GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial

Background: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Achieving minimal residual disease (MRD) negativity in CLL is an independent predictor of survival even with a variety of different treatment approaches and regardless of the line of therapy. Methods/design: GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) is a seamless phase II/III, multi-centre, randomised, controlled, open, parallel-group trial for patients with CLL who have recently responded to chemotherapy. Participants will be randomised to receive either obinutuzumab (GA-101) consolidation or no treatment (as is standard). The phase II trial will assess safety and short-term efficacy in order to advise on continuation to a phase III trial. The primary objective for phase III is to assess the effect of consolidation therapy on progression-free survival (PFS). One hundred eighty-eight participants are planned to be recruited from forty research centres in the United Kingdom. Discussion: There is evidence that achieving MRD eradication with alemtuzumab consolidation is associated with improvements in survival and time to progression. This trial will assess whether obinutuzumab is safe in a consolidation setting and effective at eradicating MRD and improving PFS. Trial registration: ISRCTN, 64035629. Registered on 12 January 2015. EudraCT, 2014-000880-42. Registered on 12 November 2014

Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial

Background Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). Methods/design FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. Discussion The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. Trial registration ISRCTN01844152. Registered on 8 August 2014, EudraCT number 2013-001944-76. Registered on 26 April 2013

Warm proglacial lake temperatures and thermal undercutting enhances rapid retreat of an Arctic glacier

Determining the characteristics of Arctic proglacial lakes is essential for understanding their current and future influence on glacier mass loss, capacity as a carbon sink and the associated impacts for downstream hydrology and ecology. Field observations of how proglacial lake properties influence rates of glacier mass loss remain sparse yet are increasingly critical for accurate projection of lake-terminating glacier responses to warming air and lake temperatures, particularly in high-latitude Scandinavia under the influence of Arctic amplification. Here we combine satellite and field observations of Kaskasapakte Glacier (KG) (a lake-terminating glacier in Arctic Sweden) to reveal the interplay between lake parameters and glacier mass loss from 2008 to 2019. We present the first field evidence of warmer-than-expected water temperatures (>4 °C at the ice front) at a Scandinavian proglacial lake and illustrate how these drove rapid thermo-erosional undercutting and calving at the terminus, with width-averaged retreat rates of up to 25m/yr and frontal ablation accounting for ~30% of glacier volume loss between 2015 and 2019

Observing America: what mass-observation reveals about British views of the USA

Since its foundation in 1937, the social research organisation Mass-Observation has systematically documented the opinions of a British public experiencing profound societal change. This includes the most extensive data available on grassroots attitudes towards the USA, from the outbreak of the Second World War to the final phase of the Cold War. Most of the scholarship on Anglo-American relations focuses on the political and diplomatic elites of Britain and the USA. The extent to which their interaction reflected and reinforced public opinion is seldom considered. This article uses the Mass-Observation archive to situate elite interaction within the broader context of public opinion. In so doing, it assesses the extent to which British political leaders have in their dealings with the USA represented the views of the electorate they serve

Do guidelines influence breathlessness management in advanced lung diseases? A multinational survey of respiratory medicine and palliative care physicians

Background: Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung disease (fILD) and lung cancer (LC), and the influence of practice guidelines was explored via an online survey. Methods: A voluntary, online survey was distributed to RM and PC physicians via society newsletter mailing lists. Results: 450 evaluable questionnaires (348 (77%) RM and 102 (23%) PC) were analysed. Significantly more PC physicians indicated routine use (often/always) of opioids across conditions (COPD: 92% vs. 39%, fILD: 83% vs. 36%, LC: 95% vs. 76%; all p < 0.001) and significantly more PC physicians indicated routine use of benzodiazepines for COPD (33% vs. 10%) and fILD (25% vs. 12%) (both p < 0.001). Significantly more RM physicians reported routine use of a breathlessness score (62% vs. 13%, p < 0.001) and prioritised exercise training/rehabilitation for COPD (49% vs. 7%) and fILD (30% vs. 18%) (both p < 0.001). Overall, 40% of all respondents reported reading non-cancer palliative care guidelines (either carefully or looked at them briefly). Respondents who reported reading these guidelines were more likely to: routinely use a breathlessness score (χ2 = 13.8; p < 0.001), use opioids (χ2 = 12.58, p < 0.001) and refer to pulmonary rehabilitation (χ2 = 6.41, p = 0.011) in COPD; use antidepressants (χ2 = 6.25; p = 0.044) and refer to PC (χ2 = 5.83; p = 0.016) in fILD; and use a handheld fan in COPD (χ2 = 8.75, p = 0.003), fILD (χ2 = 4.85, p = 0.028) and LC (χ2 = 5.63; p = 0.018). Conclusions: These findings suggest a need for improved dissemination and uptake of jointly developed breathlessness management guidelines in order to encourage appropriate use of existing, evidence-based therapies. The lack of opioid use by RM, and continued benzodiazepine use in PC, suggest that a wider range of acceptable therapies need to be developed and trialled

A biomarker enrichment trial of anti-EGFR agents in right primary tumor location (rPTL), <i>RAS</i> wild-type (<i>RAS</i>-wt) advanced colorectal cancer (aCRC): ARIEL (ISRCTN11061442).

TPS3633 Background: Meta-analysis of 6 RCTs indicates that anti-EGFR agents are ineffective in rPTL RAS-wt aCRC (Arnold D, et al. Ann Oncol. 2017;28:1713-1729). However, data from the phase III PICCOLO and COIN trials suggest high tumor expression of the EGFR ligands, EREG and AREG, confers sensitivity to anti-EGFR agents in a subset of this population (Adams RA, et al. J Clin Oncol. 2012;30(30_suppl):32-32; Seligmann JF, et al. Ann Oncol. 2020;31:1021-1029). More data is needed before ligand assessment can be integrated into routine care: to date, EREG/AREG mRNA has only been assessed retrospectively, and feasibility of timely delivery of results must be demonstrated. The ARIEL trial aims to determine whether first-line chemotherapy plus cetuximab or panitumumab is more effective than chemotherapy alone in achieving early tumor shrinkage (ETS) after 8 weeks of treatment in patients (pts) with EREG/AREG-high rPTL RAS-wt aCRC. Methods: ARIEL is a multicentre, phase IV, open label, biomarker enrichment RCT. Pts with previously untreated rPTL RAS-wt (or RAS-unknown) aCRC are eligible for registration and EREG/AREG assessment using archival FFPE tumor tissue. Those confirmed as RAS-wt EREG/AREG-high (expression above 30th centile based on PICCOLO)3 are eligible for randomization to chemotherapy alone (fluoropyrimidine backbone plus irinotecan or oxaliplatin) vs chemotherapy (FOLFOX or FOLFIRI) plus anti-EGFR therapy (panitumumab or cetuximab) (options at physician’s discretion). Pts with EREG/AREG-low tumors are not eligible for randomization but may consent to translational research and follow-up. The primary endpoint is ETS at 8 weeks (≥30%, yes vs no). Secondary endpoints are depth of response at 16 weeks, overall survival, overall treatment utility, pt-reported quality of life, cost per QALY, pt acceptability of trial procedures, and safety. Pre-trial work-up included cross-validation of the EREG/AREG RT-qPCR assay at trial laboratories in Leeds and Birmingham, UK demonstrating reproducibility of biomarker results. Recruitment to an internal pilot phase is currently ongoing to demonstrate feasibility of timely delivery of biomarker results to sites (lower limit of 90% CI of mean result delivery time for first 20 pts must include 3 weeks). Mean monthly recruitment rate will be assessed at 18 months to determine likelihood of completion of the trial within the 3 year recruitment period. ARIEL is funded by the UK National Institute for Health Research (NIHR) and opened the first of 40 sites in February 2022. 440 pts will be registered for biomarker assessment in order to randomize 162 pts. All pts will be followed-up to 1 year post-randomisation, with a final assessment in all pts when the last pt has completed a year of follow-up (median 3.5 years). ARIEL is participating in the NIHR Associate PI scheme. Clinical trial information: 11061442. </jats:p