Ongoing Phase 1/2 Study Of Incb050465, A Selective Pi3kδ Inhibitor, For The Treatment Of Patients (Pts) With Relapsed/Refractory (R/R) B‐Cell Malignancies (Citadel‐101)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137307/1/hon2438_139.pd

Quality-of-life analysis of pembrolizumab vs brentuximab vedotin for relapsed/refractory classical Hodgkin lymphoma

KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (.90%) and through week 24 (.80%) was demonstrated across treatment groups (PRO analysis set: Pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/ quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31]; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74]; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT0119307

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores

Objective: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Methods: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. Results: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4–87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99–1.97, p < 0.0001, for baseline CMTES-R score 0–9). Conclusion: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. ClinicalTrials.gov identifier NCT01193075

2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects

Objective. The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM. Methods. Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data. Results. Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference. Conclusion. Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival