Association Between Vonoprazan and the Risk of Gastric Cancer After Helicobacter pylori Eradication.

BACKGROUND & AIMS: Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk. METHODS: Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study. RESULTS: Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users. CONCLUSIONS: The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.

Combination therapy with tamsulosin and traditional herbal medicine for lower urinary tract symptoms due to benign prostatic hyperplasia: A double-blinded, randomized, pilot clinical trial.

OBJECTIVES: To evaluate the efficacy and safety of tamsulosin and Hachimijiogan or Ryutanshakanto in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. METHODS: A prospective, randomized, double-blind method was used to determine the efficacy and safety of the combination or placebo at baseline and 4, 8, and 12 weeks of study. The International Prostate Symptom Score, quality of life index, complete voiding diary, and National Institutes of Health-Chronic Prostatitis Symptom Index were studied. Uroflowmetery and postvoid residual urine volume were measured and compared. Laboratory tests including prostate-specific antigen were performed. RESULTS: In all groups, International Prostate Symptom Score and quality of life showed improvement, but no significant differences were shown among the groups. Prostate volume increased after treatment, and uroflowmetric parameters showed improvements after treatment without significance among the three groups. The total score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant improvement in all groups, without significant differences among the groups. Only the pain sub-score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant decrease in the tamsulosin with Ryutanshakanto group compared to the control group. A total of 11 adverse reactions occurred, but they were mild and not related to the study drugs. CONCLUSION: Ryutanshakanto can provide pain relief in patients with chronic prostatitis and chronic pelvic pain syndrome. If more research is conducted, Hachimijiogan and Ryutanshakanto may be applied as add-on treatments in patients with storage symptoms with alpha-blocker monotherapy.

Dangerous interaction of bitter melon (Momordica charantia) with pazopanib: A case of acute pancreatitis.

INTRODUCTION: Acute pancreatitis associated with Pazopanib has been reported in the literature. Bitter Melon (Momordica Charantia) is traditionally used as a folk medicine in many regions. In this report, we describe a 65-year-old patient with a diagnosis of renal cell carcinoma, admitted to the hospital with symptoms of acute pancreatitis at the 8th year of pazopanib treatment. CASE REPORT: The patient diagnosed with renal cell carcinoma was admitted to the hospital with the complaint of abdominal pain, nausea, and vomiting in the 8th year of Pazopanib treatment. It was noticed from the patient's history that he had received Bitter Melon extract for 4 days prior to the beginning of his complaints (100-150 ml/day). Levels of serum amylase and lipase were measured as 9163 U/L and 14,206 U/L, respectively. MANAGEMENT & OUTCOME: Pazopanib drug was held. The patient was treated for acute pancreatitis. Pazopanib treatment was started again after the clinical condition of the patient had improved and levels of serum amylase and lipase had returned to normal levels. Levels of serum amylase and lipase did not increase again after re-administration of pazopanib treatment. DISCUSSION: It is thought that Bitter Melon extract and pazopanib interaction might have led to acute pancreatitis. To the best of our knowledge, this case is the first to highlight the interaction of Bitter Melon extract with pazopanib. The Drug Interaction Probability Scale indicates that there is a probable association between bitter melon and acute pancreatitis.

Real-World Efficacy and Safety of Multi-Tyrosine Kinase Inhibitors in Radioiodine Refractory Thyroid Cancer.

Background: The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. Patients and Methods: We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Results: Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib (n = 33), lenvatinib (n = 53), and pazopanib (n = 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Conclusions: Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.

Therapeutic Effects of Add-On Tenapanor for Hemodialysis Patients with Refractory Hyperphosphatemia.

INTRODUCTION: Phosphate binders are used to treat hyperphosphatemia. Some patients have inappropriately controlled serum phosphorus levels, which may occur for many reasons, including a high pill burden and adverse events (AEs). Tenapanor selectively inhibits the passive paracellular transfer of phosphate in the gastrointestinal tract, thereby reducing serum phosphorus levels. This novel mechanism of action may contribute to improved phosphate management. The efficacy and safety of tenapanor have not been evaluated in Japanese patients with high serum phosphorus levels despite treatment with phosphate binders. This study aimed to assess the efficacy and safety of add-on tenapanor therapy for reducing serum phosphorus levels in this population. METHODS: This multicenter, double-blind, randomized, placebo-controlled trial enrolled patients with refractory hyperphosphatemia undergoing hemodialysis. Patients were randomly assigned in a 1:1 ratio to receive tenapanor or placebo as an add-on to their phosphate binder regimen for 6 weeks. Change in serum phosphorus levels at week 6 (day 43) compared with the baseline value (day 1, week 0) (primary endpoint), achievement of target serum phosphorus levels (serum phosphorus level ≤6.0 or ≤5.5 mg/dL), and safety, based on all AEs and drug-related AEs, were among the outcomes evaluated. RESULTS: In total, 24 patients were randomly assigned to the placebo group and 23 to the tenapanor group. The mean serum phosphorus level decreased from 7.01 mg/dL on day 1 to 6.69 mg/dL on day 43 in the placebo group and from 6.77 mg/dL on day 1 to 4.67 mg/dL on day 43 in the tenapanor group. In the placebo and tenapanor groups (modified intent-to-treat population), the mean (standard deviation) change in the serum phosphorus level at day 43 (last observation carried forward [LOCF]) was 0.08 (1.52) mg/dL and -1.99 (1.24) mg/dL, respectively, with a between-group difference of -2.07 (95% confidence interval: -2.89, -1.26; p < 0.001). The target achievement rate (serum phosphorus level ≤6.0 mg/dL at week 6 [LOCF]) was 37.5 and 87.0% in the placebo and tenapanor groups, respectively. Diarrhea was the most common drug-related AE, and it occurred in 8.3 and 65.2% of patients in the placebo and tenapanor groups, respectively. No specific AEs were observed with add-on tenapanor or with phosphate binders. DISCUSSION/CONCLUSION: Therapy with existing phosphate binders and add-on tenapanor resulted in a significant decrease in serum phosphorus level compared with the placebo group in patients with refractory hyperphosphatemia despite treatment with phosphate binders. No new safety signals were raised, and add-on tenapanor was generally well tolerated.

Outcomes and complications of naftopidil versus tamsulosin for elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to assess the outcomes and complications of naftopidil in treating elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and compared them with those administered with tamsulosin. A literature review was performed to identify the available randomised controlled trials concerning the comparison between naftopidil and tamsulosin for men with LUTS/BPH. We searched the following databases: the Cochrane Library Database, PubMed, Embase and Web of Science. Eleven publications involving 1,114 men (557 in the naf group and 557 in the tam group) were pooled in our analysis. We found no significant differences in the total IPSS, IPSS storage score, IPSS voiding score, quality of life index, peak urinary flow rate, average flow rate and post-void residual volumes. We assessed cardiovascular and sexual adverse events, acute urinary retention, surgical intervention, withdrawals due to any reason and withdrawals due to adverse events. The incidence of adverse events was similar among patients in naf and tam groups. In conclusion, naftopidil shared comparable efficacy and similar incidence of adverse events with tamsulosin and appears to be a promising agent for and alternative to tam. However, more prospective trials with high quality and long-term treatment duration are needed to verify this observation.

A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY).

BACKGROUND: Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis. METHODS: This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4. RESULTS: Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, P<0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively. CONCLUSIONS: A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: AMPLIFY, NCT03824587.

Targeted therapy for metastatic renal cell carcinoma.

BACKGROUND: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs.

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.

Real-world Clinical Outcomes of Pazopanib Immediately After Discontinuation of Immunotherapy for Advanced Renal Cell Carcinoma.

INTRODUCTION: In the first-line (1L) setting, pazopanib (PAZ) has been recommended by the National Comprehensive Cancer Network for the treatment of advanced renal cell carcinoma (aRCC). In 2018, immuno-oncology (IO) therapy became a commonly used 1L treatment option for aRCC. We report the real-world clinical outcomes of PAZ after IO therapy for patients with aRCC. MATERIALS AND METHODS: We performed a longitudinal, retrospective medical record review study. The included patients were aged ≥ 18 years, had initiated second-line and/or beyond PAZ after IO therapy for clear cell aRCC on or before October 2017, and had complete medical records available from the diagnosis of aRCC to the discontinuation of PAZ, death, or the medical record extraction date (May 2018), whichever occurred first. The primary outcome variable was the PAZ duration of therapy. The secondary outcomes were progression-free survival and overall survival since PAZ initiation, the reasons for PAZ discontinuation, and the occurrence of adverse events (AEs). RESULTS: A total of 258 eligible patients had initiated IO therapies before PAZ as follows: nivolumab (68%), nivolumab plus ipilimumab (14%), pembrolizumab (12%), and ipilimumab (3%). Overall, the median PAZ duration of therapy was 13.4 months (95% confidence interval [CI], 10.1-16.0 months). The median progression-free survival with PAZ after IO therapy was 13.5 months (95% CI, 11.8 months to not reached). The estimated overall survival rate of PAZ after IO therapy at 6 and 12 months was 93% and 89%, respectively. A total of 109 patients (42%) had reported an AE. The most frequently reported AEs were fatigue (29%) and diarrhea (14%). No additional safety signal of hepatotoxicity was observed (increased aspartate aminotransferase, 5%; increased alanine transaminase, 6%). CONCLUSIONS: In the present real-world study, second-line and/or beyond PAZ after previous IO therapy was well-tolerated and effective for patients with aRCC.

Comparing drug interaction frequencies of various hepatitis C treatment regimens among monoinfected patients.

INTRODUCTION AND OBJECTIVES: Four regimens are recommended for treating hepatitis C (HCV) genotype 1 infection. Study aims were to (1) compare frequencies of contraindicated drug interactions (XDDIs) when each HCV regimen is added to medication profiles of HCV-monoinfected patients, (2) quantify the proportion of patients with XDDIs to all four regimens and (3) determine covariates independently associated with having a XDDI to all four regimens. MATERIALS AND METHODS: A cross-sectional study was performed within Upstate New York Veterans Healthcare Administration. INCLUSION CRITERIA: (1) age ≥18 years, (2) HCV monoinfection and (3) available medication list. Data extracted were: demographics, comorbidities, and medication list. Primary outcome was XDDIs involving patient's home medications and each HCV regimen. University of Liverpool drug interaction website was used to define XDDIs. Two-way comparisons of regimens were performed using McNemar's test where p<0.0083 was considered statistically significant. Multivariate regression analyses were performed to determine predictors. RESULTS: Of the 4047 subjects, mean±standard deviation age was 59.8±7.6. Median (interquartile range) number of medications used was 7 [4-11]. Frequencies of XDDIs after the addition of each regimen ranged from 2.8% to 17.8% and were mostly statistically different from one another. There were 95 (2.3%) patients with XDDIs to all four regimens. Predictors of having XDDIs to all four regimens were ≥6 medications and HCV infection ≥10 years. CONCLUSION: The frequencies of XDDIs varied between HCV regimens. Number of medications and duration of HCV infection were predictors of having XDDIs to all four regimens.

Oral small molecules for the treatment of atopic dermatitis: a systematic review.

Introduction: Atopic dermatitis (AD) is a chronic, inflammatory skin disease. Conventional treatments include topical emollients, corticosteroids, calcineurin inhibitors, phototherapy, and systemic immunomodulatory agents, however, these medications have limitations in the treatment of moderate to severe AD. Current literature demonstrates that oral small molecules may be an effective modality to treat AD. Method: Using PubMed/MEDLINE, Embase, Cochrane Skin databases and clinicaltrials.gov a search with terms 'atopic dermatitis or atopic eczema' and 'name of the oral small molecule' was conducted resulting in 1197 articles. Inclusion criteria were studies involving human subjects treated with oral small molecule medication for AD and written in English. Randomized clinical trials, open-label prospective trials, and case reports/series were reviewed. Results: Seven articles, with a total of 250 patients, were included for review. Oral small molecules studied include: apremilast, baricitinib, JNJ-39758979, and tofacitinib. Small molecules demonstrate improvement in AD disease scores, patient-reported outcomes, and quality of life. Conclusion: Preliminary results demonstrate that oral small molecules are an effective treatment option in AD with minimal side effects. Additional randomized studies with larger sample sizes are needed to determine the efficacy and long-term side effects of these novel therapies.

Venetoclax for the treatment of multiple myeloma.

Introduction: Treatment of multiple myeloma (MM) in the relapsed setting remains challenging, despite recent impressive advances in the management of these patients. Venetoclax (ABT-199) is a BCL-2 inhibitor recently approved by the US food and drug administration for treatment of chronic lymphocytic leukemia but the drug has shown activity in a number of hematological malignancies. Venetoclax has broadened the treatment options for patients with relapsed or refractory MM. Approximately, 20% of myeloma patients will exhibit t (11;14) associated with high BCL-2 expression making venetoclax an attractive therapeutic option. The efficacy of venetoclax is not uniquely restricted to this population. Areas covered: This review will summarize the mechanism of action, toxicity profile, and published data on venetoclax use in MM, moving the field toward personalized medicine in the treatment of myeloma. Expert commentary: Numerous phase 1/2 clinical trials are evaluating the efficacy and safety of venetoclax monotherapy and in combinations in the relapse setting. These trials show better outcomes in the subgroup of patients harboring t(11;14).

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials. DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI -0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events. AUTHORS' CONCLUSIONS: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.

Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients.

PURPOSE: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). RESULTS: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). CONCLUSIONS: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia.

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

Twelve weeks of ombitasvir/paritaprevir/r and dasabuvir without ribavirin is effective and safe in the treatment of patients with HCV genotype 1b infection and compensated cirrhosis: results from a real-world cohort study.

OBJECTIVE: To explore the effectiveness and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV) for 12 weeks without ribavirin in adults with chronic HCV genotype 1b infection and compensated cirrhosis. METHODS: Observational study of a prospective cohort of adult patients with HCV genotype 1b infection and compensated cirrhosis who received 12 weeks of OBV/PTV/r and DSV without ribavirin. Effectiveness was assessed by recording the percentage of patients achieving sustained virological response at week 12 post-treatment (SVR12). Safety outcomes were based on the incidence of adverse events. RESULTS: Seventy-eight patients were included. The SVR12 rate was 96.1% (95%CI 89.2-99.2). Adverse events were recorded in 78.0% of patients. Of these, 97.7% were grade 1/2. One patient discontinued treatment prematurely owing to adverse events. Eighty-six interactions were detected in 43 patients (55.1%). Overall, 81.4% of interactions required close monitoring, alteration of drug dosage, or timing of administration. In 7.0% of cases, the interactions arose from contraindications that required the suspension of the concomitant drug. In 11.6% of cases, medicinal plants or foods were withdrawn. CONCLUSIONS: The simplified regimen of OBV/PTV/r+DSV administered for 12 weeks is effective and safe in patients with chronic HCV genotype 1b infection and compensated cirrhosis. No adverse reactions related to drug-drug interactions were recorded.

Impact of Allergy and Resistance on Antibiotic Selection for Recurrent Urinary Tract Infections in Older Women.

OBJECTIVES: To review the impact of antibiotic allergy and resistance in older women with recurrent urinary tract infections (RUTIs) as determinants for a suitable oral antibiotic treatment choice. METHODS: A prospectively maintained database of women 65 years old and older with documented RUTIs (≥3 UTI/y) and trigonitis on cystoscopy was reviewed. Demographic data, known drug allergies, renal function, antibiotic susceptibility of most recent urine culture, allergy, or resistance to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and nitrofurantoin were obtained. RESULTS: From 2006 to 2014, 86 women with RUTIs met study criteria. Mean age was 77.9 ± 7.8, with 94% being Caucasian. An estimated glomerular filtration rate >30 mL/min was noted in 94%. The percentage of women allergic, resistant, or both allergic and resistant to TMP-SMX was 33%, 29%, and 15%, to fluoroquinolones was 14%, 34%, and 8.1%, or nitrofurantoin was 16%, 14%, and 5%, respectively. Twenty-eight percent (24 of 86) of women who were allergic and/or resistant to TMP-SMX and fluoroquinolones were sensitive to nitrofurantoin. Twenty percent (17 of 86) were allergic and/or resistant to all 3 antibiotics. Women who were allergic or resistant to TMP-SMX had a significantly higher number of other antibiotic resistances compared with women sensitive to TMP-SMX (4.9 ± 3.6 vs 2.1 ± 2.3; P < .0001). Similarly, women with fluoroquinolone allergy or resistance had significantly more antibiotic resistances than those who were fluoroquinolone sensitive (5.8 ± 3.5 vs 2.3 ± 2.5; P < .0001). CONCLUSION: Because of allergy and/or antibiotic resistance, several first-line antibiotics are not available for many older women with RUTIs. In nearly a third of women, nitrofurantoin was the only viable alternative.

Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents.

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158-64. ©2017 AACR.