Bayes methods in group sequential clinical trials

Bayesian methods for group sequential clinical trials have received increasing at­tention recently. They offer an approach for dealing with many difficult problems and have some practical advantages over frequentist methods. This thesis covers Bayesian methods for group sequential clinical trials comparing two treatments using both the Bayes sequential procedure and the Bayes sequential decision pro­cedure. The main outcome measures for clinical trials are distributed as normal, binomial, and exponential and the proportional hazard model for survival time data. Under the framework of Bayes sequential procedure for group sequential clini­cal trials, the student t prior distribution for the parameter of interest is proposed as a replacement for the normal prior distribution when the sample mean is very distant from the mean of the prior distribution. The framework of Bayes sequen­tial procedure in clinical trials on normal distribution responses with variance unknown is given. Bayes sequential decision theory is applied to group sequential clinical trials. First, Bayes sequential decision procedures with piecewise continuous loss func­tions are used in clinical trials on normal distribution responses. The procedures with loss functions which consider treatment efficacy and patient horizon are then given in clinical trials on binary responses. Approximation methods of Bayes sequential decision procedures are explored in clinical trials with survival time data. Robust Bayes analysis in clinical trials is presented to address the criticism on the subjective prior distribution for parameters of interest

Detection of disease change using a biological marker and clinical application: CA125 in ovarian cancer patients

In Oncology drug development, the great majority of phase 3 trials are negative.. New strategies are required to rapidly identify novel agents prior to large randomised trials. The CA125 doubling trial successfully showed that an effective drug could be identified more efficiently by testing whether the rate of increase in the tumour marker CA125 decreased after starting the novel agent, at a point identified by CA125 rising to four times it’s nadir level. However efficiency could be improved, if more patients could be included. This work explores identifying an earlier effective starting point by analysing the time course of CA125 rise.Non peer reviewe

497. Safety and tolerability of 2000mg intravenous sotrovimab dose in immunocompromised participants uninfected with SARS-CoV-2 in the PROTECT-V trial

Background: There remains a need for pre-exposure prophylaxis against SARS-CoV-2 infection in vulnerable patients in whom response to vaccination is often sub-optimal. The PROTECT-V platform trial is testing pre-exposure prophylactic interventions for COVID-19 in vulnerable patient populations: transplant recipients, individuals with oncological/haematological diagnoses, immune deficiency, autoimmune diseases requiring immunosuppression, and individuals receiving dialysis. Methods: Sotrovimab is a dual-action monoclonal antibody and the second agent to be added to the PROTECT-V platform (Clinicaltrials.gov: NCT04870333; EudraCT: 2020-004144-28). Although a single sotrovimab 500mg intravenous (IV) dose has been widely used for early treatment, data on a 2000mg IV dose are limited. Tolerability data in the first 143 participants randomized to this arm of the trial are presently available. Patients are randomized 1:1 sotrovimab to placebo. Data remain blinded. Results: Median age was 66 years (range 21 – 86) and 82 (57%) patients were female. 132 (96%) had received ≥3 doses of SARS-CoV-2 vaccine. Patient populations were: 82 (57%) autoimmune disease; 26 (18%) haematological/oncological diseases; 21 (15%) transplant recipients; 12 (8%) immunodeficiency; 2 (1%) on dialysis. Two (1%) participants experienced a mild infusion related reaction (IRR). The infusion was briefly interrupted, but completed. Thirty (21%) participants experienced at least one symptom in the 24 hours post-infusion, but none were severe or required hospital admission. The most common symptoms were dizziness (7 [5%]), headache (7 [5%]), rigors (5 [4%]) and fever (4 [3%]). No severe adverse events were reported within 72 hours of IMP infusion at the time of writing. The first 55 patients underwent routine hematological and biochemical blood test evaluation 72 hours post-infusion. Ten events from 9 participants exhibited worsening of laboratory parameters, meeting at least grade two DAIDS criteria or worse. None of these were clinically significant. Conclusion: A 2000mg IV dose of sotrovimab was tolerated well in this blinded analysis of immunocompromised participants, with no severe IRRs or significant change in haematological or biochemical markers up to 72 hours post infusion. Disclosures: Davinder Dosanjh, n/a, Astrazeneca: Honoraria|Astrazeneca: Employee|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Gilead: Advisor/Consultant|GSK: Grant/Research Support|Synairgen: Advisor/Consultant Louise Crowley, n/a, GSK: Grant/Research Support Michael Chen-Xu, n/a, GSK: Grant/Research Support Rona M. Smith, MD MRCP, GSK: Grant/Research Support|Union Therapeutics: Grant/Research Suppor

Trajectories of Haemoglobin and incident stroke risk: a longitudinal cohort study.

BACKGROUND: Studies have demonstrated that high or low haemoglobin increases the risk of stroke. Previous studies, however, performed only a limited number of haemoglobin measurements, while there are dynamic haemoglobin changes over the course of a lifetime. This longitudinal cohort study aimed to classify the long-term trajectory of haemoglobin and examine its association with stroke incidence. METHODS: The cohort consisted of 11,431 participants (6549 men) aged 20 to 50 years whose haemoglobin was repeatedly measured 3-9 times during 2004-2015. A latent class growth mixture model (LCGMM) was used to classify the long-term trajectory of haemoglobin concentrations, and hazard ratios (HRs) and 95% confidence intervals (95% CI) according to the Cox proportional hazard model were used to investigate the association of haemoglobin trajectory types with the risk of stroke. RESULTS: Three distinct trajectory types, high-stable (n = 5395), normal-stable (n = 5310), and decreasing (n = 726), were identified, with stroke incidence rates of 2.7, 1.9 and 3.2 per 1000 person-years, respectively. Compared to the normal-stable group, after adjusting for the baseline covariates, the decreasing group had a 2.94-fold (95% CI 1.22 to 7.06) increased risk of developing stroke. Strong evidence was observed in men, with an HR (95% CI) of 4.12 (1.50, 11.28), but not in women (HR = 1.66, 95% CI 0.34, 8.19). Individuals in the high-stable group had increased values of baseline covariates, but the adjusted HR (95% CI), at 1.23 (0.77, 1.97), was not significant for the study cohort or for men and women separately. CONCLUSIONS: This study revealed that a decreasing haemoglobin trajectory was associated with an increased risk of stroke in men. These findings suggest that long-term decreasing haemoglobin levels might increase the risk of stroke

Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0I0149 and 0I0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0I001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.Peer reviewedFinal Accepted Versio

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

Funder: NIHR Cambridge Biomedical Research CentreFunder: Addenbrooke’s Charitable TrustFunder: National Institute for Health Research (NIHR)Funder: Mark Foundation For Cancer ResearchFunder: Cambridge Commonwealth, European and International TrustFunder: Cancer Research UKFunder: Cambridge Clinical Trials UnitFunder: Cancer Research UK Cambridge CentreFunder: Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and ManchesterFunder: Cambridge Experimental Cancer Medicine CentrePURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). CONCLUSIONS: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. TRIAL REGISTRATION: EudraCtNo: 2005-004502-82

Isobavachalcone exhibits antifungal and antibiofilm effects against C. albicans by disrupting cell wall/membrane integrity and inducing apoptosis and autophagy

Isobavachalcone (IBC) is a natural flavonoid with multiple pharmacological properties. This study aimed to evaluate the efficacy of IBC against planktonic growth and biofilms of Candida albicans (C. albicans) and the mechanisms underlying its antifungal action. The cell membrane integrity, cell metabolic viability, and cell morphology of C. albicans treated with IBC were evaluated using CLSM and FESEM analyses. Crystal violet staining, CLSM, and FESEM were used to assess the inhibition of biofilm formation, as well as dispersal and killing effects of IBC on mature biofilms. RNA-seq combined with apoptosis and autophagy assays was used to examine the mechanisms underlying the antifungal action of IBC. IBC exhibited excellent antifungal activity with 8 μg/mL of MIC for C. albicans. IBC disrupted the cell membrane integrity, and inhibited biofilm formation. IBC dispersed mature biofilms and damaged biofilm cells of C. albicans at 32 μg/mL. Moreover, IBC induced apoptosis and autophagy-associated cell death of C. albicans. The RNA-seq analysis revealed upregulation or downregulation of key genes involved in cell wall synthesis (Wsc1 and Fks1), ergosterol biosynthesis (Erg3, and Erg11), apoptisis (Hsp90 and Aif1), as well as autophagy pathways (Atg8, Atg13, and Atg17), and so forth, in response to IBC, as evidenced by the experiment-based phenotypic analysis. These results suggest that IBC inhibits C. albicans growth by disrupting the cell wall/membrane, caused by the altered expression of genes associated with β-1,3-glucan and ergosterol biosynthesis. IBC induces apoptosis and autophagy-associated cell death by upregulating the expression of Hsp90, and altering autophagy-related genes involved in the formation of the Atg1 complex and the pre-autophagosomal structure. Together, our findings provide important insights into the potential multifunctional mechanism of action of IBC

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit.

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan-Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68-1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival