Characterization of the Cynomolgus Macaque Model of Marburg Virus Disease and Assessment of Timing for Therapeutic Treatment Testing.

Marburg virus (MARV) causes severe disease and high mortality in humans. The objective of this study was to characterize disease manifestations and pathogenesis in cynomolgus macaques exposed to MARV. The results of this natural history study may be used to identify features of MARV disease useful in defining the ideal treatment initiation time for subsequent evaluations of investigational therapeutics using this model. Twelve cynomolgus macaques were exposed to a target dose of 1000 plaque-forming units MARV by the intramuscular route, and six control animals were mock-exposed. The primary endpoint of this study was survival to Day 28 post-inoculation (PI). Anesthesia events were minimized with the use of central venous catheters for periodic blood collection, and temperature and activity were continuously monitored by telemetry. All mock-exposed animals remained healthy for the duration of the study. All 12 MARV-exposed animals (100%) became infected, developed illness, and succumbed on Days 8-10 PI. On Day 4 PI, 11 of the 12 MARV-exposed animals had statistically significant temperature elevations over baseline. Clinically observable signs of MARV disease first appeared on Day 5 PI, when 6 of the 12 animals exhibited reduced responsiveness. Ultimately, systemic inflammation, coagulopathy, and direct cytopathic effects of MARV all contributed to multiorgan dysfunction, organ failure, and death or euthanasia of all MARV-exposed animals. Manifestations of MARV disease, including fever, systemic viremia, lymphocytolysis, coagulopathy, and hepatocellular damage, could be used as triggers for initiation of treatment in future therapeutic efficacy studies.

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF.

WHAT IS THIS SUMMARY ABOUT?: Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®) are medicines used to treat a type of melanoma that has a change in the BRAF gene, called advanced or metastatic BRAF V600-mutant melanoma. Participants with advanced or metastatic BRAF V600-mutant melanoma took either encorafenib plus binimetinib together (COMBO group), compared with encorafenib alone (ENCO group) or vemurafenib (ZELBORAF®) alone (VEMU group). WHAT WERE THE RESULTS?: In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time. WHAT DO THE RESULTS MEAN?: Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone. Clinical Trial Registration: NCT01909453 (ClinicalTrials.gov).

COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma.

PURPOSE: Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453). METHODS: Patients with locally advanced unresectable or metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned. RESULTS: Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard. CONCLUSION: In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.

Factors that influence use of a home cardiorespiratory monitor for infants: the collaborative home infant monitoring evaluation.

BACKGROUND: As part of the Collaborative Home Infant Monitoring Evaluation, a home monitor was developed to record breathing, heart rate, other physiologic variables, and the time the monitor was used. OBJECTIVE: To determine the frequency of monitor use, factors that influence use, and validity of a model developed to predict use. DESIGN: We developed a model to predict monitor use using multiple linear regression analysis; we then tested the validity of this model to predict adherence for the first week of monitoring and for the subsequent 4-week period (weeks 2-5). SETTING: Clinical research centers in Chicago, Ill; Cleveland, Ohio; Honolulu, Hawaii; Los Angeles, Calif; and Toledo, Ohio. Patients Preterm infants, infants younger than 1 month with a history of autopsy-confirmed sudden infant death syndrome in a sibling, and infants with an idiopathic apparent life-threatening event were divided into 2 cohorts based on enrollment date. Main Outcome Measure Mean hours of monitor use per week. RESULTS: In cohort 1, the variables available before monitoring were only weakly associated with total hours of monitor use in weeks 2 to 5 (total model r(2) = 0.08). However, when hours of monitor use in week 1 were included as a variable to predict monitor use in weeks 2 to 5, the r(2) increased to 0.64 for hours of monitor use per week. CONCLUSIONS: Our data show that monitor use in the first week was the most important variable for predicting subsequent monitor use. The study suggests that a major focus of home monitoring should be adherence in the first week, although it remains to be tested whether this adherence can be altered.

Cardiorespiratory events detected by home memory monitoring and one-year neurodevelopmental outcome.

OBJECTIVE: To determine if infants with cardiorespiratory events detected by home memory monitoring during early infancy have decreased neurodevelopmental performance. STUDY DESIGN: Infants (n = 256) enrolled in the Collaborative Home Infant Monitoring Evaluation also completed the Bayley Scales of Infant Development II at 92 weeks' postconceptional age. Infants were classified as having 0, 1 to 4, or 5+ cardiorespiratory events. Events were defined as apnea >or=20 seconds or heart rate <60 to 80 bpm or <50 to 60 bpm, for >or=5 to 15 seconds, depending on age. RESULTS: For term infants, having 0, 1 to 4, and 5+ cardiorespiratory events was associated with unadjusted mean Mental Developmental Index (MDI) values (+/-SD) of 103.6 (10.6), 104.2 (10.7), and 97.7 (10.9), respectively, and mean Psychomotor Developmental Index (PDI) values of 109.5 (16.6), 105.8 (16.5), and 100.2 (17.4). For preterm infants, having 0, 1 to 4, and 5+ cardiorespiratory events was associated with unadjusted mean MDI values of 100.4 (10.3), 96.8 (11.5), and 95.8 (10.6), respectively, and mean PDI values of 91.7 (19.2), 93.8 (15.5), and 94.4 (17.7). The adjusted difference in mean MDI scores with 5+ events compared with 0 events was 5.6 points lower in term infants ( P = .03) and 4.9 points lower in preterm infants ( P = .04). CONCLUSIONS: Having 5+ conventional events is associated with lower adjusted mean differences in MDI in term and preterm infants.