Efficacy and safety of ruxolitinib in patients with newly-diagnosed polycythemia vera: futility analysis of the RuxoBEAT clinical trial of the GSG-MPN study group.

Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Designing A Pathogen-Focused Study To Address The High Unmet Medical Need Represented By Carbapenem-Resistant Gram-Negative Pathogens - The International, Multicenter, Randomized, Open-Label, Phase 3 CREDIBLE-CR Study.

Carbapenem-resistant (CR) Gram-negative infections, including those caused by Enterobacteriaceae and the non-fermenters, represent the greatest unmet need for new effective treatments. The clinical development of new antibiotics for the treatment of CR infections is challenging and should focus on the individual pathogens irrespective of the infection site. However, the drug approval pathway is generally infection-site specific and rarely includes such drug-resistant pathogens. To overcome this limitation, a streamlined clinical development program may include a pathogen-focused clinical study, such as the CREDIBLE-CR study, to meet the expectations of some health authorities (ie, the European Medicines Agency [EMA]) and the medical community. Cefiderocol is a novel siderophore cephalosporin designed to target CR pathogens, including CR strains of Enterobacteriaceae (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and also Stenotrophomonas maltophilia, which is intrinsically CR. The CREDIBLE-CR study was planned to evaluate cefiderocol in patients with CR Gram-negative infections regardless of species or infection-site source. Rapid diagnostic testing and/or selective media were provided to facilitate detection of CR pathogens to rapidly enroll patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Patients were randomized 2:1 to receive cefiderocol or best available therapy. There were no pre-specified statistical hypotheses for this study, as the sample size was driven by enrollment feasibility and not based on statistical power calculations. The objective of the CREDIBLE-CR study was to provide descriptive evidence of the efficacy and safety of cefiderocol for the target population of patients with CR infections, including the non-fermenters. The CREDIBLE-CR study is currently the largest pathogen-focused, randomized, open-label, prospective, Phase 3 clinical study to investigate a new antibiotic in patients with CR Gram-negative infections. Here we describe the design of this pathogen-focused study and steps taken to aid patient enrollment into the study within an evolving regulatory environment. CLINICALTRIALSGOV REGISTRATION: NCT02714595. EUDRA-CT REGISTRATION: 2015-004703-23.

Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial.

INTRODUCTION: Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem-vaborbactam monotherapy versus best available therapy (BAT) for CRE. METHODS: A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem-vaborbactam (2 g/2 g over 3 h, q8h for 7-14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings. RESULTS: Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, - 44.7% to 9.3%) for meropenem-vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem-vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk-benefit analyses of composite clinical failure or nephrotoxicity favored meropenem-vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, - 74.6% to - 22.9%; P < 0.001). CONCLUSIONS: Monotherapy with meropenem-vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT. CLINICAL TRIALS REGISTRATION: NCT02168946. FUNDING: The Medicines Company.