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Therapeutics to reduce intracranial pressure are an unmet need. Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling. Here, we translate these findings into patients by conducting a randomized, placebo-controlled, double-blind trial to assess the effect of exenatide, a GLP-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure >25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 h, 24 h and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28 ± 9, body mass index 38.1 ± 6.2 kg/m2, intracranial pressure 30.6 ± 5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 h −5.7 ± 2.9 cmCSF (P = 0.048); 24 h −6.4 ± 2.9 cmCSF (P = 0.030); and 12 weeks −5.6 ± 3.0 cmCSF (P = 0.058). No serious safety signals were noted. These data provide confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlight the potential to utilize GLP-1 receptor agonist in other conditions characterized by raised intracranial pressure.

Sponsors have a responsibility to minimise risk to participants in clinical studies through safety monitoring. The FDA Final Rule for IND Safety Reporting requires routine aggregate safety evaluation, including in ongoing blinded studies. We are interested in estimating the probability that the true adverse event rate in the experimental arm exceeds that in the control arm. We developed a Bayesian approach that specifies an informative meta-analytic predictive prior on the event probability in the control arm and an uninformative prior on that in the experimental arm. We combined these priors with a mixture likelihood that considers each patient in the ongoing blinded study may belong to the experimental or control arm. This allowed us to estimate the quantity of interest without unblinding. We evaluated our method by simulation, pairing scenarios that differed only in whether a safety signal was present or missing, and quantifying the ability of our model to discriminate using signal detection theory. Our approach shows benefit. It detects safety signals more reliably with greater sample sizes and for common rather than rare events. Performance does not deteriorate markedly when historical studies exhibit heterogeneous hazards or non-constant hazards. Our method will allow us to monitor safety signals in ongoing blinded studies with the goal of earlier identification and risk mitigation. Our method could be adapted to use informative priors on both arms or predictive covariates where pertinent data exist. We stress that ongoing safety monitoring should involve a multi-disciplinary team where statistical methods are paired with medical judgement.

Background: \ud Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability.\ud \ud Methods: \ud MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib–FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented.\ud \ud Findings: \ud Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36–48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3–4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia).\ud \ud Interpretation: \ud Ponatinib–FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers.\ud \ud Funding: \ud Blood Cancer UK and Incyte.

Objective Headache is the predominant disabler in idiopathic intracranial hypertension (IIH). The aim was to characterise headache and investigate the association with intracranial pressure. Methods IIH:WT was a randomised controlled parallel group multicentre trial in the United Kingdom investigating weight management methods in IIH. Participants with active IIH (evidenced by papilloedema) and a body mass index (BMI) ≥35 kg/m2 were recruited. At baseline, 12 months and 24 months headache characteristics and quality of life outcome measures were collected and lumbar puncture measurements were performed. Results Sixty-six women with active IIH were included with a mean age of 32.0 years (SD ± 7.8), and mean body mass index of 43.9 ± 7.0 kg/m2. The headache phenotype was migraine-like in 90%. Headache severity correlated with ICP at baseline (r = 0.285; p = 0.024); change in headache severity and monthly headache days correlated with change in ICP at 12 months (r = 0.454, p = 0.001 and r = 0.419, p = 0.002 respectively). Cutaneous allodynia was significantly correlated with ICP at 12 months. (r = 0.479, p Conclusions We demonstrate a positive relationship between ICP and headache and cutaneous allodynia, which has not been previously reported in IIH. Those with the greatest reduction in ICP over 12 months had the greatest reduction in headache frequency and severity; this was associated with improvement of quality of life measures. Trial registration This work provides Class IIa evidence of the association of raised intracranial pressure and headache. ClinicalTrials.gov number, NCT02124486.

center dot OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON).center dot DESIGN: Multicenter cohort study. center dot METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. Main Outcome Measures: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile.center dot RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. center dot CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON. (Am J Ophthalmol 2022;241: 927. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))

PurposeUsing the Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) data, this study aimed to determine if point analysis of the Humphrey visual field (HVF) could be more informative than the perimetric mean deviation (PMD) as an IIH trial outcome measure.MethodsIIH:WT was a randomized controlled trial that recruited 66 people with active IIH (mean ± standard deviation age 32 ± 7.8 years). Event-based analysis using a pointwise analysis of the numerical sensitivity data was performed. The number of participants that would be eligible for analysis was calculated when the data were enriched to reflect a medically treated cohort defined as a PMD between -2dB to -7dB.ResultsThe HVF 24-2 mean ± standard deviation PMD in the worse eye was ™3.5 ± 1.1dB, (range,™2.0 to ™6.4dB), and point sensitivity showed a preference for peripheral and blind spot locations. Those points between 0 and -10dB demonstrated negligible ability to improve compared with those between -10dB and -25dB. In evaluating feasibility for a medical intervention trial, 346 points were available for analysis between -10dB and -25dB bilaterally compared with 4123 in baseline sensitivities of 0 to -10dB.ConclusionsMildly affected baseline sensitivities were unlikely to show considerable change over 24 months. There were fewer points available for analysis and greater variability if moderately affected baseline points were chosen. If point analysis was used as an outcome measure in a medical intervention trial, the majority of points would not demonstrate clinically meaningful change, thus offering little advantage over PMD.

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%–50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the Ki value for the 5-HT3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t1/2 range of 1.6–4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced “on-target” side-effect profile relative to 5-HT3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT3 receptor is thought to be implicated in the pathophysiology. Because 5-HT3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.

Background and ObjectivesThe idiopathic intracranial hypertension randomized controlled weight trial (IIH:WT) established that weight loss through bariatric surgery significantly reduced intracranial pressure when compared with a community weight management intervention. This substudy aimed to evaluate the amount of weight loss required to reduce intracranial pressure and to explore the effect of different bariatric surgical approaches.MethodsIIH:WT was a multicenter randomized controlled trial. Adult women with active idiopathic intracranial hypertension and a body mass index ≥35 kg/m2 were randomized to bariatric surgery or a community weight management intervention (1:1). This per-protocol analysis evaluated the relationship between intracranial pressure, weight loss, and the weight loss methods. A linear hierarchical regression model was used to fit the trial outcomes, adjusted for time, treatment arm, and weight.ResultsSixty-six women were included, of whom 23 had received bariatric surgery by 12 months; the mean age was 31 (SD 8.7) years in the bariatric surgery group and 33.2 (SD 7.4) years in the dietary group. Baseline weight and intracranial pressure were similar in both groups with a mean weight of 119.5 (SD 24.1) and 117.9 (SD 19.5) kg and mean lumbar puncture opening pressure of 34.4 (SD 6.3) and 34.9 (SD 5.3) cmCSF in the bariatric surgery and dietary groups, respectively. Weight loss was significantly associated with reduction in intracranial pressure (R2 = 0.4734, p ≤ 0.0001). Twenty-four percentage of weight loss (weight loss of 13.3 kg [SD 1.76]) was associated with disease remission (intracranial pressure [ICP] ≤ 25 cmCSF). Roux-en-Y gastric bypass achieved greater, more rapid, and sustained ICP reduction compared with other methods.DiscussionThe greater the weight loss, the greater the reduction in ICP was documented. Twenty four percentage of weight loss was associated with disease remission. Such magnitude of weight loss was unlikely to be achieved without bariatric surgery, and hence, consideration of referral to a bariatric surgery program early for those with active idiopathic intracranial hypertension may be appropriate.Trial RegistrationClinicalTrials.gov Identifier: NCT02124486; ISRCTN registry number ISRCTN40152829; doi.org/10.1186/ISRCTN40152829.Classification of EvidenceThis study provides Class II evidence that weight loss after bariatric surgery results in reduction in intracranial pressure in adult women with idiopathic intracranial hypertension. This study is Class II because of the use of a per-protocol analysis.

Structured AbstractBackgroundImpaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered.ObjectiveTo systematically examine the influence of dystonia, dystonia subtype and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex.MethodsOriginal neurophysiological data from all published studies were shared to an age and sex matched control group. Two raters blinded to participant identity scored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block was entered into a mixed repetitive measures model.ResultsMuch variability of eyeblink conditioning was seen in both groups. All dystonia versus controls showed no difference in conditioning (p=0.517). Analysis of dystonia subgroup, with age and sex as covariates did not reveal evidence that eyeblink conditioning is impaired in specific subtypes (cervical dystonia, DYT-TOR1A, DYT-THAP1 or focal hand dystonia). The presence of tremor did not significantly influence levels of eyeblink conditioning.ConclusionsCollaborative efforts such as this article allow larger number of patients to be evaluated and provide more balanced estimates of disease effects over experimental outcomes. Intact eyeblink conditioning is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question.

Background The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. Methods We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. Results We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. Conclusions Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.

Objective: Headache is the predominant disabler in idiopathic intracranial hypertension (IIH). The aim was to characterise headache and investigate the association with intracranial pressure.Methods: IIH:WT was a randomised controlled parallel group multicentre trial in the United Kingdom investigating weight management methods in IIH. Participants with active IIH (evidenced by papilloedema) and a body mass index (BMI) ≥35kg/m2 were recruited. At baseline, 12 months and 24 months headache characteristics and quality of life outcome measures were collected and lumbar puncture measurements were performed.Results: Sixty-six women with active IIH were included with a mean age of 32.0 years (SD ± 7.8), and mean body mass index of 43.9 ± 7.0 kg/m2. The headache phenotype was migraine-like in 86%. Headache severity correlated with ICP at baseline (r=0.285; p=0.024); change in headache severity and monthly headache days correlated with change in ICP at 12 months (r=0.454, p=0.001 and r=0.419, p=0.002 respectively). Cutaneous allodynia was significantly correlated with ICP at 12 months. (r=0.479, pConclusions: We demonstrate a positive relationship between ICP and headache and cutaneous allodynia, which has not been previously reported in IIH. Those with the greatest reduction in ICP over 12 months had the greatest reduction in headache frequency and severity; this was associated with improvement of quality of life measures.Classification of evidence: This work provides Class IIa evidence of the association of raised intracranial pressure and headache. ClinicalTrials.gov number, NCT02124486.

Key Points Question Is bariatric surgery superior to a community weight management intervention in sustaining the weight loss necessary to achieve sustained remission among patients with idiopathic intracranial hypertension? Findings In this randomized clinical trial of 66 women with idiopathic intracranial hypertension and a body mass index of 35 or higher, bariatric surgery was superior to a community weight management intervention in decreasing intracranial pressure, with continued improvement at 2 years. Meaning The study’s findings indicate that, among women with idiopathic intracranial hypertension and a body mass index of 35 or higher, bariatric surgery is an effective treatment to reduce intracranial pressure and for sustained disease remission., Importance Idiopathic intracranial hypertension (IIH) causes headaches, vision loss, and reduced quality of life. Sustained weight loss among patients with IIH is necessary to modify the disease and prevent relapse. Objective To compare the effectiveness of bariatric surgery with that of a community weight management (CWM) intervention for the treatment of patients with active IIH. Design, Setting, and Participants This 5-year randomized clinical trial (Idiopathic Intracranial Hypertension Weight Trial) enrolled women with active IIH and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or higher at 5 National Health Service hospitals in the UK between March 1, 2014, and May 25, 2017. Of 74 women assessed for eligibility, 6 did not meet study criteria and 2 declined to participate; 66 women were randomized. Data were analyzed from November 1, 2018, to May 14, 2020. Interventions Bariatric surgery (n = 33) or CWM intervention (Weight Watchers) (n = 33). Main Outcomes and Measures The primary outcome was change in intracranial pressure measured by lumbar puncture opening pressure at 12 months, as assessed in an intention-to-treat analysis. Secondary outcomes included lumbar puncture opening pressure at 24 months as well as visual acuity, contrast sensitivity, perimetric mean deviation, and quality of life (measured by the 36-item Short Form Health Survey) at 12 and 24 months. Because the difference in continuous outcomes between groups is presented, the null effect was at 0. Results Of the 66 female participants (mean [SD] age, 32.0 [7.8] years), 64 (97.0%) remained in the clinical trial at 12 months and 54 women (81.8%) were included in the primary outcome analysis. Intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, −6.0 [1.8] cm cerebrospinal fluid [CSF]; 95% CI, −9.5 to −2.4 cm CSF; P = .001) and at 24 months (adjusted mean [SE] difference, −8.2 [2.0] cm CSF; 95% CI, −12.2 to −4.2 cm CSF; P, This randomized clinical trial examines the efficacy of bariatric surgery compared with a community weight management intervention for the treatment of patients with idiopathic intracranial hypertension.

PURPOSE Salvage options for patients who relapse after allogeneic stem-cell transplantation (allo-SCT) for acute myeloid leukemia (AML) and myelodysplasia (MDS) remain limited, and novel treatment strategies are required. Both lenalidomide (LEN) and azacitidine (AZA) possess significant antitumor activity effect in AML. Administration of LEN post-transplantation is associated with excessive rates of graft-versus-host disease (GVHD), but AZA has been shown to ameliorate GVHD in murine transplantation models. We therefore examined the tolerability and activity of combined LEN/AZA administration in post-transplantation relapse. PATIENTS AND METHODS Twenty-nine patients who had relapsed after allo-SCT for AML (n = 24) or MDS (n = 5) were treated with sequential AZA (75 mg/m2 for 7 days) followed by escalating doses of LEN on days 10 to 30. Dose allocation and maximum tolerated dose (MTD) estimation were guided by a modified Bayesian continuous reassessment method (CRM). RESULTS Sequential AZA and LEN therapy was well tolerated. The MTD of post-transplantation LEN, in combination with AZA, was determined as 25 mg daily. Three patients developed grade 2 to 4 GVHD. There was no GVHD-related mortality. Seven of 15 (47%) patients achieved a major clinical response after LEN/AZA therapy. CD8+ T cells demonstrated impaired interferon-γ/tumor necrosis factor–α production at relapse, which was not reversed during LEN/AZA administration. CONCLUSION We conclude LEN can be administered safely post-allograft in conjunction with AZA, and this combination demonstrates clinical activity in relapsed AML/MDS without reversing biologic features of T-cell exhaustion. The use of a CRM model delivered improved efficiency in MTD assessment and provided additional flexibility. Combined LEN/AZA therapy represents a novel and active salvage therapy in patients who had relapsed post-allograft.

AimTo determine whether Optical Coherence Tomography (OCT) of the optic nerve head in papil- loedema could act as a surrogate measure of intracranial pressure (ICP).MethodsThis is a longitudinal cohort study using data collected from three randomised controlled trials, between from April 1st, 2014 to August, 1st 2019. OCT imaging and automated perimetry was followed immediately by ICP measurement on the same day. Cohort 1 utilised continuous sitting telemetric ICP monitoring (Raumedic Neurovent P-tel device) on one visit. Cohort 2 were evaluated at baseline, 3, 12 and 24 months and underwent lumbar puncture assessment of ICP.Results104 patients were recruited. Amongst cohort 1 (n=15), the range of OCT protocols were evaluated and optic nerve head central thickness was found to be most closely associated with ICP (right eye: p=0.017, r = 0.60; left eye: p = 0.002; r = 0.73). Subsequently, cohort 2 (n=89) confirmed the correlation between central thickness and ICP longitudinally (12 and 24 months). Finally, bootstrap surrogacy analysis noted a positive association between central thickness and ICP treatment effects at all time points (e.g. at 12 months, an decrease in central thickness of 50µm predicted a decrease in ICP of 5 cmCSF).ConclusionOCT optic nerve head volume measures reproducibly correlates with ICP and surrogacy analysis demonstrated its ability to inform ICP changes. This data suggests that OCT can non-invasively predict ICP.soozmollan@doctors.org.uk58

ObjectiveHeadache is the predominant disabler in idiopathic intracranial hypertension (IIH). The aim was to characterise headache and investigate the association with intracranial pressure (ICP).MethodsIIH:WT was a randomised controlled parallel group multicentre trial investigating weight manage- ment methods in IIH. Participants with active IIH (evidenced by papilloedema) and a body mass index (BMI) ≥35kg/m2 were recruited. At baseline, 12 months and 24 months headache characteristics and quality of life outcome measures were collected and lumbar puncture measurements were performed.ResultsSixty-six women were included (mean age 32.0 years (SD ± 7.8)), and mean body mass index of43.9 ± 7.0 kg/m2. The headache phenotype was migraine-like in 86%. Headache severity correlated with ICP) at baseline (r=0.285; p=0.024); change in headache severity and monthly headache days correlated with change in ICP at 12 months (r=0.454, p=0.001 and r=0.419, p=0.002 respectively). Cutaneous allodynia was significantly correlated with ICP at 12 months. (r=0.479, pConclusionsWe demonstrate a positive relationship between ICP and headache and cutaneous allodynia, which has not been previously reported in IIH. Those with the greatest reduction in ICP had the greatest reduction in headache frequency and severity.soozmollan@doctors.org.uk

BackgroundPre-clinical data demonstrates the ability of Exenatide, a GLP-1R agonist, to reduce CSF secretion and ICP.1 Existing GLP-1R agonists are widely used to treat obesity and diabetes (but do not cause hypoglycaemia).MethodsRandomised, placebo controlled, double-blind trial of Exenatide in women with active IIH. Participants were randomised 1:1 to Exenatide (10mcg twice daily sub-cutaneous) or placebo for 12 weeks. Telemetric, intraparenchymal ICP monitors (Raumedic) recorded ICP over 12 weeks. Analysis was by hierarchical regression, significance level set at p Results16 participants were recruited, 15 completed the study: BMI 38.1(6.2) kg/m2, ICP 30.6(5.1) cmCSF. ICP, the primary endpoint, fell significantly (2.5 hours -5.7(2.9) cmCSF (p=0.048), 24 hours -6.4 (2.9) cmCSF (p=0.030) and 12 weeks -5.6 (3.0) cmCSF (p=0.058)). Monthly headache days fell in the Exenatide treated cohort (-7.7 (9.2) p=0.069) and vision improved (logMar acuity -0.1 (0.04) p=0.004).ConclusionsExenatide reduced ICP acutely and after chronic dosing. GLP-1R agonists represent a new approach to treat IIH.1. Botfield HF, Uldall MS, Westgate CSJ, Mitchell JL, Hagen SM, Gonzalez AM, Hodson DJ, Jensen RH, Sinclair AJ. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydro- cephalus. Sci Transl Med. 2017 Aug 23;9(404):eaan0972. doi: 10.1126/scitranslmed.aan0972.jamesmitchell4@nhs.net20

Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1—revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1—to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.

Summary Background Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding Cancer Research UK.

Background Bayesian adaptive methods are increasingly being used to design clinical trials and offer several advantages over traditional approaches. Decisions at analysis points are usually based on the posterior distribution of the treatment effect. However, there is some confusion as to whether control of type I error is required for Bayesian designs as this is a frequentist concept. Methods We discuss the arguments for and against adjusting for multiplicities in Bayesian trials with interim analyses. With two case studies we illustrate the effect of including interim analyses on type I/II error rates in Bayesian clinical trials where no adjustments for multiplicities are made. We propose several approaches to control type I error, and also alternative methods for decision-making in Bayesian clinical trials. Results In both case studies we demonstrated that the type I error was inflated in the Bayesian adaptive designs through incorporation of interim analyses that allowed early stopping for efficacy and without adjustments to account for multiplicity. Incorporation of early stopping for efficacy also increased the power in some instances. An increase in the number of interim analyses that only allowed early stopping for futility decreased the type I error, but also decreased power. An increase in the number of interim analyses that allowed for either early stopping for efficacy or futility generally increased type I error and decreased power. Conclusions Currently, regulators require demonstration of control of type I error for both frequentist and Bayesian adaptive designs, particularly for late-phase trials. To demonstrate control of type I error in Bayesian adaptive designs, adjustments to the stopping boundaries are usually required for designs that allow for early stopping for efficacy as the number of analyses increase. If the designs only allow for early stopping for futility then adjustments to the stopping boundaries are not needed to control type I error. If one instead uses a strict Bayesian approach, which is currently more accepted in the design and analysis of exploratory trials, then type I errors could be ignored and the designs could instead focus on the posterior probabilities of treatment effects of clinically-relevant values.

Background: Therapeutic blockade of the axis of programmed cell death 1 (PD-1) and its ligand (PD-L1) has transformed the management of non-small-cell lung cancer (NSCLC). Clinical trials with pembrolizumab have enrolled patients with performance status (PS) 0–1. However, around 18% of patients with NSCLC are PS2, and the activity and safety of pembrolizumab in these patients is unclear. We aimed to evaluate the safety and efficacy of pembrolizumab in these patients. Methods: We did a multicentre, single-arm, open-label, phase 2 trial (PePS2) in ten hospitals in the UK, in which patients with NSCLC and a rigorous ascription of PS2 were given pembrolizumab 200 mg every 3 weeks. No masking was used in this trial. We stratified the treatment evaluation by tumour proportion score (TPS) and line of therapy. Co-primary outcomes were: (1) durable clinical benefit (DCB), defined as the occurrence of complete response, partial response, or stable disease that continues until at least the second CT scan scheduled at 18 weeks; and (2) toxicity, defined as the occurrence at any time of treatment-related dose delay or treatment discontinuation due to an adverse event. Analysis included all patients who received any pembrolizumab. As well as reporting simple observed incidence for the co-primary outcomes, DCB and toxicity, we also estimated incidence using a model-based method for correlated binary outcomes. This study is registered with ClinicalTrials.gov, NCT02733159; EudraCT, 2015-002241-55; and ISRCTN, 10047797. Findings: Between Jan 4, 2017, and Feb 13, 2018, of 112 patients assessed for eligibility, we recruited 62 patients. 60 patients were evaluable for the co-primary outcomes. Median age was 72 years (IQR 65–75); 33 (55%) of participants were male and 27 (45%) were female. The observed incidence for DCB was 38% (95% CI 21–57) in first-line patients (n=24) and 36% (22–52) in subsequent-line patients (n=36); DCB was 22% (11–41) in patients with a TPS less than 1% (n=27), 47% (25–70) in patients with a TPS of 1–49% (n=15), and 53% (30–75) in patients with a TPS of 50% or greater (n=15). An increase in DCB incidences with TPS was also shown in model-based estimates. Toxicity was observed in 28% (95% CI 19–41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression. The most common grade 3–4 adverse events were dyspnoea (n=9), hyponatraemia (n=5), and anorexia (n=4). There were ten serious adverse events considered to be related to treatment, comprising diarrhoea (n=3) and acute kidney injury, adrenal insufficiency, hyperbilirubinaemia, oral mucositis, rash, urinary tract infection, and vomiting (n=1 each). Interpretation: Patients with NSCLC of PS2 are a group of patients of unmet therapeutic need. The PePS2 trial shows that pembrolizumab can be safely administered to these patients, with no increase in the risk of immune-related or other toxicities. Efficacy outcomes are at least as good as those in patients with PS0–1 and the data provides clinicians with the confidence to incorporate pembrolizumab into the treatment pathway of patients with NSCLC of PS2. Funding: Merck, Sharp & Dohme.

This study reports the efficacy of VBL and blue light (BL) and their antimicrobial activity against mature biofilms of a range of important nosocomial pathogens. While this study investigated the antibacterial activity of a range of wavelengths of between 375 and 450 nm and identified a specific wavelength region (∼405 nm) with increased antibacterial activity, decontamination was dependent on the bacterial species, strain, irradiation parameters, and experimental conditions. Further research with controlled experiments that ameliorate the heating effects and improve the optical properties are required to optimize the dosing parameters to advance the successful clinical translation of this technology., Light-emitting diodes (LEDs) demonstrate therapeutic effects for a range of biomedical applications, including photodisinfection. Bands of specific wavelengths (centered at 405 nm) are reported to be the most antimicrobial; however, there remains no consensus on the most effective irradiation parameters for optimal photodisinfection. The aim of this study was to assess decontamination efficiency by direct photodisinfection of monomicrobial biofilms using a violet-blue light (VBL) single-wavelength array (SWA) and multiwavelength array (MWA). Mature biofilms of nosocomial bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus) were grown on 96-well polypropylene PCR plates. The biofilms were then exposed to VBL for 2,700 s (SWA) and 1,170 s (MWA) to deliver 0 to 670 J/cm2, and the antibacterial activity of VBL was assessed by comparing the seeding of the irradiated and the nonirradiated biofilms. Nonirradiated groups were used as controls. The VBL arrays were characterized optically (spectral irradiance and beam profile) and thermally. The SWA delivered 401-nm VBL and the MWA delivered between 379-nm and 452-nm VBL, albeit at different irradiances and with different beam profiles. In both arrays, the irradiated groups were exposed to increased temperatures compared to the nonirradiated controls. All bacterial isolates were susceptible to VBL and demonstrated reductions in the seeding of exposed biofilms compared with the nonirradiated controls. VBL at 405 nm exerted the most antimicrobial activity, exhibiting reductions in seeding of up to 94%. Decontamination efficiency is dependent on the irradiation parameters, bacterial species and strain, and experimental conditions. Controlled experiments that ameliorate the heating effects and improve the optical properties are required to optimize the dosing parameters to advance the successful clinical translation of this technology. IMPORTANCE This study reports the efficacy of VBL and blue light (BL) and their antimicrobial activity against mature biofilms of a range of important nosocomial pathogens. While this study investigated the antibacterial activity of a range of wavelengths of between 375 and 450 nm and identified a specific wavelength region (∼405 nm) with increased antibacterial activity, decontamination was dependent on the bacterial species, strain, irradiation parameters, and experimental conditions. Further research with controlled experiments that ameliorate the heating effects and improve the optical properties are required to optimize the dosing parameters to advance the successful clinical translation of this technology.

PURPOSE The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.

Trials of surgical procedures in the treatment of malignant disease face a unique set of challenges. This review aimed to describe recommendations for the design, delivery and reporting of randomised trials in surgical oncology. A literature search was carried out without date limits to identify articles related to trial methodology research in surgery and surgical oncology. A narrative review was framed around two open National Institute of Health Research portfolio trials in colon and rectal cancer: the STAR-TREC trial (ISRCTN14240288) and the ROCCS trial (ISRCTN46330337). Twelve specific challenges were highlighted: standardisation of technique; pilot and feasibility studies; balancing treatments; the recruitment pathway; outcome measures; patient and public representation; trainee-led networks; randomisation; novel techniques and training; learning curves; blinding; follow-up. Evidence-based recommendations were made for the future design and conduct of surgical oncology trials. Better understanding of the challenges facing trials in the surgical treatment of cancer will accelerate high-quality evaluation and rapid adoption of innovation for the benefit of patient care.

IntroductionThe improvements in short-term outcome after severe trauma achieved through early resuscitation and acute care can be offset over the following weeks by an acute systemic inflammatory response with immuneparesis leading to infection, multiorgan dysfunction/multiorgan failure (MOF) and death. Serum levels of the androgen precursor dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, steroids with immune-enhancing activity, are low after traumatic injury at a time when patients are catabolic and immunosuppressed. Addressing this deficit and restoring the DHEA(S) ratio to cortisol may provide a range of physiological benefits, including immune modulatory effects.ObjectiveOur primary objective is to establish a dose suitable for DHEA supplementation in patients after acute trauma to raise circulating DHEA levels to at least 15 nmol/L. Secondary objectives are to assess if DHEA supplementation has any effect on neutrophil function, metabolic and cytokine profiles and which route of administration (oral vs sublingual) is more effective in restoring circulating levels of DHEA, DHEAS and downstream androgens.Methods and analysisA prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its profile in trauma, with a planned recruitment between April 2019 and July 2021, that will investigate DHEA supplementation and its effect on serum DHEA, DHEAS and downstream androgens in trauma. A maximum of 270 patients will receive sublingual or oral DHEA at 50, 100 or 200 mg daily over 3 days. Females aged ≥50 years with neck of femur fracture and male and female major trauma patients, aged 16–50 years with an injury severity score ≥16, will be recruited.Ethics and disseminationThis protocol was approved by the West Midlands – Coventry and Warwickshire Research Ethics Committee (Reference 18/WM/0102) on 8 June 2018. Results will be disseminated via peer-reviewed publications and presented at national and international conferences.Trial registrationThis trial is registered with the European Medicines Agency (EudraCT: 2016-004250-15) and ISRCTN (12961998). It has also been adopted on the National Institute of Health Research portfolio (CPMS ID:38158).Trial progressionThe study recruited its first patient on 2 April 2019 and held its first data monitoring committee on 8 November 2019. DHEA dosing has increased to 100 mg in both male cohorts and remains on 50 mg in across all female groups.

Background: Ibrutinib (IBR) inhibits CLL proliferation and effects prolonged remission without eradicating disease. Obinutuzumab (OBI) is an anti-CD20 monoclonal antibody that can effect depletion of measurable residual disease (MRD) below 0.01%. In the IcICLLe study (ISRCTN12695354), 20 treatment-naïve (TN) CLL patients & 20 with relapsed/refractory (R/R) CLL received IBR until complete remission with Aim: To assess the long-term MRD response status for patients treated with IBR as a sole agent or in combination with OBI. Patients: Patients received continuous IBR (420mg OD) with the addition of 6 cycles of OBI given over 6 months in the extension study. 20 TN patients received IBR monotherapy; 20 R/R patients (median 2 prior treatments, range 1-7) initiated IBR monotherapy of which 10/20 enrolled in the Extension study receiving OBI after >1year of IBR monotherapy; and 30 IBR-naïve R/R (median 1 prior treatment, range 1-3) started OBI 24 hours after first IBR dose. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: IBR monotherapy in TN patients was well tolerated with 18/20 patients alive and 13/20 remaining on IBR after median 4.9 years follow-up (range 0-5.9). IBR was stopped due to toxicity (3), progression/relapse (2) or other causes (2). IBR-monotherapy resulted in median 0.65 log depletion per year in years 1-2, followed by relatively stable disease levels (median 0.2 log depletion per year) in the subsequent 3 years in 13/20 evaluable patients. Only 1 patient showed >0.3log increase in PB MRD level and this preceded clinical progression. No patients achieved an IWCLL CR/CRi and MRD was >0.01% in PB/BM in all patients at all time points. In the R/R group initially receiving IBR-monotherapy, 11/20 patients remain alive and 3/20 remain on IBR after a median 3.9 years follow-up (range 0.3-5.3). In this heavily pre-treated group, 10 did not enrol on the OBI Extension study (1 died, 1 progression/relapse, 4 ineligible/other causes, 4 patient preference) with 10/20 receiving OBI at median 16.2 months (range 13-19) after starting IBR-monotherapy of which 7/10 had resolved any lymphadenopathy pre-OBI. 2/10 achieved MRD-negative remission and stopped treatment, while 6/10 have since stopped IBR due to death (2), progression/relapse (3) or other causes (1). 30 R/R patients with no prior IBR exposure (most in first relapse) started IBR & OBI at the same time: 26/30 remain alive and 18/30 remain on IBR after median 3.0 years follow-up (range 0.8-4.2). IBR was stopped in 2/30 patients achieving MRD-negative remission while 10 stopped IBR due to death (2), disease progression/transformation (3), toxicity (4), or patient decision (1). There were no Grade 5 adverse events related to OBI. 3 months post-OBI, patients with >1 year prior IBR-monotherapy achieved a higher response rate (CR/CRi 50% vs. 30%), MRD response ( The deepest PB MRD responses were observed 6-12 months after the last OBI infusion. MRD levels showed little change in the following year to month 24 (median 0 log depletion, range 1.3 log depletion to 2.5 log increase). After 2 years of IBR exposure, the MRD levels shows a similar pattern to TN patients on IBR monotherapy, being generally very stable (0.3log increase at two sequential timepoints of which 4/7 have shown clinical disease progression and 3/7 still have low ( Conclusions: The addition of OBI to IBR may substantially improve depletion of CLL cells from the PB and BM. A greater impact in MRD response rate and depth was seen when OBI was introduced after >1 year of IBR treatment and tumour bulk was low. One fifth of patients maintain Figure 1 Disclosures Rawstron: Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding. Hillmen:AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Eli Lilly: Other: Consulting and speaker fees; Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Pettitt:Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; Celgene: Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding; Napp: Research Funding; Roche: Honoraria, Other: Hospitality, Research Funding. Fox:Abbvie: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Atarabio: Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Hillmen:Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau.

Background: The Blood Cancer UK TAP CLARITY trial for relapsed or refractory CLL combined IBR with VEN in order to eradicate detectable disease with a plan to stop therapy early if measurable residual disease (MRD) Aims: To provide long term follow up data for the combination of IBR and VEN for R/R CLL patients. IWCLL response status and MRD responses status at the 38 month time point are now presented in this abstract. Methods: CLARITY is a Phase II trial combining IBR with VEN in 50 patients with R/R CLL. After 2 months of IBR, VEN was added initially at a daily dose of 10mg or 20mg/day escalating weekly to a final daily dose of 400mg/day. CLL MRD was quantified using >6 colour ERIC-standard flow cytometry (detection limit 10-5/0.001%). Paired PB & BM samples were assessed at months 8, 14, 26 and longitudinal PB samples were taken at multiple time points. Fifty-four patients were recruited from May 2016 to November 2017. The median number of prior therapies was 1 (range: 1-6). 20% patients had del(17p); 25% del(11q); 75% had unmutated IGVH. Four patients that discontinued treatment due to ibrutinib-related adverse events in the first 8 weeks before starting VEN were replaced so that, in total, 50 patients received the combination of IBR and VEN. The interruption of therapy was indicated following confirmation of a CR according to the iwCLL2008 criteria and MRD reduction Results: Of the 50 evaluable patients recruited to the study, 23 patients stopped both treatments at or before M38; the majority due to achieving MRD4 (17/23). 27/50 patients were still receiving at least one trial treatment at this time point, with M38 response data pending for 11 patients. Of the 27 evaluable patients on treatment, the overall response rate (ORR), comprising of 10 patients with CR and 3 with CRi, was 81% compared to an ORR of 91% in the 36 patients receiving at least one trial treatment at M26 respectively. One additional patient discontinued treatment due to MRD negativity after M38. Of the 18 patients stopping due to MRD negativity, 14/18 continue to have Overall, MRD responses continued to improve after the first year of combination treatment with 24/50 (48%) patients achieving MRD4 in the BM at month 26 compared to 20/50 (40%) at month 14. After 4 months of combination, the median log CLL depletion was 2.9 (range 0.2-4.8) for patients achieving There was only one case of biochemical TLS. Other side-effects were mild and/or manageable, most commonly neutropenia (3/37 grade 2, 34/37 grade 3/4). Two Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported (abdominal pain and pemphigus), 44 Serious Adverse Events (SAEs), and 1153 Adverse Events (AEs) (of which 141 were grade 3 or 4) were reported. Summary/Conclusion: After 38 months, the response to IBR+VEN is sustained despite planned discontinuation of therapy in MRD negative patients. The initial rate of disease depletion (during the first two months of combined IBR+VEN exposure) is highly predictive of longer-term response to combination IBR+VEN treatment in relapsed/refractory CLL. Patients who do not show rapid disease clearance and have persistent MRD after 12 months of combination IBR+VEN usually have stable or slowly decreasing disease levels akin to that seen in IBR monotherapy. These data will be updated at ASH 2020. Disclosures Hillmen: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs; Eli Lilly: Other: Consulting and speaker fees; AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company. Schuh:Illumina: Other: Consulting fees; Abbvie: Other: Consulting fees; Gilead: Other: Consulting fees; Roche: Other: Consulting fees. Pettitt:Roche: Honoraria, Other: Hospitality, Research Funding; Napp: Research Funding; Celgene: Other: Hospitality, Research Funding; Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding. Gribben:Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria; Celgene: Research Funding. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Fox:Celgene: Current equity holder in publicly-traded company; Sunesis: Current equity holder in publicly-traded company; Atarabio: Current equity holder in publicly-traded company; Abbvie: Current equity holder in private company, Current equity holder in publicly-traded company; Gilead: Current equity holder in private company, Current equity holder in publicly-traded company; Adienne: Current equity holder in private company, Current equity holder in publicly-traded company; Roche: Current equity holder in private company, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company; Takeda: Current equity holder in private company, Current equity holder in publicly-traded company. Forconi:Roche: Honoraria; Janssen: Honoraria, Other: Fees for cosulting or advisory role, received travel and expenses, Speakers Bureau; AbbVie: Honoraria, Other: Fees for cosulting or advisory role, received travel and expenses, Speakers Bureau; Gilead: Research Funding; Astra Zeneca: Other: Fees for cosulting or advisory role; Menarini: Other: Fees for cosulting or advisory role; Novartis: Honoraria. Rawstron:BD Biosciences (Intrasure): Patents & Royalties. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.

IntroductionRaised intracranial pressure (ICP) causes significant morbidity and mortality in a range of conditions including idiopathic intracranial hypertension (IIH) and traumatic brain injury (TBI). Exenatide is a GLP-1 receptor agonist; pre-clinical data demonstrates its ability to reduce ICP. GLP-1R agonists have also been shown to have neuro-protective properties in pre-clinical models of TBI. The objectives of this study are to assess the biological effect of a Glucagon-like Peptide 1 (GLP-1) agonist on ICP in a cohort of participants with IIH, a raised ICP model.MethodsRandomised, placebo controlled, double-blind physiology study of Exenatide in women with active IIH (>25 cmCSF lumbar puncture opening pressure and papilloedema). Telemetric, intraparenchymal ICP monitors were implanted to enable gold standard, long-term ICP monitoring (Raumedic p-Tel, Helmbrechts, Germany). Participants were randomised 1:1 to receive Exenatide (10 mcg BD sub-cutaneous) or placebo for 12 weeks. ICP was recorded over a 24-hour baseline visit, at two weeks and 12 weeks. Monthly headache diaries were completed at baseline and 8–12 weeks. Significance was set at pResultsOf the 16 participants recruited, 15 were randomised and completed the study: age 29.5 ±9.5 years, BMI 38.1 ±6.2 kg/m2, ICP 30.6±5.1 cmCSF. All ICP monitor implants were well tolerated and allowed successful ICP quantification. A significant reduction in ICP was noted at all timepoints: at 2.5 hours -5.7 cm CSF (p=0.031), at 24 hours -6.3 cmCSF (p=0.095), and at 12 weeks -5.6 cmCSF (p=0.064).ConclusionsWe report the first human study to assess the biological effect of the GLP-1 agonist Exenatide on ICP in IIH utilising highly accurate implantable telemetric ICP monitors. Exenatide reduced ICP at all timepoints including acutely at 2.5 hrs and during chronic dosing. New therapies for ICP modulation are a significant un-met need in both military and civilian spheres.

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT

The experimental design presented here is motivated by a phase II clinical trial called PePS2, investigating the efficacy and safety of an immunotherapy called pembrolizumab in a specific subgroup of lung cancer patients. Previous trials have shown that the probability of efficacy is correlated with particular patient variables. There are clinical trial designs that investigate co-primary efficacy and toxicity outcomes in phase II, but few that incorporate covariates. We present here the approach we developed for PePS2, latterly recognised to be a special case of a more general method originally presented by Thall, Nguyen and Estey. Their method incorporates covariates to conduct a dose-finding study but has been scarcely used in trials. Dose-finding is not required in PePS2 because a candidate dose has been widely tested. Starting from the most general case, we introduce our method as a novel refinement appropriate for use in phase II, and evaluate it using a simulation study. Our method shares information across patient cohorts. Simulations show it is more efficient than analysing the cohorts separately. Using the design in PePS2 with 60 patients to test the treatment in six cohorts determined by our baseline covariates, we can expect error rates typical of those used in phase II trials. However, we demonstrate that care must be taken when specifying the models for efficacy and toxicity because more complex models require greater sample sizes for acceptable simulated performance.

Prolonged exposure to antigens can lead to a state of reduced T cell responsiveness termed exhaustion. Restoring T cell functions from this state of reduced functionality by, for example, blockade of inhibitory immune checkpoints is now an established therapeutic modality with lasting impact on survival for some patients. Modelling human T cell exhaustion and its reversal in vitro can be challenging in medium or high-throughput assays. We have therefore sought to develop and characterize an in vitro model of T cell exhaustion using human T cells. Long-term (14-day) prolonged stimulation of human T cells in vitro led to both an up-regulation of established exhaustion markers PD-1, LAG-3 and TIM-3, and a lack of responsiveness to subsequent stimulation with human allogeneic monocyte-derived dendritic cells (DCs) as assessed by, for instance, IFNγ and TNFα production. Subsequent addition of blocking antibodies against PD-1 (pembrolizumab and nivolumab) led to a robust reversal of exhausted state by, for instance, restoration of cytokine secretion. The magnitude and nature of the response also correlated with the response of dissociated cells from lung and colon carcinomas. This response also showed greater sensitivity to PD-1 blockade compared to freshly isolated T cells or when using PBMCs stimulated with a pool of EBV peptides. By performing intracellular cytokine staining of human exhausted T cells stimulated with allogeneic dendritic cells, we further noted that PD-1 blockade using either pembrolizumab or nivolumab increased the percentage of cells producing IFNγ suggesting a greater responding pool of T cells. However, whilst the levels of the IFNγ in the supernatants of the exhausted T cell/allogeneic dendritic cell cultures was fully restored when compared to ‘fresh' T cell/allogeneic dendritic cell cultures, the percentage of IFNγ+ cells was not, nor was it fully restored by the inclusion of PMA/ionomycin. Taken together, this would suggest that PD-1 blockade induces responding cells to produce more IFNγ. We suggest that this chronic activation model of human T cell exhaustion with a robust assay window, and responsive to the clinically validated anti-PD-1 antibodies, nivolumab and pembrolizumab, may provide a platform for the discovery of new immuno-oncology therapeutics as well as the assessment of differences in mechanism of action between them. Citation Format: Omar S. Qureshi, Alexander Roberts, Lindsay Bentley, Tina Tang, Fay Stewart, Graham Wallace, Alison Cooper, Aaron Scott, David Thickett, Babu Naidu, Thomas Pinkney, Graham Taylor, Kristian Brock, Louise Healy, Zania Stamataki, Catherine Brady, S J. Curnow, John Gordon, Nicholas M. Barnes. A robust enhancement of cytokine production in a human chronic activation model of T cell exhaustion in vitro through blockade of PD-1/PDL-1 interactions using pembrolizumab or nivolumab; correlation with dissociated tumor immune cell responses [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3274.

Background: The outcome of patients with blast phase chronic myeloid leukaemia (CML) remains extremely poor despite the advent of tyrosine kinase inhibitors (TKIs), and the majority of blast phase patients have already failed the currently licensed TKIs during the chronic phase. Currently there is no standard therapy for patients with blast phase CML, but most will receive 2 or 3 courses of chemotherapy or a TKI, followed by stem cell transplantation (alloSCT). In the PACE clinical trial of ponatinib, 23% of patients with blast phase CML achieved major cytogenetic response, with overall survival of 20% at 12 months. To date, there has been no prospective evaluation of salvage chemotherapy in combination with ponatinib. Methods: MATCHPOINT is a seamless Phase I/II trial to determine the optimal dose of ponatinib in combination with conventional chemotherapy (fludarabine, cytarabine, idarubicin and G-CSF; FLAG-IDA) for the treatment of CML in blast phase. An efficient Bayesian design, EffTox, which utilises both efficacy and toxicity to select desirable doses for subsequent patient cohorts, was used. Given the observed patient outcomes and the investigators' prior beliefs, the next cohort's dose is chosen adaptively to optimize the risk-benefit trade-off between efficacy and toxicity. The initial ponatinib dose was 30mg daily, commenced on day 1 of FLAG-IDA chemotherapy. Where possible, ponatinib was given continuously during the remission-induction phase, but ponatinib therapy was interrupted from day 28 of each cycle if haematologic recovery had not occurred. Patients received one or two cycles of FLAG-IDA chemotherapy plus ponatinib at the allocated dose level, and then proceeded to alloSCT followed by ponatinib maintenance. The co-primary outcome measured toxicity (dose-limiting toxicity; DLT) during the first therapy cycle and efficacy (clinical response; haematologic or cytogenetic) after the first cycle. Results: A total of 17 patients were recruited between March 2015 and May 2018. Eight presented with de-novo blast phase CML and 9 had progressed on TKI. Eight patients had additional cytogenetic abnormalities and 3 had BCR-ABL kinase domain mutations (E255K x2 and T315I x1) at study entry. Nine and 8 patients commenced 1 or 2 cycles of FLAG-IDA + ponatinib, respectively. Of these, 16 patients were evaluable for the primary analysis. Treatment-related mortality (TRM) occurred in 3 patients during remission-induction (cardiomyopathy x1, pulmonary haemorrhage x1 and marrow aplasia x1). During cycle 1, 4/16 patients experienced a DLT (raised ALT x1, fulminant cardiomyopathy x1, cerebral sinus vein thrombosis x1, elevated amylase x1). Eleven of 16 (69%) patients achieved a clinical response, defined as either complete haematologic (3 patients) or cytogenetic response (1 minor and 9 major [2 partial and 7 complete]). Five patients achieved major molecular remission after cycle 1. All patients were recommended to be dosed at the 30mg dose, which was defined as the optimal dose for ponatinib with FLAG-IDA. Nine patients proceeded to alloSCT (7 myeloablative and 2 reduced intensity). Four patients developed acute GvHD (grades 2-4) and 3 had CMV reactivation. Four patients re-started ponatinib maintenance post alloSCT, and de-escalated to 15mg if major molecular remission was maintained. Overall 1-year survival was 45.8% (95% CI 26.9-77.7%), estimated using Kaplan Meier. Summary/Conclusion: We report the first prospective trial of ponatinib and conventional chemotherapy for blast phase CML. The EffTox model combined Phase I and II, and delivered efficiency in determining the trial's optimal dose. This innovative statistical model has the potential to be applied in other rare malignancies. We confirm that FLAG-IDA + ponatinib 30mg, is a tolerable combination in blast phase CML, with promising response and survival. Post-transplant ponatinib was well tolerated and no excess toxicity was observed when ponatinib was used both pre- and post alloSCT. The combination of ponatinib and FLAG-IDA represents a potentially important advance in the treatment of blast phase CML, a rare complication which currently has a very poor outcome. Disclosures Copland: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel: Research Funding. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Brock:Astrazeneca: Equity Ownership, Honoraria. De Lavallade:Incyte biosciences: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Clark:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad/Incyte: Honoraria; Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Yap:Celgene: Honoraria; Faron Pharmaceuticals: Other: Consultancy. OffLabel Disclosure: Ponatinib is a tyrosine kinase inhibitor (TKI). It is licensed to treat: - chronic myeloid leukaemia where the leukaemic cells have gene change (mutation) called T315I - acute lymphoblastic leukaemia that has an abnormal chromosome called the Philadelphia chromosome, or has the T315I mutation

Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of Pseudomonas keratitis, applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available., Ophthalmology: novel eye drop brings sustained drug delivery to ocular surface An eye drop formulation that applies anti-scarring drugs to the surface of the eye helps reverse infection-induced corneal damage in mice. Hill et al. from the University of Birmingham, UK, formulated a fluid gel loaded with a wound-healing protein called decorin that conforms to the ocular surface and is cleared gradually through blinking. With colleagues in California, they applied the therapeutic eye drop to mice with bacterial eye infections that trigger sight-threatening corneal scarring. Within a matter of days, the team saw improvements in corneal transparency, with reductions in scar tissue and reconstitution of healthy cells. Such a drug delivery system, if successful in humans, could help save many people’s sight and reduce the need for corneal transplantation.

Introduction The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM’s uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. Methods To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. Results An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. Conclusions The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials. Electronic supplementary material The online version of this article (10.1186/s12874-018-0638-z) contains supplementary material, which is available to authorized users.

BACKGROUND Antigen-mediated proliferation and Bcl-2 mediated survival are key to chronic lymphocytic leukemia (CLL) pathogenesis. Ibrutinib is an oral BTK inhibitor affecting antigen-induced proliferation and cell adhesion/migration whilst venetoclax is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival. The treatment of CLL has been revolutionized by these targeted therapies. Both significantly improve survival in CLL but rarely lead to eradication of detectable minimal residual disease (MRD) when given as single agents. The Bloodwise TAP CLARITY trial combined ibrutinib with venetoclax in order to eradicate detectable CLL with the intention of stopping therapy. METHODS AND PATIENTS CLARITY is a Phase II trial combining ibrutinib with venetoclax in 50 patients with relapsed or refractory CLL. After 8 weeks of ibrutinib monotherapy (420mg/day), venetoclax was added first at a dose of 10mg/day with weekly escalations to 20mg, 50mg, 100mg, 200mg to a final dose of 400mg/day. No tumour lysis syndrome (TLS) was seen for the first 3 patients starting at 10mg/day of venetoclax so all subsequent patients began at 20mg/day. The primary end-point of CLARITY was the eradication of MRD ( RESULTS There were no cases of clinical tumor lysis syndrome (TLS) and only a single case of biochemical TLS (grade 3) which resolved with treatment. Other side-effects were mild and/or manageable, most commonly neutropenia (3/32 grade 2, 29/32 grade 3/4) or gastro-intestinal events (268/278 grade 1/2, 10/278 grade 3/4). Two Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported (abdominal pain and pemphigus), 31 Serious Adverse Events (SAEs), and 918 Adverse Events (AEs) (of which 75 were grade 3 or 4) were reported. Notably there were nine grade 3 or 4 infections and 29 events of grade 3 or 4 neutropenia. Thus far all SAEs have resolved with appropriate management, and all patients remained on trial following resolution. After 6 months of combined ibrutinib plus venetoclax, undetectable MRD was achieved in 19/49 (39%) patients in peripheral blood (PB) and 12/49 (24%) in bone marrow (BM). After 12 months of combined therapy all patients had responded by IWCLL criteria and 23/40 (58%) had achieved a complete remission (CR or CRi). In addition after 12 months of combined therapy 27/31 (87%) have no morphological evidence of CLL in the BM biopsy, 32/34 (94%) had less than 1% CLL cells in the BM aspirate, undetectable MRD (MRD4) was achieved in 23/40 (58%) patients in PB and 17/41 (41%) in BM. There was a continuous improvement in the depth of MRD reduction with 41% of patients achieving less than MRD4 and 29% having undetectable disease by flow cytometry ( CONCLUSIONS The combination of ibrutinib and venetoclax was well tolerated in patients with relapsed or refractory CLL. Every patient responded and there was a high rate of MRD eradication, in some cases leading to the cessation of therapy. Figure Figure. Disclosures Hillmen: Pharmacyclics: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Rawstron:Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beckman Coulter: Research Funding; BD Biosciences: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Lilly: Honoraria; Roche: Other: Reimbursement of expenses; Merck Sharp Dohme: Other: Reimbursement of conference fees. Fegan:Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria; Gilead Sciences, Inc.: Honoraria; Janssen: Honoraria. McCaig:AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Napp: Research Funding; Chugai: Research Funding. Gribben:NIH: Research Funding; Novartis: Honoraria; Cancer Research UK: Research Funding; Medical Research Council: Research Funding; TG Therapeutics: Honoraria; Abbvie: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria. Patten:L Hoffman La Roche: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding; AbbVie Inc: Honoraria, Other: travel; Janssen: Honoraria, Other: travel. Devereux:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Personal fees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bloor:AbbVie: Research Funding; Janssen: Research Funding. Fox:Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau. Forconi:Janssen-Cilag: Consultancy; Abbvie: Consultancy. Munir:Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Alexion: Honoraria; MorphoSys: Membership on an entity's Board of Directors or advisory committees.

Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naïve, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naïve trial participants compared to those treated with >1 year prior ibrutinib. Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naïve with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved 1 year prior to combination with obinutuzumab (see Table 1). Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving PB MRD levels continued to improve in ibrutinib-naïve patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD 1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab. Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naïve patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour bulk was low. For patients with persistent disease during/ following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates. Disclosures Rawstron: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Forecasting recruitment to clinical trials is often too simplistic and rarely statistical. This is unfortunate because modelling trial recruitment is simple using Poisson processes. The simplest case is to assume patients arrive randomly at a constant rate, using homogeneous Poisson processes to simulate sample recruitment curves. In contrast, time-varying complexity can be incorporated using non-homogeneous Poisson processes. This necessitates a recruitment intensity function, 0 ≤ p(t) ≤1, (t ≥ 0), to describe the instantaneous rate of recruitment potential at time t, as a proportion of the maximum rate possible. Using this method, one can incorporate important factors like seasonal trends, staggered opening of recruitment centres, accelerating and decelerating recruitment and planned suspensions (for instance, due to interim assessments), to reflect more accurately the possible recruitment patterns over time. There are many benefits to investing the time to model trial recruitment. Guidance on plausible recruitment scenarios can inform inventory needs and forewarn the impact of recruitment shocks, both welcome and unwelcome. In designs with time-to-event outcomes, the rate of patient recruitment can affect statistical operating characteristics. In complicated trial designs, it may be especially important to model recruitment to demonstrate trial feasibility. We present the mathematics of the homogeneous and non-homogeneous cases, along with simple, versatile algorithms for simulating each using open-source R code. We discuss the insights we garnered by modelling recruitment to the National Lung Matrix trial, a multi-arm, multi-drug, phase II adaptive design stratified by random genetic changes in non-small cell lung cancer patients.