Patient-Reported Outcomes With Belantamab Mafodotin Treatment in Patients With Triple-Class Refractory Multiple Myeloma.

In the randomized phase II DREAMM-2 study, single-agent belantamab mafodotin demonstrated deep and durable responses and a manageable safety profile in triple-class refractory relapsed/refractory multiple myeloma (RRMM). We present patient-reported outcomes (PROs) from this study for patients treated with the approved dose of belantamab mafodotin (2.5 mg/kg q3w). Disease and treatment-related symptoms, health-related quality of life (HRQOL), functioning, and patient-reported ocular changes were assessed using questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life questionnaires EORTC-QLQ-C30 and EORTC-QLQ-MY20, Ocular Surface Disease Index [OSDI], and the National Eye Institute Visual Functioning Questionnaire 25 [NEI VFQ-25]) at baseline, during treatment (every 3 or 6 weeks), and at the end of treatment (EOT). Eye examinations were conducted at baseline, prior to each treatment cycle, and at EOT. Patients reported ocular symptoms in the OSDI and NEI VFQ-25 questionnaires, with the median time to worst severity of 45 to 64 days depending on symptoms considered. Some limitations in driving and reading were reported. Ocular symptoms were improved and median time to recovery was 23.5 to 44.0 days. EORTC-QLQ-C30 data suggest core MM symptoms (including fatigue and pain), overall HRQOL, and patient functioning were maintained while patients continued belantamab mafodotin treatment, even if meaningful worsening of vision-related symptoms occurred. These PRO results, together with the clinical efficacy of belantamab mafodotin, support its use in patients with RRMM and further evaluation of its use at earlier lines of therapy.

Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

Variable selection for joint models with time-varying coefficients.

Many clinical studies collect longitudinal and survival data concurrently. Joint models combining these two types of outcomes through shared random effects are frequently used in practical data analysis. The standard joint models assume that the coefficients for the longitudinal and survival components are time-invariant. In many applications, the assumption is overly restrictive. In this research, we extend the standard joint model to include time-varying coefficients, in both longitudinal and survival components, and we present a data-driven method for variable selection. Specifically, we use a B-spline decomposition and penalized likelihood with adaptive group LASSO to select the relevant independent variables and to distinguish the time-varying and time-invariant effects for the two model components. We use Gaussian-Legendre and Gaussian-Hermite quadratures to approximate the integrals in the absence of closed-form solutions. Simulation studies show good selection and estimation performance. Finally, we use the proposed procedure to analyze data generated by a study of primary biliary cirrhosis.

Scaffold-Based Analytics: Enabling Hit-to-Lead Decisions by Visualizing Chemical Series Linked across Large Datasets.

We present a method for visualizing and navigating large screening datasets while also taking into account their activities and properties. Our approach is to annotate the data with all possible scaffolds contained within each molecule. We have developed a Spotfire visualization, coupled to a fuzzy clustering approach based on the scaffold decomposition of the screening deck, used to drive the hit triage process. Progression decisions can be made using aggregate scaffold parameters and data from multiple datasets merged at the scaffold level. This visualization reveals overlaps that help prioritize hits, highlight tractable series, and posit ways to combine aspects of multiple hits. The structure-activity relationship of a large and complex hit is automatically mapped onto all constituent scaffolds making it possible to navigate, via any shared scaffold, to all related hits. This scaffold "walking" helps address bias toward a handful of potent and ligand-efficient molecules at the expense of coverage of chemical space. We consider two scaffold generation methods and explored their similarities and differences both qualitatively and quantitatively. The workflow of a Spotfire visualization used in combination with fuzzy clustering and structure annotation provides an intuitive view of large and diverse screening datasets. This allows teams to effortlessly navigate between structurally related molecules and enriches the population of leads considered and progressed in a manner complementary to established approaches.

Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study.

Interim analyses of a phase I study with GSK2857916, an antibody-drug conjugate against B cell maturation antigen, have previously reported a 60% overall response and 7.9 months progression-free survival in relapsed/refractory multiple myeloma (MM). We provide updated safety and efficacy results of the BMA117159 trial following an additional 14 months' follow-up. This open-label, first-in-human, phase I study was conducted at nine centres in the USA, Canada and the UK, and included adults with MM and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators. In part 1, the recommended dose of 3.4 mg/kg was identified; in part 2, patients received GSK2857916 3.4 mg/kg once every 3 weeks. Selected part 2 safety/tolerability and efficacy endpoints are reported. Twenty-one (60.0%; 95% confidence interval (CI) 42.1-76.1) of 35 patients achieved partial response or better, including two stringent complete responses and three complete responses. The median progression-free survival was 12 months and median duration of response was 14.3 months. Thrombocytopenia and corneal events were commonly reported; no new safety signals were identified. GSK2857916 was well tolerated and demonstrated a rapid, deep and durable response in heavily pre-treated patients with relapsed/refractory MM, consolidating the interim analyses conclusions that GSK2857916 is a promising treatment for these patients.

Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial.

BACKGROUND: B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma. METHODS: We did an international, multicentre, open-label, first-in-human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0·03-4·60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment. FINDINGS: Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose-expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3·40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 [53%] of 38 patients in part 1 and 22 [63%] of 35 in part 2); most (18 [47%] in part 1 and 19 [54%] in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anaemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60·0%; 95% CI 42·1-76·1) of 35 patients achieved an overall response. INTERPRETATION: At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma. FUNDING: GlaxoSmithKline.

Triamterene Enhances the Blood Pressure Lowering Effect of Hydrochlorothiazide in Patients with Hypertension.

BACKGROUND: Triamterene, because of its potassium-sparing properties, is frequently used in combination with hydrochlorothiazide (HCTZ) to treat patients with hypertension. By inhibiting the epithelial sodium channel (ENaC) in the cortical collecting duct, triamterene reduces potassium secretion, thus reducing the risk of hypokalemia. Whether triamterene has an independent effect on blood pressure (BP) has not been well studied. OBJECTIVE: To determine if triamterene provides an effect to further lower BP in patients treated with HCTZ. DESIGN: We conducted an observational study using electronic medical record data from the Indiana Network for Patient Care. Participants were 17,291 patients with the diagnosis of hypertension between 2004 and 2012. MAIN MEASURES: BP was the primary outcome. We compared the BP between patients who were taking HCTZ, with and without triamterene, either alone or in combination with other antihypertensive medications, by using a propensity score analysis. For each medication combination, we estimated the propensity score (i.e., probability) of a patient receiving triamterene using a logistic regression model. Patients with similar propensity scores were stratified into subclasses and BP was compared between those taking triamterene or not within each subclass; the effect of triamterene was then assessed by combining BP differences estimated from all subclasses. KEY RESULTS: The mean systolic BP in the triamterene + HCTZ group was 3.8 mmHg lower than in the HCTZ only group (p < 0.0001); systolic BP was similarly lower for patients taking triamterene with other medication combinations. Systolic BP reduction was consistently observed for different medication combinations. The range of systolic BP reduction was between 1 and 4 mm Hg, depending on the concurrently used medications. CONCLUSIONS: In the present study, triamterene was found to enhance the effect of HCTZ to lower BP. In addition to its potassium-sparing action, triamterene's ability to lower BP should also be considered.

Simultaneous variable selection for joint models of longitudinal and survival outcomes.

Joint models of longitudinal and survival outcomes have been used with increasing frequency in clinical investigations. Correct specification of fixed and random effects is essential for practical data analysis. Simultaneous selection of variables in both longitudinal and survival components functions as a necessary safeguard against model misspecification. However, variable selection in such models has not been studied. No existing computational tools, to the best of our knowledge, have been made available to practitioners. In this article, we describe a penalized likelihood method with adaptive least absolute shrinkage and selection operator (ALASSO) penalty functions for simultaneous selection of fixed and random effects in joint models. To perform selection in variance components of random effects, we reparameterize the variance components using a Cholesky decomposition; in doing so, a penalty function of group shrinkage is introduced. To reduce the estimation bias resulted from penalization, we propose a two-stage selection procedure in which the magnitude of the bias is ameliorated in the second stage. The penalized likelihood is approximated by Gaussian quadrature and optimized by an EM algorithm. Simulation study showed excellent selection results in the first stage and small estimation biases in the second stage. To illustrate, we analyzed a longitudinally observed clinical marker and patient survival in a cohort of patients with heart failure.

A genome-wide association study reveals association between common variants in an intergenic region of 4q25 and high-grade myopia in the Chinese Han population.

High-grade myopia (HM) is highly heritable, and has a high prevalence in the Han Chinese population. We carried out a genome-wide association study involving 102 HM cases suffering from retinal degeneration, and 335 controls who were free from HM and fundus diseases. Significant single-nucleotide polymorphisms were replicated in two follow-up studies: stage I involved 2628 independent cases and 9485 controls, and stage II involved a further 263 cases and 586 HM-free controls. The results were combined in a meta-analysis. Cases and controls were drawn from the Chinese Han population. A locus in an intergenic region at 4q25, within MYP11 (4q22-q27, OMIM: 609994), was found to be associated with HM (rs10034228, P(meta) = 7.70 × 10(-13), allelic odds ratio = 0.81, 95% confidence interval 0.76-0.86). There are no known genes in the region but a number of expressed sequence tags (ESTs) have been located there, one of which (BI480957) has been reported to express in the native human retinal pigment epithelium. In addition, a predicted gene was identified in this region. The gene's predicted protein sequence is highly similar to tubulin, beta 8 and beta-tubulin 4Q. Several previous studies have shown that tubulin plays an important role in eye development. Our result is compatible with a previous linkage study in the Han Chinese population (mapping in MYP11, 4q22-q27), and provides a more accurate locus for HM. Although there is insufficient evidence to indicate that expressed EST and the predicted gene play an important role in developing HM, this region merits further study as a candidate for the disease.

Genetic diversity of the apolipoprotein E gene and diabetic nephropathy: a meta-analysis.

In the past decade, a number of case-control studies have been carried out to investigate the relationship between the ApoE polymorphism and diabetic nephropathy. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the ApoE polymorphism and DN. The 23 studies in the meta- analysis included 6,012 diabetic patients with (n = 2,979) and without (n = 3,033) DN. The ApoE ε2 allele was significantly associated with DN (OR = 1.64, 95% CI: 1.26-2.13; P(Z) = 0.00027), whereas the ε4 allele was non-significantly associated with DN (OR = 0.93, 95% CI: 0.78-1.11; P(Z) = 0.418). However, significant heterogeneity was detected. In further subgroup analyses, genotyping methods, outcome of cases and duration of diabetes in controls were found to explain some of the heterogeneity. Genotypic analysis also found a strong association between the ε2 carriers and DN (OR = 1.61, 95% CI: 1.22-2.13; P(Z) = 0.001) and indicated that ε4 tended to have a marginally significant protective effect for DN (OR = 0.82, 95% CI: 0.65-1.03; P(Z) = 0.085). The results of our meta-analysis support a genetic association between the ApoE polymorphism and DN. ε2 increases the risk of DN in diabetes patients, while ε4 trends to be protective. These findings may have implications for therapeutic intervention in diabetic nephropathy.

The Val/Met functional polymorphism in COMT confers susceptibility to bipolar disorder: evidence from an association study and a meta-analysis.

The COMT gene is considered as one of the prominent candidate genes for susceptibility to BP, and most studies focused a functional polymorphism in the gene: the Val/Met polymorphism (rs4680). However, results from these studies are sometimes contradictory, due to small sample size or heterogeneity. In this study, we first investigate the possible association between the Val/Met polymorphism in COMT and bipolar disorder in the Han population, which has never been done before. Then a systematic meta-analysis was conducted to determine if the low-activity allele (Met) increases the risk of BP in different ethnic groups. A total of 478 BP patients and 469 healthy subjects were recruited in our case/control study. MIX software package was employed to perform the meta-analysis on 19 studies after careful search and selection. We observed statistically-significant differences in allele (p = 0.00060) and genotype (p = 0.00203) frequencies between patients and controls in our samples. The meta-analysis also provided a significant pooled OR for association of the Met allele in rs4680 with BP in the total population (p = 0.0223) and in the Asian population (p = 0.0232). Although a significant pooled OR was also found for the Caucasian population (p = 0.0409) after one of the studies as discussed below was removed, the role for Val/Met polymorphism in BP in Caucasian ethnicity was not yet to be confirmed. In conclusion, the low-activity allele (Met) of rs4680 in COMT gene possibly confers risk for bipolar disorder in the Han population, while it needs further evidence for concluding its association with BP in the Caucasian population.

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population.

BACKGROUND: The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene. METHOD: We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls. RESULT: No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global chi2=1.318, P=0.725, df=3). CONCLUSION: Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.

The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis.

Dopamine D3 receptor (DRD3) binds antipsychotic drugs and is abundant in the limbic system of the brain. It has been shown to play important roles in schizophrenia. A number of studies investigated the Ser9Gly polymorphism of the DRD3 gene to test its possible association with schizophrenia; however, the results were inconsistent. Our study aims to further evaluate the possible association between the Ser9Gly polymorphism and schizophrenia using a case-control association study within the Han Chinese population as well as a meta-analysis covering all previous studies. Our study, based on 329 schizophrenic patients and 288 controls, found no significant difference in the genotype or allele distributions of Ser9Gly polymorphism, the meta-analysis showed that the Ser9Gly polymorphism was not associated with Schizophrenia. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia in the Chinese population.

No genetic association between polymorphisms in the kainate-type glutamate receptor gene, GRIK4, and schizophrenia in the Chinese population.

BACKGROUND: Schizophrenia is a chronic psychiatric disorder with a strong genetic component. Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and that the kainate ionotropic glutamate receptors are involved in this mechanism. A recent study provides cytogenetic and genetic evidence to support a role for the kainate-type glutamate receptor gene (GRIK4), in schizophrenia. A systematic case-control association study of GRIK4 involving a Scottish population found that three SNPs, rs4935752, rs6589846 and rs4430518, were associated with schizophrenia. METHODS: Here, we investigated rs4935752, rs6589846, rs4430518 and other 2 SNPs within the GRIK4 gene in an association study of the Chinese population. Our sample consisted of 288 schizophrenia and 288 control subjects. All recruits were Han Chinese drawn from the city of Shanghai. RESULTS: No individual SNP nor any haplotype was associated with schizophrenia in our study. CONCLUSION: These results suggest that the five SNPs within the GRIK4 gene are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.

No significant association between the genetic polymorphisms in the GSK-3 beta gene and schizophrenia in the Chinese population.

The GSK-3 beta gene encodes a protein kinase which is abundant in the brain, and its product is involved in signal transduction cascades of neuronal cell development, energy metabolism and body pattern formation. Previous studies have suggested that GSK-3 beta might act as a potential candidate locus for schizophrenia susceptibility. We genotyped six SNPs within the gene and conducted a case-control study involving 329 schizophrenic patients and 288 healthy subjects in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in the subtype of paranoid schizophrenic patients as well as schizophrenic subjects in general. Our results fail to replicate the association of the GSK-3 beta gene with susceptibility to schizophrenia in the Chinese population.

An association study between the genetic polymorphisms within TBX1 and schizophrenia in the Chinese population.

The strong association between common psychiatric disorders and the 22q11.2 microdeletion suggests that haploinsufficiency of one or more genes in the region confers susceptibility to these disorders. Recent mouse studies have shown that the T-box 1 (TBX1) gene in the 22q11.2 region can cause prepulse inhibition (PPI) impairment in the heterozygous state. A study has also shown that phenotypic features of 22q11 deletion syndrome (22q11DS) were segregated with an inactivating mutation of TBX1 in one family, suggesting that the TBX1 gene plays a role in the pathogenesis of some psychiatric disorders. We performed an association study between three single nucleotide polymorphisms (SNPs) in the TBX1 gene and schizophrenia. However, we found no significant difference in the genotype or allele distributions between the 328 schizophrenics and 288 controls for any of the polymorphisms, nor was there any haplotype association. Our data suggest that the genetic polymorphisms within TBX1 do not confer an increased susceptibility to schizophrenia in the Chinese population.

The PIP5K2A gene and schizophrenia in the Chinese population--a case-control study.

Results from a number of molecular and pharmacological studies suggest that the phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A) gene may be involved in the development of schizophrenia. A recent family-based transmission disequilibrium test in the German and Israeli populations found that four single nucleotide polymorphisms, rs1417374, rs10828317, rs746203 and rs8341 in this gene or nearby intergenic regions are significantly associated with schizophrenia. The objective of our study was to investigate whether these four SNPs are also associated with schizophrenia in the Chinese population. Our study found that SNP rs8341 (p=0.0045, Odds Ratio=1.415, 95%CI=1.113-1.799 for the minor allele) and a haplotype (p=0.0039, Odds Ratio=1.440, 95%CI=1.123-1.845) are significantly associated with schizophrenia. Our results confirm that the PIP5K2A gene merits further study as a susceptible gene for schizophrenia.