Confirmatory prediction-driven RCTs in comparative effectiveness settings for cancer treatment.

BACKGROUND: Medical advances in the treatment of cancer have allowed the development of multiple approved treatments and prognostic and predictive biomarkers for many types of cancer. Identifying improved treatment strategies among approved treatment options, the study of which is termed comparative effectiveness, using predictive biomarkers is becoming more common. RCTs that incorporate predictive biomarkers into the study design, called prediction-driven RCTs, are needed to rigorously evaluate these treatment strategies. Although researched extensively in the experimental treatment setting, literature is lacking in providing guidance about prediction-driven RCTs in the comparative effectiveness setting. METHODS: Realistic simulations with time-to-event endpoints are used to compare contrasts of clinical utility and provide examples of simulated prediction-driven RCTs in the comparative effectiveness setting. RESULTS: Our proposed contrast for clinical utility accurately estimates the true clinical utility in the comparative effectiveness setting while in some scenarios, the contrast used in current literature does not. DISCUSSION: It is important to properly define contrasts of interest according to the treatment setting. Realistic simulations should be used to choose and evaluate the RCT design(s) able to directly estimate that contrast. In the comparative effectiveness setting, our proposed contrast for clinical utility should be used.

Confidence bands in survival analysis.

BACKGROUND: Providing estimates of uncertainty for statistical quantities is important for statistical inference. When the statistical quantity of interest is a survival curve, which is a function over time, the appropriate type of uncertainty estimate is a confidence band constructed to account for the correlation between points on the curve, we will call this a simultaneous confidence band. This, however, is not the type of confidence band provided in standard software, which is constructed by joining the confidence intervals at given time points. METHODS: We show that this type of band does not have desirable joint/simultaneous coverage properties in comparison to simultaneous bands. RESULTS: There are different ways of constructing simultaneous confidence bands, and we find that bands based on the likelihood ratio appear to have the most desirable properties. Although there is no standard software available in the three major statistical packages to compute likelihood-based simultaneous bands, we summarise and give code to use available statistical software to construct other simultaneous forms of bands, which we illustrate using a study of colon cancer. CONCLUSIONS: There is a need for more user-friendly statistical software to compute simultaneous confidence bands using the available methods.

Prediction-driven pooled testing methods: Application to HIV treatment monitoring in Rakai, Uganda.

Chronic medical conditions often necessitate regular testing for proper treatment. Regular testing of all afflicted individuals may not be feasible due to limited resources, as is true with HIV monitoring in resource-limited settings. Pooled testing methods have been developed in order to allow regular testing for all while reducing resource burden. However, the most commonly used methods do not make use of covariate information predictive of treatment failure, which could improve performance. We propose and evaluate four prediction-driven pooled testing methods that incorporate covariate information to improve pooled testing performance. We then compare these methods in the HIV treatment management setting to current methods with respect to testing efficiency, sensitivity, and number of testing rounds using simulated data and data collected in Rakai, Uganda. Results show that the prediction-driven methods increase efficiency by up to 20% compared with current methods while maintaining equivalent sensitivity and reducing number of testing rounds by up to 70%. When predictions were incorrect, the performance of prediction-based matrix methods remained robust. The best performing method using our motivating data from Rakai was a prediction-driven hybrid method, maintaining sensitivity over 96% and efficiency over 75% in likely scenarios. If these methods perform similarly in the field, they may contribute to improving mortality and reducing transmission in resource-limited settings. Although we evaluate our proposed pooling methods in the HIV treatment setting, they can be applied to any setting that necessitates testing of a quantitative biomarker for a threshold-based decision.

Evaluating the use of the ABCD2 score as a clinical decision aid in the emergency department: Retrospective observational study.

OBJECTIVE: Clinical decision aids (CDAs) can help clinicians with patient risk assessment. However, there is little data on CDA calculation, interpretation and documentation in real-world ED settings. The ABCD2 score (range 0-7) is a CDA used for patients with transient ischaemic attack (TIA) and assesses risk of stroke, with a score of 0-3 being low risk. The aim of this study was to describe ABCD2 score documentation in patients with an ED diagnosis of TIA. METHODS: Retrospective observational study of patients with a working diagnosis of a TIA in two Australian EDs. Data were gathered using routinely collected data from health informatics sources and medical records reviewed by a trained data abstractor. ABCD2 scores were calculated and compared with what was documented by the treating clinician. Data were presented using descriptive analysis and scatter plots. RESULTS: Among the 367 patients with an ED diagnosis of TIA, clinicians documented an ABCD2 score in 45% (95% CI 40-50%, n = 165). Overall, there was very good agreement between calculated and documented scores (Cohen's kappa 0.90). The mean documented and calculated ABCD2 score were similar (3.8, SD = 1.5, n = 165 vs 3.7, SD = 1.8, n = 367). Documented scores on the threshold of low and high risk were more likely to be discordant with calculated scores. CONCLUSIONS: The ABCD2 score was documented in less than half of eligible patients. When documented, clinicians were generally accurate with their calculation and application of the ABCD2. No independent predictors of ABCD2 documentation were identified.

Hematopoietic Cell Transplantation after CD19 Chimeric Antigen Receptor T Cell-Induced Acute Lymphoblastic Lymphoma Remission Confers a Leukemia-Free Survival Advantage.

Consolidative hematopoietic cell transplantation (HCT) after CD19 chimeric antigen receptor (CAR) T cell therapy is frequently performed for patients with refractory/ relapsed B cell acute lymphoblastic leukemia (B-ALL). However, there is controversy regarding the role of HCT following remission attainment. We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects following CD19 CAR T cell induced remission. We evaluated the effect of consolidative HCT on LFS in pediatric and young adult subjects treated with a 41BB-CD19 CAR T cell product on a phase 1/2 trial, Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02 (ClinicalTrials.gov identifier NCT02028455), using a time-dependent Cox proportional hazards statistical model. Fifty of 64 subjects enrolled in PLAT-02 phase 1 and early phase 2 were evaluated, excluding 14 subjects who did not achieve remission, relapsed, or died before day 63 post-CAR T cell therapy. An improved LFS (P = .01) was observed in subjects who underwent consolidative HCT after CAR T cell therapy versus watchful waiting. Consolidative HCT improved LFS specifically in subjects who had no prior history of HCT, with a trend toward significance (P = .09). This benefit was not evident when restricted to the cohort of 34 subjects with a history of prior HCT (P = .45). However, for subjects who had CAR T cell functional persistence of 63 days or less, inclusive of those with a history of prior HCT, HCT significantly improved LFS outcomes (P = .01). These data support the use of consolidative HCT following CD19 CAR T cell-induced remission for patients with no prior history of HCT and those with short functional CAR T cell persistence.

Modified Manufacturing Process Modulates CD19CAR T-cell Engraftment Fitness and Leukemia-Free Survival in Pediatric and Young Adult Subjects.

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.

Liquid azide salts.

Ionic liquid azides from azidoethyl, alkyl, and alkenyl substituted derivatives of 1,2,4- and 1,2,3-amino-triazoles were prepared and examined for the first time to investigate their structural and physical properties. All reported salts possess melting points below 100 degrees C. The unique character of these newly discovered ionic liquid azides is based upon the fact that these molecules are not simple protonated salts like previously reported substituted hydrazinium azides. The presence of quaternary nitrogen confers both thermal stability and negligible volatility.