ObjectiveFamily studies and twin studies demonstrate that lower urinary tract symptoms and pelvic organ prolapse are heritable. This review aimed to identify genetic polymorphisms tested for an association with lower urinary tract symptoms or prolapse, and to assess the strength, consistency, and risk of bias among reported associations.Study DesignPubMed and HuGE Navigator were searched up to May 1, 2014, using a combination of genetic and phenotype key words, including “nocturia,” “incontinence,” “overactive bladder,” “prolapse,” and “enuresis.” Major genetics, urology, and gynecology conference abstracts were searched from 2005 through 2013. We screened 889 abstracts, and retrieved 78 full texts. In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes. Fixed and random effects metaanalyses were conducted using codominant models of inheritance. We assessed the credibility of pooled associations using the interim Venice criteria.ResultsIn pooled analysis, the rs4994 polymorphism of the ADRB3 gene was associated with overactive bladder (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7–3.6; n = 419). The rs1800012 polymorphism of the COL1A1 gene was associated with prolapse (OR, 1.3; 95% CI, 1.0–1.7; n = 838) and stress urinary incontinence (OR, 2.1; 95% CI, 1.4–3.2; n = 190). Other metaanalyses, including those for polymorphisms of COL3A1,LAMC1,MMP1,MMP3, and MMP9 did not show significant effects. Many studies were at high risk of bias from genotyping error or population stratification.ConclusionThese metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and variation of COL1A1 with prolapse. Clinical testing for any of these polymorphisms cannot be recommended based on current evidence.

Purpose: No standard treatment exists for platinum-refractory, recurrent/metastatic nasopharyngeal cancer (NPC). This phase II study (NCT02605967) evaluated progression-free survival (PFS) of spartalizumab, an antiprogrammed cell death protein-1 (PD-1) monoclonal antibody, versus chemotherapy, in NPC. Patients and Methods: Patients with nonkeratinizing recurrent/metastatic NPC who progressed on/after platinum-based chemotherapy were enrolled. Spartalizumab was dosed 400 mg once every 4 weeks, and chemotherapy was received per investigator's choice. Results: Patients were randomized to receive either spartalizumab (82 patients) or chemotherapy (40 patients). The most common spartalizumab treatment-related adverse events were fatigue (10.3%) and pruritus (9.3%). Median PFS in the spartalizumab arm was 1.9 months versus 6.6 months in the chemotherapy arm (P = 0.915). The overall response rate in the spartalizumab arm was 17.1% versus 35.0% in the chemotherapy arm. Median duration of response was 10.2 versus 5.7 months in the spartalizumab versus chemotherapy arms, respectively. Median overall survival was 25.2 and 15.5 months in the spartalizumab and chemotherapy arms, respectively. Tumor RNA sequencing showed a correlation between response to spartalizumab and IFNγ, LAG-3, and TIM-3 gene expression. Conclusions: Spartalizumab demonstrated a safety profile consistent with other anti–PD-1 antibodies. The primary endpoint of median PFS was not met; however, median overall survival and median duration of response were longer with spartalizumab compared with chemotherapy.

ContextAlthough family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS.ObjectiveTo systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations.Evidence acquisitionA systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies.Evidence synthesisWe identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49–0.83) with moderate heterogeneity (I2 = 27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes.ConclusionsFew putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses.Patient summaryCombining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.

Background Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. Methods This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100–1000 mg once daily (QD; n = 38) and 200–400 mg twice daily (BID; n = 30). Results First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81–15.28) for QD and 4.6 months (range: 0.33–58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99–41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. Conclusion These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

We assessed the safety, tolerability, PK, PD and efficacy of the PKC inhibitor LXS196 in patients with metastatic uveal melanoma (MUM). As of 30 Sep 2018, 68 patients received LXS196 at doses ranging from 100 to 1000 mg once daily (QD; 38 patients) and 200 to 400 mg twice daily (BID; 30 patients). All patients in the QD regimen had discontinued treatment due to progressive disease. Five patients in the BID regimen remain on study. LDH was > ULN in 38 patients (55.9%), and 60 patients (88.2%) had liver involvement. Dose limiting toxicities (DLTs) in cycle 1 were reported in 7 of 38 patients on the QD schedule and in 2 of 17 patients on the BID schedule who were evaluable for the dose determination. The most common DLT was hypotension, manageable with LXS196 interruption and dose reduction. The most frequent AEs (all grades, in ≥ 20% of patients) suspected to be related to LXS196 in patients across both dosing schedules (n = 68) included nausea (66.2%), diarrhea (45.6%), vomiting (30.9%), hypotension (22.1%), increased ALT (22.1%), and fatigue (20.6%). The majority of gastrointestinal and constitutional AEs were of low grade (grade 1 or 2). Grade 3 or 4 AEs suspected to be related to LXS196 were reported in 17 patients (25.0%), the most frequent being hypotension (8.8%). BID dosing was better tolerated than QD dosing with fewer grade 3 or 4 AEs reported (20% with BID vs 28.9% with QD dosing) and fewer drug-related SAEs (6.7% with BID vs 15.8% with QD). In this study, MTDs were determined at 500mg QD and 400 mg BID and the RDE was declared at 300mg BID. The most common AEs suspected to be related to LXS196 (any grade, in >15% of patients) at the RDE (n = 18) included nausea (77.8%), diarrhea (61.1%), vomiting (38.9%), increased ALT (27.8%), asthenia, dry skin and rash (22.2% each), hypotension, fatigue, increased AST, dermatitis acneiform, and peripheral edema (16.7% each). Clinical PK demonstrates rapid absorption of LXS196 with Tmax of ~1 hr post dose and consistent terminal T1/2 across different doses (~ 11 hr). Exposure at doses above 300 mg QD and 200 mg BID are in the efficacious range from preclinical projections. LXS196 results in reduction of pMARCKS and pPKC delta, evident of target engagement in on-treatment tumor biopsies. Overall, amongst 66 evaluable patients, per RECIST v1.1, 6 had a PR (2 in QD; 4 in BID) and 45 had SD as their best response. At the RDE, of 17 evaluable patients, 2 had confirmed PRs and 12 had SD as their best response (including 2 patients with > 30% tumor reduction/unconfirmed PRs). The median duration of exposure is 3.71 months (range; 1.81 - 15.28 months) and 4.6 months (range; 0.33 - 20.01 months) for patients in the QD and BID regimens, respectively. Of the 5 ongoing patients in the BID regimen, 2 maintain a PR (200 and 300 mg BID) and 3 have SD (all at 300 mg BID). All 5 patients have remained on study for > 13 months. These results suggest encouraging clinical activity of LXS196 as a single agent with manageable toxicity profile in patients with MUM. Citation Format: Ellen Kapiteijn, Matteo Carlino, Valentina Boni, Delphine Loirat, Frank Speetjens, John Park, Emiliano Calvo, Richard Carvajal, Marta Nyakas, Juan Gonzalez-Maffe, Xu Zhu, Ramu Thiruvamoor, Padmaja Yerramilli-Rao, Sophie Piperno-Neumann. A Phase I trial of LXS196, a novel PKC inhibitor for metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT068.