-
1.
How we manage Bing-Neel syndrome.
Castillo, JJ, Treon, SP
British journal of haematology. 2019;(3):277-285
-
-
Free full text
-
Abstract
Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.
-
2.
Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.
Cho, BC, Obermannova, R, Bearz, A, McKeage, M, Kim, DW, Batra, U, Borra, G, Orlov, S, Kim, SW, Geater, SL, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019;(7):1255-1265
-
-
Free full text
-
Abstract
INTRODUCTION In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. METHODS Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). CONCLUSION Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
-
3.
Transcriptomic analysis of Chlorimuron-ethyl degrading bacterial strain Klebsiella jilinsis 2N3.
Zhang, C, Hao, Q, Zhang, S, Zhang, Z, Zhang, X, Sun, P, Pan, H, Zhang, H, Sun, F
Ecotoxicology and environmental safety. 2019;:109581
Abstract
Chlorimuron-ethyl is a sulfonylurea herbicide with a long residual period in the field and is toxic to rotational crops. Klebsiella jilinsis 2N3 is a gram-negative bacterium that can rapidly degrade Chlorimuron-ethyl. In this study, the gene expression changes in strain 2N3 during degradation of Chlorimuron-ethyl was analyzed by RNA-Seq. Results showed that 386 genes were up-regulated and 453 genes were down-regulated. KEGG pathway enrichment analysis revealed the highest enrichment ratio in the pathway of sulfur metabolism. On the basis of the functional annotation and gene expression, we predicted that carboxylesterase, monooxygenase, glycosyltransferase, and cytochrome P450 were involved in the metabolism of Chlorimuron-ethyl biodegradation. Results of qRT-PCR showed that the relative mRNA expression levels of these genes were higher in treatment group than those in control group. The cytochrome P450 encoded by Kj-CysJ and the alkanesulfonate monooxygenase encoded by Kj-SsuD were predicted and further experimentally confirmed by gene knockout as the key enzymes in the biodegradation process. Cultured in basal medium containing Chlorimuron-ethyl (5 mg L-1) in 36 h, the strains of ΔKj-CysJ, ΔKj-SsuD, and WT reached the highest OD600 values of 0.308, 0.873, and 1.085, and the highest degradation rates of Chlorimuron-ethyl of 11.83%, 96.21%, and 95.62%, respectively.
-
4.
Impact of elagolix treatment on fatigue experienced by women with moderate to severe pain associated with endometriosis.
Surrey, ES, Soliman, AM, Agarwal, SK, Snabes, MC, Diamond, MP
Fertility and sterility. 2019;(2):298-304.e3
Abstract
OBJECTIVE To evaluate the efficacy of elagolix, an oral GnRH antagonist, for the reduction of fatigue in women with moderate or severe endometriosis-associated pain. DESIGN Randomized, double-blind, multicenter, placebo-controlled phase III trial. SETTING Clinics. PATIENT(S): A total of 860 women treated with elagolix or placebo. INTERVENTION(S): Women received either elagolix at 150 mg daily (QD) orally, elagolix at 200 mg twice daily (BID) orally, or placebo. MAIN OUTCOME MEASURE(S): Change from baseline to month 1, 3, and 6 visits, in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 6a questionnaire T-scores. RESULTS(S): At baseline, 54%-74% of women with moderate to severe pain associated with endometriosis reported having fatigue-related issues "quite a bit" or "very much," depending on the question asked. Fatigue extent was reduced to 29%-43% and 14%-29% for women treated with elagolix at 150 mg QD and 200 mg BID, respectively, at 6 months, compared with 35%-50% with placebo. The resultant decrease in fatigue T-scores was significant after elagolix treatment compared with placebo at 6 months, with changes of -2.21 and -5.90 with elagolix at 150 mg QD and 200 mg BID, respectively. Significant reduction in fatigue scores were observed among patients reporting clinically meaningful response "reduction" in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia (-7.31, -6.62, and -4.31, respectively) compared with nonresponders. CONCLUSION(S): In women with moderate to severe endometriosis related pain, elagolix significantly reduces fatigue levels.
-
5.
Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.
Frölich, L, Wunderlich, G, Thamer, C, Roehrle, M, Garcia, M, Dubois, B
Alzheimer's research & therapy. 2019;(1):18
Abstract
BACKGROUND There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2). METHODS Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints. RESULTS Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated. CONCLUSIONS Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated. TRIAL REGISTRATION ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.
-
6.
A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer.
Bang, YJ, Kang, YK, Ng, M, Chung, HC, Wainberg, ZA, Gendreau, S, Chan, WY, Xu, N, Maslyar, D, Meng, R, et al
European journal of cancer (Oxford, England : 1990). 2019;:17-24
Abstract
BACKGROUND Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC. PATIENTS AND METHODS In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments. RESULTS In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively. CONCLUSIONS Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed. TRIAL REGISTRATION ClinicalTrials.gov (NCT01896531).
-
7.
The journey from gene knockout to clinical medicine: telotristat and sotagliflozin.
Rendell, MS
Drug design, development and therapy. 2019;:817-824
Abstract
Gene knockout has been a powerful technique to evaluate the physiologic role of selected gene products. Lexicon pioneered high-throughput gene knockout technology and went further in designing agents to inhibit products of gene expression. Two agents have entered late-stage development. Telotristat is an inhibitor of tryptophan hydroxylase (TPH), preventing the production of serotonin. Although this agent blocks the two isoforms of TPH, it does not cross the blood-brain barrier, thus avoiding central neurologic manifestations. It inhibits the peripheral production of serotonin, and in particular prevents serotonin action in the intestines, resulting in decreased peristaltic action. Lexicon successfully developed telotristat to treat carcinoid syndrome not responding adequately to somatostatin inhibitors. Sotagliflozin development proceeded from the observation that dual inhibition of SGLT2 in the kidneys and SGLT1 in the intestines resulted in increased renal glucose excretion, reduced early-phase glucose absorption, as well as increased blood levels of GLP-1 and PYY. Initial development efforts focused on type 1 diabetes and have shown reduced postprandial glucose levels, less tendency to hypoglycemia, and lower HbA1c. Several other SGLT2 inhibitors have been associated with increased frequency of diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin-treated individuals experienced DKA at a higher rate than placebo-treated patients. The sotagliflozin development program has now been extended to trials on type 2 diabetes. Long-term clinical trials will determine the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.
-
8.
Pazopanib with low fat meal (PALM) in advanced renal cell carcinoma.
Reimers, MA, Shango, MM, Daignault-Newton, S, Dedinsky, R, Karsies, D, Kraft, S, Riddle, L, Felton, JA, Wen, B, Gersch, C, et al
Investigational new drugs. 2019;(2):323-330
Abstract
Background Pazopanib is approved for metastatic renal cell carcinoma (RCC). We assessed the safety and efficacy of pazopanib with a low fat meal (LFM): <400 cal and < 20% fat or 10 g per meal. Methods A single arm study of pazopanib with a LFM in 16 adult patients with metastatic RCC with a clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤ 2, and ≤ 3 prior therapies. Pazopanib at 400 mg daily given with LFM for 12 weeks. Incremental dose increases up to 800 mg, or irreversible decreases to 200 mg, allowed every 2 weeks. Primary study endpoint was safety; adverse events (AE) measured per CTCAE version 4.0. Secondary endpoints of RECIST 1.1 response with assessment as 12 weeks; pharmacokinetic (PK) analysis at nine time points, and CYP3A4 polymorphism evaluation. Results Pazopanib with a LFM was well tolerated; 13 of 16 subjects completed all 12 weeks. Three patients withdrew due to adverse events (AEs), with five occurrences of grade 3 AEs. Conclusions Pazopanib with a LFM has acceptable safety and comparable efficacy to fasting administration. Total median pazopanib dose per subject for the study duration was 63.5% of maximum possible conventional dose. A larger study is warranted. Clinical Trial Registration Number: NCT02729194.
-
9.
Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain.
Barra, F, Scala, C, Ferrero, S
Drugs of today (Barcelona, Spain : 1998). 2019;(4):237-246
Abstract
First-line medical therapies for treating pain associated with endometriosis mainly consist in combined oral contraceptives and progestins. However, some women, having persistence of symptoms, may require further therapeutic options. Among these, gonadotropin-releasing hormone (GnRH) agonists (GnRH-as) have been widely employed in the last 30 years, despite being characterized by an unfavorable safety profile. Currently, new alternative investigational options are being investigated to treat this benign chronic disease. GnRH antagonists (GnRH-ants) are innovative hormonal drugs that do not induce flare-up effects and present also a limited onset of hypoestrogenic symptoms; in fact, their pharmacological mechanism of action, which consists in pure antagonistic activity, differs from that of traditional GnRH-as. In July 2018, the U.S. Food and Drug Administration (FDA) approved elagolix sodium for the management of moderate to severe pain associated with endometriosis, after the drug showed promising efficacy and safety results in previous phase III trials. This monograph aims to provide a complete overview of the pharmacokinetics, clinical efficacy and safety of this GnRH-ant for treat¬ing patients with endometriosis.
-
10.
Concomitant targeting of Hedgehog signaling and MCL-1 synergistically induces cell death in Hedgehog-driven cancer cells.
Meister, MT, Boedicker, C, Linder, B, Kögel, D, Klingebiel, T, Fulda, S
Cancer letters. 2019;:1-11
Abstract
In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the glioma-associated oncogene homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family member MCL-1 by A-1210477 synergistically induces cell death in HH-driven cancers, i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB) cells. Combined genetic and pharmacological inhibition emphasized that co-treatment of GANT61 and A-1210477 indeed relies on inhibition of GLI1 (by GANT61) and MCL-1 (by A-1210477). Mechanistic studies revealed that A-1210477 triggers the release of BIM from MCL-1 and its shuttling to BCL-xL and BCL-2. Indeed, BIM proved to be required for GANT61/A-1210477-induced cell death, as genetic silencing of BIM using siRNA significantly rescues cell death upon GANT61/A-1210477 co-treatment. Similarly, genetic silencing of NOXA results in a significant reduction of GANT61/A-1210477-mediated cell death. Also, overexpression of MCL-1 or BCL-2 significantly protects RMS cells from GANT61/A-1210477-triggered cell death. Addition of the pan-caspase inhibitor zVAD.fmk significantly decreases GANT61/A-1210477-stimulated cell demise, indicating apoptotic cell death. In conclusion, GANT61 and A-1210477 synergize to engage mitochondrial apoptosis. These findings provide the rationale for further evaluation of dual inhibition of HH signaling and MCL-1 in HH-driven cancers.