpose: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor].

Experimental Design: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks).

Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial.

Background: Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD.

Methods: GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries.

First-in-human, phase I study of PF-06647263, an anti-EFNA4 calicheamicin antibody-drug conjugate, in patients with advanced solid tumors.

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W).

Bayesian methods for the design and analysis of noninferiority trials.

The gold standard for evaluating treatment efficacy of a medical product is a placebo-controlled trial. However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efficacy is through a noninferiority (NI) study where a test treatment is compared to an active control treatment. The minimal objective of such a study is to determine whether the test treatment is superior to placebo.

Bayesian probability of success for clinical trials using historical data.

Developing sophisticated statistical methods for go/no-go decisions is crucial for clinical trials, as planning phase III or phase IV trials is costly and time consuming. In this paper, we develop a novel Bayesian methodology for determining the probability of success of a treatment regimen on the basis of the current data of a given trial. We introduce a new criterion for calculating the probability of success that allows for inclusion of covariates as well as allowing for historical data based on the treatment regimen, and patient characteristics.

Bayesian methods for design and analysis of safety trials.

Safety assessment is essential throughout medical product development. There has been increased awareness of the importance of safety trials recently, in part due to recent US Food and Drug Administration guidance related to thorough assessment of cardiovascular risk in the treatment of type 2 diabetes. Bayesian methods provide great promise for improving the conduct of safety trials.

The asthma disease activity score: a discriminating, responsive measure predicts future asthma attacks.

Background: Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used.

Objectives: We sought to develop a weighted and responsive measure of asthma disease activity.

Methods: Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6).

Airway obstruction lability helps distinguish levels of disease activity in asthma.

Classifying disease activity in asthma relies on clinical and physiological variables, but these variables do not capture all aspects of asthma that distinguish levels of disease activity. We used data from two pivotal trials of montelukast in asthma to classify disease activity as "high" or "low". We performed a principal component analysis (PCA) of disease activity using 21 efficacy outcome variables, including several novel derived outcome variables reflecting clinical and airway obstruction lability.

Development and validation of a composite score based on clinically meaningful events for the opioid-related symptom distress scale.

Purpose: To develop and validate a composite score based on clinically meaningful events (CMEs) for the opioid-related symptom distress scale (OR-SDS) that would be appropriate for use in postoperative clinical trials.

Methods: Secondary analysis of data from 2 multi-site Phase III randomized clinical safety trials: a general surgery trial (N = 1,050) and a coronary artery bypass graft surgery trial (N = 1,636). Validating measures include daily opioid consumption and physician and patient global evaluations of study medication.

Validity of 24-h recall ratings of pain severity: biasing effects of "Peak" and "End" pain.

Despite the frequent use of pain recall ratings in clinical research, there remains doubt about the ability of individuals to accurately recall their pain. In particular, previous research indicates the possibility that the most pain experienced during a recall period and the most recent pain experienced (known as peak and end effects, respectively) might bias recall ratings. The current study used data from a published clinical trial to determine the relative validity of a 24-h recall rating of average post-operative pain and the nature and extent of any biasing influence of peak and end effects on nine separate 24-h recall ratings.

Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice.

In vivo models have demonstrated that interleukin-13 (IL-13) plays an important role in asthma; however, few studies have evaluated the effect of inhibition of IL-13 on established and persistent disease. In the present study, we have investigated the effect of a therapeutic dosing regimen with an anti-IL-13 monoclonal antibody (mAb) in a chronic mouse model of persistent asthma. BALB/c mice were sensitized to allergen [ovalbumin (OVA); on days 1 and 8] and challenged with OVA weekly from day 22.