and 9 Gilead Sciences Inc., Foster City, CA Key Points• Concomitant PI3Kd and SYK inhibition resulted in treatment-emergent pneumonitis, necessitating early study termination.• Initial trials of novel combinations should use conservative designs that are focused on safety.Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase d and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatmentemergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-g and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity.

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Lessons Learned. Trebananib leveraging anti‐angiogenic mechanism that is distinct from the classic sorafenib anti‐vascular endothelial growth factor inhibition did not demonstrate improved progression‐free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang‐2 levels’ association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang‐2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang‐2.Background.Ang‐1 and Ang‐2 are angiopoietins thought to promote neovascularization via activation of the Tie‐2 angiopoietin receptor. Trebananib sequesters Ang‐1 and Ang‐2, preventing interaction with the Tie‐2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang‐2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).Methods.Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs‐Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression‐free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang‐2.Results.Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar‐plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang‐2 dichotomized at the median was associated with improved OS in both cohorts.Conclusion.There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

In this conceptual article the topic of "Prospective Ergonomics" will be discussed within the context of innovation, design thinking and design processes & methods. Design thinking is essentially a human-centred innovation process that emphasises observation, collaboration, interpretation, visualisation of ideas, rapid concept prototyping and concurrent business analysis, which ultimately influences innovation and business strategy. The objective of this project is to develop a roadmap for innovation, involving consumers, designers and business people in an integrative process, which can be applied to product, service and business design. A theoretical structure comprising of Innovation perspectives (1), Worldviews supported by rationalist-historicist and empirical-idealistic dimensions (2) and Models of "design" reasoning (3) precedes the development and classification of existing methods as well as the introduction of new ones.

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