BACKGROUND: In the current study, the authors sought to determine the maximum tolerated dose (MTD) of the novel class 1 selective histone deacetylase inhibitor CXD101 in a dose escalation study in patients with advanced solid tumors or recurrent/refractory lymphoma. METHODS: The authors escalated the dose of CXD101 from 1 mg twice daily orally for 5 days in a 21-day cycle (3+3 design). RESULTS: A total of 39 patients were enrolled, 36 of whom received CXD101. Of the 30 patients in the escalation cohort, 29 were evaluable for determination of the dose-limiting toxicity (DLT). DLTs were noted at doses of 16 mg twice daily (1 of 6 patients), 20 mg twice daily (1 of 6 patients), and 24/25 mg twice daily (2 of 5 patients, both of whom developed neutropenic fever). The MTD was 20 mg twice daily, which achieved maximal plasma concentrations (±standard deviation) of 231 ± 76 nM to 342 ± 126 nM, which was within the biologically active range. Six patients received 20 mg twice daily in an expansion cohort. The most frequent adverse events were fatigue, nausea, and reversible cytopenia. Key grade 3 to 4 adverse events (according to Common Terminology Criteria for Adverse Events criteria [version 4.03]) included thrombocytopenia (11%), neutropenia (17%), and neutropenic fever (2%) across the 133 CXD101 cycles given. The toxicity profile was similar to that of licensing studies with other histone deacetylase inhibitors. In 22 evaluable patients receiving a dose of ≥16 mg twice daily (17 of whom had lymphoma and 5 of whom had solid tumors), 3 partial responses (2 in patients with classic Hodgkin lymphoma after allogenic stem cell transplantation and 1 in a patient with angioimmunoblastic T-cell lymphoma) and 1 complete response (in a patient with follicular lymphoma) were noted (overall response rate of 18%) in addition to 9 patients who achieved durable stable disease. Responses were noted predominantly among patients with lymphoma (tumor reduction noted in 63% of patients on standard computed tomography). CONCLUSIONS: The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma. Cancer 2019;125:99-108.

Background:Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases.Methods:In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials.Results:Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6–5.6) in the vandetanib group and 2.5 months (90% CI: 0.2–4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6–6.3) and 2.5 months (90% CI: 0.2–7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments.Conclusions:The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.

Nurses are essential to effective global cancer control, influencing treatment, education, research, and policy issues-at local, national, and international levels. Empowering cancer nurses to lead and take on key leadership roles across the cancer continuum and within different levels of the healthcare system is imperative to addressing the burden of cancer globally. In some countries, addressing inequalities and dismantling professional hierarchies is central to enabling nurses to exercise their leadership capabilities, even if they are not in a leadership role, to improve cancer care outcomes. Although every cancer nurse will be required to demonstrate skills as leaders, not all will be in leadership roles. More nursing leadership roles are needed at national, regional, and global levels. In some countries, more cancer nursing leadership opportunities are provided/available than in others. For example, in many countries, inequalities and professional hierarchies exist, which often prohibit leadership opportunities for cancer nurses. Investment in developing leadership among nurses at all levels is a global priority. 1,2 Leadership is the ability to achieve collaborative effort, enabling people to work together to achieve common goals. It is multifaceted, characterized by the ability to provide and deliver direction and support, motivation, coordination, collaboration, effective communication, and advocacy for patients, communities, and other nurses. Leadership is about interpersonal relationships, and empowering the workforce to be innovative and creative to solve challenges is going to be important moving forward. 3 Strengthening nursing leadership in global health ("no one left behind") is a priority. The consistent messaging in the "Triple Impact Report," 4 the Nursing Now initiative, 5 and in the State of the World's Nursing 6 and the Global Strategic Priorities for Nursing and Midwifery 7 reports is that influential nurse leaders are more critical than ever. As the most significant global health workforce, 8 nursing needs to focus its attention on the development of nurse leaders across clinical care, research, education, policy, and administration if the World Health Organization sustainable development goals 9 and the global strategic priorities for nursing are to be met. The Institute of Medicine report on the Future of Nursing: Leading Change, Advancing Health 10 and more recently the National Academy of Medicine report on the Future of Nursing 2020-2030, 11 both call for nurses to lead interprofessional teams and healthcare systems to benefit patient outcomes and system-level efficiency. Not only has the COVID-19 pandemic powerfully illustrated the knowledge, skills, commitment, and leadership of nurses globally, it has also demonstrated why person-centered, culturally safe, evidence-based care and Universal Health Coverage 12 cannot be achieved without nurses and nurse leaders.Nurses, as informal and formal leaders, need to be fostered and recognized across all aspects and levels of nursing work. Nu...