A novel approach to visualize clinical benefit of therapies for chronic graft versus host disease (cGvHD): the probability of being in response (PBR) applied to the REACH3 study.

Overall response rate (ORR) is commonly used as key endpoint to assess treatment efficacy of chronic graft versus host disease (cGvHD), either as ORR at week 24 or as best overall response rate (BOR) at any time point up to week 24 or beyond. Both endpoints as well as duration of response (DOR) were previously reported for the REACH3 study, a phase 3 open-label, randomized study comparing ruxolitinib (RUX) versus best available therapy (BAT). The comparison between RUX and BAT was performed on ORR and BOR using all randomized patients, while DOR was derived for the subgroup of responders only.

Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.

Background: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.

Quantitative assessment of adverse events in clinical trials: Comparison of methods at an interim and the final analysis.

In clinical study reports (CSRs), adverse events (AEs) are commonly summarized using the incidence proportion (IP). IPs can be calculated for all types of AEs and are often interpreted as the probability that a treated patient experiences specific AEs. Exposure time can be taken into account with time-to-event methods.

Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts.

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS).

Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial.

Background: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus.

Patient-reported outcomes in a phase iii study of everolimus versus placebo in patients with metastatic carcinoma of the kidney that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.

Purpose: A phase III, randomized, double-blind, placebo-controlled trial was conducted in patients with metastatic renal cell carcinoma. The focus of this paper is to evaluate the patient-reported outcomes.

Methods: Patients were randomly assigned (2:1) to receive oral everolimus 10 mg once daily or placebo.

A proof of concept phase II non-inferiority criterion.

Traditional phase III non-inferiority trials require compelling evidence that the treatment vs control effect bfθ is better than a pre-specified non-inferiority margin θ(NI) . The standard approach compares this margin to the 95 per cent confidence interval of the effect parameter. In the phase II setting, in order to declare Proof of Concept (PoC) for non-inferiority and proceed in the development of the drug, different criteria that are specifically tailored toward company internal decision making may be more appropriate.

Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors.

Background: A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.

Methods: Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care.

Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.

Background: Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.

Methods: Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care.