Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types.

BACKGROUND: Nivolumab 480 mg every 4 weeks (Q4W) is approved in the European Union, United States, and several other markets across multiple tumor types. Its approval was supported by quantitative efficacy/safety analyses bridging to 3 mg/kg every 2 weeks (Q2W). PATIENTS AND METHODS: The benefit-risk profile of nivolumab 480 mg Q4W relative to 3 mg/kg Q2W was evaluated using population pharmacokinetic modeling and exposure-response (E-R) analyses for safety and efficacy. Pharmacokinetic exposures were predicted for 3203 patients with melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous cell carcinoma of the head and neck, urothelial carcinoma, or classical Hodgkin lymphoma. Quantitative models analyzed E-R to predict 480-mg Q4W safety across all indications and efficacy for melanoma, NSCLC, and RCC. Intratumoral receptor occupancy (RO) was predicted for parameters representing different tumor types. RESULTS: Time-averaged concentrations for 480 mg Q4W versus 3 mg/kg Q2W were higher during the first 28 days (26.8%) and similar at steady state (5.2%). The maximum concentration (Cmax) after the first dose was higher (110.4%), and the trough concentration at day 28 was lower (-22.1%) with 480 mg Q4W versus 3 mg/kg Q2W. The Cmax achieved with 480 mg Q4W was lower than the previously established safe dose of 10 mg/kg Q2W. The probability of adverse events for key safety end points was similar for 480 mg Q4W and 3 mg/kg Q2W. The predicted overall survival and objective response rates with 480 mg Q4W were comparable to 3 mg/kg Q2W. The predicted high intratumoral RO provided additional evidence to support 480 mg Q4W across tumor types. CONCLUSIONS: The benefit-risk profile for nivolumab 480 mg Q4W was predicted to be similar to that of 3 mg/kg Q2W across tumor types while providing a convenient and flexible option for patients and their caregivers.

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine.

BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.

Application of nonlinear dynamics to human postural control system.

Instability, fear of falling and fall injuries are common problems for the older population and individuals with chronic disabilities. Development of screening tools and outcome measures of balance performance and fall risk has become of great interest for health professionals and researchers in the field of rehabilitation. Although linear modeling is desirable due to its simplicity, however, most physiological systems are too complicated to lend themselves to linear analysis because the human body is multi-segmental, and there are feedforward and feedback control schemes of mutual relationship between the segments. In this study, we investigated the use of nonlinear dynamic tools to extract characteristic features of postural sway. Among various methods of nonlinear dynamics, the Rényi fractal dimension and the Rényi spectrum are presented as quantitative descriptors. The center of foot pressure (COP) was recorded during four quiet standing tasks of increasing difficulty (eliminating vision and use of a compliant surface). The COP trajectories' Rényi dimension and Rényi spectra of young healthy subjects with no history of neurological disorder were investigated in comparison to that of elderly patients with balance impairment and history of frequent falls. Sway path, the common linear parameter of postural sway, was also used to investigate its distinction from non-linear parameters. The results of this study suggest the COP trajectories' Rényi dimension and sway path can be used as classifiers for balance disorders, and they provided different indications of postural control system characteristics between the two groups and different task demands.

Copper deficiency as an anti-cancer strategy.

Copper is a tightly regulated trace element. Disruptions of copper homeostasis are rare and they cause serious disorders such as Wilson's disease and Menkes disease. Copper also plays an important role in promoting physiological and malignant angiogenesis. Formation of new blood vessels by a tumor enables tumor growth, invasion and metastasis. The copper chelator tetrathiomolybdate (TM), which quickly and effectively depletes copper stores, is under investigation as an anti-angiogenic agent. Promising results in vitro, in pre-clinical animal models and in an early (phase I) clinical trial have led to ongoing phase II evaluation of TM in patients with advanced cancers.

A comprehensive assessment of satisfaction with care for cancer patients.

The present paper reports on the initial development of a comprehensive questionnaire for assessing cancer patients' perception of the quality of care received in the oncology hospital. This questionnaire is primarily intended to evaluate interventions aimed at improving quality of life and focuses on patients' interactions with doctors and nurses. The current questionnaire includes 61 items assessing doctors' and nurses' technical competence, communication skills, interpersonal qualities, and availability; aspects of the hospital environment and treatment planning; and general satisfaction. Most items refer to an aspect of care rated on a five-point Likert scale from "Poor" to "Excellent". Additionally, each aspect of care is also evaluated by a dichotomous (yes/no) question on the patient's wish (or not) for its improvement. This questionnaire is the result of consecutive pilot tests (from April 1994 to September 1995). Analysis of patients' comments, items that patients omitted to respond to and score distributions have identified items needing to be rephrased, reworded, eliminated or placed in specific sections. Items showing low scores or acceptable score distributions have been stressed as appropriate for inclusion in the final questionnaire version.

Assessment of the value of positive pressure breathing apparatus in inducing cough.

In the last decade, numerous papers have discussed what has been called the indiscriminate use of intermittent positive pressure breathing therapy (IPPB) for the treatment of obstructive airways disease (Curtis et al., 1968; Loke and Anthonisen, 1974; Cheney et al., 1976; Baker, 1974; Murray, 1974; Barach and Segal, 1975; Sheldon and Gold, 1976; Dolovich et al., 1977). These papers have all failed to show any advantage of positive pressure breathing therapy, either in the acute or chronic stages of obstructive airways disease. IPPB apparatus is expensive, requires careful maintenance and cleaning and may lead to patient dependence. However, physiotherapists in this hospital gained the impression that patients who were receiving nebulisation with positive pressure appeared to cough more frequently, and to produce greater volumes of sputum, suggesting that IPPB apparatus may be a useful adjunct of physiotherapy. Therefore a study was designed to compare the effectiveness of nebulisation therapy, with and without positive pressure, on the production of cough and sputum volume in patients with chronic obstructive airways disease.