Significant Improvement In Efficacy Research Articles

Early in-stent restenosis after revascularization in patients with ST-elevation myocardial infarction

Background and aim: Obstructive coronary disease is one of the most important causes of death worldwide. Percutaneous coronary intervention is one of the most important treatments of this pathology. Using of coronary artery stents represented a major advance in interventional cardiology. While bare metal stents (BMS) set the reference point for improved safety over balloon-angioplasty, first-generation drug-eluting stents demonstrated significant improvements in efficacy, but not necessarily safety, and further technologic developments have focused on optimizing both. Methods: We studied 228 patients with STEMI in the last 6 months, divided in 2 groups – in the first group are 122 patients (53.5%) who developed in stent restenosis and the second group has 106 patients had no signs of restenosis (46.5%). The mean time of performing the angiographic reevaluation was 111 days for the first group and 154 days for the second group. The clinical signs that indicate the need of coronary reevaluation was stable angina (116, 50.87%), acute coronary syndrome (58, 25.4%) and asymptomatic patients (64, 28.9%). The cardiovascular risk factors correlate with high risk of restenosis was diabetes (24.3% in first group and 12.2% in the second one, p=0.004), active smoking (p=0.010) and metabolic syndrome (p=0.003). The stent’s length >28mm, stent’s diameter ≤ 2.5 mm and chronic occlusion correlate with high risk of in-stent restenosis in BMS. Conclusion: Understanding the importance of risk factors control, will reduce the risk of restenosis, of other cardiovascular event, even sudden death.

Efficacy and safety of etanercept in psoriasis and psoriatic arthritis in the PRESTA study: analysis in patients from Central and Eastern Europe

Background: Data are limited on the effectiveness of anti-TNF and other biologics on psoriatric arthritis (PsA) in Central and Eastern Europe (CEE). The objective of this analysis was to evaluate the efficacy of etanercept (ETN) in PsA patients from CEE.Methods: In PRESTA, patients were randomized to receive ETN 50 mg BIW or 50 mg QW for 12 weeks (double-blind phase) and ETN 50 mg QW for 12 additional weeks (open label). In this analysis, only patients from Czech Republic, Hungary, Poland and Serbia were included. The primary efficacy variable was the proportion of subjects achieving a physician global assessment (PGA) of psoriasis status: “clear” or “almost clear” at week 12.Results: In the 307 patients, 54% BIW/QW compared with 40% (QW/QW) (p = .02), achieved “clear”/”almost clear” for PGA of psoriasis at week 12 increasing, to 68% and 60%, respectively (p = .134) by week 24. Mean improvement from baseline in PASI were 59% versus 49% (p = .005) at week 6 and 87% versus 81% (p < .05) at week 24, for the BIW/QW and QW/QW groups, respectively. ETN was well tolerated in both groups over 24 weeks.Conclusions: Both dose regimens of ETN provided significant improvements in efficacy in PsA treatment and were well tolerated.

Abstract LB-198: Combination of PEGylated recombinant hyaluronidase PH20 (PEGPH20) with live-attenuated, double-deleted (LADD) Listeria enhances tumor infiltrating CD8+ T cell response and antitumor efficacy in mice

Abstract Successful immunotherapy is highly dependent on inducing an efficient CD8+ T cell-mediated antitumor immune response. The trafficking and activation of these effector CD8+ T cells are often inhibited by various immunosuppressive mechanisms in the tumor microenvironment (TME). Hyaluronan (HA), a glycosaminoglycan that accumulates in the TME of many solid tumors, is associated with rapid tumor progression, poor prognosis and increased immunosuppression. We have previously demonstrated in nonclinical models that enzymatic degradation of TME HA by intravenous PEGylated recombinant human hyaluronidase PH20 (PEGPH20) facilitates delivery of chemotherapeutics to tumors and enhances checkpoint inhibitor efficacy. Based on these observations we hypothesized that PEGPH20 may improve current cancer immunotherapies by increasing immune cell infiltration into tumors. To test this hypothesis we used CT26/HAS3 tumors, CT26 murine colon carcinoma cells engineered to over-express hyaluronan synthase-3, and treated them with PEGPH20 in combination with recombinant live-attenuated double-deleted strains of Listeria monocytogenes expressing AH1 (gp70423-431, SPSYVYHQF), the immunodominant CD8+ T cell epitope of CT26 (LADD-AH1). PEGPH20 (1mpk), which results in nearly complete removal of HA at 24hrs, was administered 24hrs prior to LADD-AH1. In this model, LADD-AH1 alone inhibited tumor growth which correlated with an increase in IFNγ+ (p=0.0019) and granzyme B+ CD8+ tumor infiltrating lymphocytes (TILs) (p=0.0006). Tumor-associated macrophages (TAMs) from LADD-AH1 treated tumors were more immunostimulatory with a decrease in MHCIIlow (p=0.0205) and CD206+ TAMs (p=0.0003). Moreover, the combination of PEGPH20 and LADD-AH1 resulted in enhanced anti-tumor activity compared to either PEGPH20 (p=0.0047) or LADD-AH1 alone (p=0.0002). Significant TME changes were observed in the combination treatment with an increase in CD8+ TILs (p=0.0200, of which 88% were granzyme B+), NK cells (p=0.0205) and an increase in CD8:Treg ratio (p=0.0007).These findings were corroborated by immunohistochemical analysis demonstrating an increase in CD3+ T cells with PEGPH20 treatment. Taken together, these data suggest that HA accumulation in tumors may act as a barrier to immune cell access and that reduction of HA by PEGPH20 facilitates increased accumulation of tumor antigen-specific CD8+ effector T cells induced by LADD immunotherapy. Our findings reveal a benefit of PEGPH20 in enhancing tumor infiltration of cytotoxic CD8+ T cells induced by LADD that translate into a significant improvement in efficacy in a murine model of HA-high tumors. Citation Format: Jisook Lee, Meredith Leong, Yujun Huang, Benjamin J. Thompson, Sanna Rosengren, Barbara Blouw, Dirk G. Brockstedt, Curtis B. Thompson. Combination of PEGylated recombinant hyaluronidase PH20 (PEGPH20) with live-attenuated, double-deleted (LADD) Listeria enhances tumor infiltrating CD8+ T cell response and antitumor efficacy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2017-LB-198

Abstract P2-08-10: Time-evolution of the efficacy of first line aromatase inhibitors (AI) in hormone receptor positive (HR+) advanced breast cancer (ABC): A moving target

Abstract INTRODUCTION. Recently presented studies suggest significant improvements in efficacy of endocrine therapy trials addressing HR+ ABC. Overall, progression-free survival (PFS) has consistently improved when we analyze first line endocrine trials. This study aims to evaluate the evolution of the PFS obtained with first line AI monotherapy in patients with HR+ ABC. METHODS. We performed a systematic review of the literature searching for randomized clinical trials of endocrine therapy in HR+ ABC. All trials published since 2000 that involved a first line AI single agent arm were included. Median PFS, year of publication, sample size and population characteristics such as previous endocrine therapy exposure and presence of visceral metastases were extracted from each study and linear correlation used to access the trend of PFS along time. RESULTS. 13 studies were identified accounting for 3,446 postmenopausal patients that received monotherapy with an AI as first line treatment for HR+ ABC. The year of publication/presentation ranged from 2000 to 2016. A total of 14 treatment arms exploring AI monotherapy were identified and analyzed. One study compared exemestane to anastrozole. The other 12 studies compared AIs as single agents to other endocrine strategies. Single agent anastrozole was used in six studies while letrozole was used in five and exemestane in one trial. PFS ranged from 8.2 months in the experimental arm treated with anastrozole in a trial published in 2000 to 15.6 in the control group treated with letrozole monotherapy in a study published in 2015. Linear regression showed a significant improvement in PFS over time (p = 0.034). Table 1: studies characteristicsFIRST AUTHORAIYEAR OF PUBLICATIONPHASENPFS (m)HT NAIVE POP (%)VISCERAL METS (%)BONETTEREANASTROZOLE200033408.28833NABHOLTZANASTROZOLE2000317111.18047MOURIDSENLETROZOLE200134539.48145PARIDAENSEXEMESTANE200831829.99047ROBERTSONANASTROZOLE2010210313.17551MEHTAANASTROZOLE2012334513.56049BERGHANASTROZOLE2012325610.23351MARTINLETROZOLE2012316614.44847JOHNSTONANASTROZOLE2013210414.0NRNRWOLFFLETROZOLE201335559.060NRIWATAEXEMESTANE2013314913.8NR50IWATAANASTROZOLE2013314911.1NR50FINNLETROZOLE201428110.27248DICKLERLETROZOLE2015317015.65274FINNLETROZOLE2016322214.54350 CONCLUSION. A combination of improved medical care and patient selection factors probably explain most of this progressive improvement in PFS obtained with the same therapeutic strategy. While in general, entry criteria have not changed significantly over time, more recent clinical trials addressing first line treatment of HR+ ABC are probably including a different population of patients. Exclusion of HER2 positive tumors and of unknown hormone receptor status patients as well as the percentage of patients without previous adjuvant exposure to endocrine therapy, for example, should be taken into account as they select for a more endocrine sensitive group of patients. This observation has implications in the planning of future studies, the estimation of sample size based in expected efficacy as well as the interpretation and generalization of the results to clinical practice. Citation Format: Debiasi M, Reinert T, Bines J, Barrios C. Time-evolution of the efficacy of first line aromatase inhibitors (AI) in hormone receptor positive (HR+) advanced breast cancer (ABC): A moving target [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-10.

Health-Related Quality of Life (HRQoL) of Blinatumomab Versus Standard of Care (SOC) Chemotherapy in Patients with Relaspsed or Refractory Philadelphia Negative B-Cell Precursor Acute Lymphoblastic Leukemia in a Randomized, Open-Label Phase 3 Study (TOWER)

▪IntroductionBlinatumomab, a bispecific T-cell engager antibody construct, binds specifically to CD19 (B cells) and CD3 (T cells) to facilitate lysis of CD19-positive target B-lineage cells. Based on a single-arm phase 2 study, blinatumomab received approvals in the US (accelerated) and EU (conditional) for the treatment of Philadelphia chromosome-negative (Ph-) relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the phase 3, randomized, open-label TOWER study, blinatumomab immunotherapy significantly improved overall survival (OS) as compared to SOC chemotherapy in adult patients with Ph- r/r BCP-ALL. This abstract reports the impact of blinatumomab compared with SOC on HRQoL using data from TOWER.MethodsPatients (n=405) with r/r BCP-ALL were randomized 2:1 to receive either blinatumomab (n=271) or SOC chemotherapy (n=134). Patients in remission after 2 induction cycles were eligible to continue therapy. A 12-month maintenance phase was allowed for patients who received up to 3 consolidation cycles and continued with a bone marrow response. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) on day 1 (baseline), day 8, day 15, day 29 in each cycle of investigational therapy and safety follow up. The HRQoL analyses included subjects with baseline and ≥1 post-baseline result of any EORTC QLQ-C30 multi-item scale or single-item measure. The change from baseline was summarized by visit and by treatment arm. Time-to-deterioration (TTD) analyses were conducted to determine the treatment effect based on timing from the initiation of treatment to a 10-point deterioration from baseline in HRQoL using EORTC QLQ-C30 or time to an event free survival (EFS) event. EFS was defined as day 1 for subjects who never reached hematologic response, and as time to relapse following response or death for those who reached hematologic response.ResultsOf the 376 patients who received at least 1 dose of study drug, 342 patients had baseline and ≥1 post-baseline HRQoL results. Mean pre-treatment baseline scores were balanced between the blinatumomab (n=247) and SOC (n=95) groups. In general, patients receiving blinatumomab had better post-treatment HRQoL versus SOC across all multi-item scales or single-item measures based on visual inspection (Table1). As early as day 8 of cycle 1 in the SOC arm, mean changes from baseline suggested worsening in HRQoL in almost all subscales/single items, whereas in blinatumomab arm, mean changes from baseline suggested improvement in HRQoL in almost all subscales (Table 1). The hazard ratios (HRs) from the TTD analyses ranged from 0.588 to 0.798 in favor of blinatumomab, with the upper bounds to the 95% CI <1.0 across all subscales and single items except insomnia (Table 2).ConclusionsBlinatumomab delayed the time to clinically meaningful deterioration in HRQoL or EFS event versus SOC across almost all functional domains and symptoms relevant to oncology patients. Moreover, HRQoL benefits with blinatumomab relative to SOC could be observed as early as 8 days after treatment initiation. The benefits in HRQoL, in addition to the significant improvement in efficacy, including OS, and acceptable safety profile of blinatumomab versus SOC, support a favorable benefit-risk profile of blinatumomab in patients with Ph- r/r BCP-ALL. Limitations of the analysis include potential bias due to different cycle lengths between blinatumomab and SOC regimens (6-week cycle for blinatumomab vs variable cycle lengths for SOC) and missing data. [Display omitted] [Display omitted] DisclosuresTopp:Jazz: Consultancy; Roche: Honoraria, Other: travel; Pfizer: Consultancy, Other: Travel; Boehringer: Consultancy, Other: Travel, Research Funding; Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Dombret:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Maertens:Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy. Schuh:Amgen: Membership on an entity’s Board of Directors or advisory committees. Franklin:Amgen: Employment, Other: Stocks. Nie:Amgen: Employment. Cong:Amgen: Employment.

Abstract LB-237: BMS-986012, a fully human anti-fucosyl-GM1 antibody has potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer

Abstract Fucosyl-GM1, is a sphingolipid monosialoganglioside and tumor-associated antigen with a high prevalence in human small cell lung cancer (SCLC), while its expression is minimal in most normal tissue. Here, we report results of our preclinical studies with BMS-986012, a novel fully human, non-fucosylated, IgG1 monoclonal antibody that specifically binds to FucGM1. The binding affinity of BMS-986012 was evaluated in Biacore® and cell-based assays. BMS-986012 binds with a high affinity to FucGM1 and demonstrates no significant binding to other closely related gangliosides. The antibody was engineered in a non-fucosylated IgG1 format, resulting in a 40-fold increased affinity for FcγRIIIa (CD16). In in vitro assays, BMS-986012 binds to FucGM1 on cancer cells and activates antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-mediated phagocytosis (ADCP). The antitumor activity of BMS-986012 was profiled in a panel of SCLC lung cancer models in immunodeficient mice with varying FucGM1 target expression levels qualified using immunohistochemistry. Dose-dependent antitumor activity was observed in a panel of SCLC xenograft models with tumor regressions occurring at BMS-986012 doses greater than 0.3 mg/kg against DMS79 tumors. BMS-986012 efficacy generally correlated with FucGM1 target expression in tumor models. In mice, the antibody was well tolerated, with no adverse events observed in long term efficacy studies. Preclinical studies also explored combinations of BMS-986012 with standard-of-care (SOC) chemotherapeutics, including cisplatin, etoposide, topotecan and irinotecan. Combination therapy of BMS-986012 with SOC resulted in significantly enhanced antitumor activity compared to monotherapy. Finally, studies conducted with BMS-986012 in combination with anti-CD137 antibody resulted in significant improvement in efficacy. These data provide preclinical support for evaluation of BMS-986012 in SCLC. BMS-986012 is currently in a phase I trial. Citation Format: Bing Chen, Chin Pan, Paul Ponath, Miho Oyasu, Daniel Menezes, Pina Cardarelli. BMS-986012, a fully human anti-fucosyl-GM1 antibody has potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-237.

An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC; BRF113928).

107Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as an oncogenic driver. The BRAF inhibitor D has demonstrated clinical activity (33% overall response rate [ORR], with a median progression-free survival [PFS] of 5.5 months as monotherapy in 78 previously treated pts with metastatic BRAFV600E–mutant NSCLC (cohort A). The combination of D + T has demonstrated significant improvements in efficacy vs BRAF inhibitor monotherapy in BRAF V600–mutant metastatic melanoma. Here, the primary analysis of pts with NSCLC who experienced failure of ≥ 1 prior platinum-based therapy for advanced disease and were treated with combination D + T is presented (cohort B). Methods: This is a multicohort, sequentially enrolled phase 2 trial in pts with metastatic BRAF V600E–mutant NSCLC. The primary endpoint was investigator-assessed ORR according to RECIST v1.1. Secondary efficacy endpoints included PFS and duration of response [DOR]. D was dosed at 150 mg orally twice daily and T at 2 mg or...

Features of reversible P2Y12 receptor antagonists based on piperazinyl-glutamate-pyridines

P2Y12 receptor becomes a favorable target for therapeutic antiplatelet agents. Reversible P2Y12 receptor antagonists have more benefits than the irreversible ones on rapid absorption, onset of action and higher inhibition of platelet aggregation. As potent reversible P2Y12 receptor antagonists, piperazinyl-glutamate-pyridines exhibit a significant improvement in efficacy while maintaining a better safety profile than the irreversible ones. In this study, we developed a 3D pharmacophore model with r 2 = 0.966 based on a set of piperazinyl-glutamate-pyridines showing the important pharmacophore features (one hydrogen bond acceptor, one hydrogen bond donor, one ring aromatic and one hydrophobic feature) which is necessary for reversible P2Y12 receptor antagonists. The obtained pharmacophore models were validated by using well-known methodologies such as test molecules and Fischer’s randomization method. A docking study was also performed based on the recently released P2Y12 receptor crystal structure (PDB ID: 4NTJ) which revealed key residues (Tyr105, His 187 and Lys280) in the receptor–ligand interaction. The docking results were well in agreement with the pharmacophore model that raised the model’s reliability. The pharmacophore model was further confirmed by estimating the activity of six known drugs which can distinguish the reversible P2Y12 receptor antagonists from the irreversible ones. The results of our study provide confidence for the utility of the selected chemical features to retrieve further compounds as reversible P2Y12 receptor antagonists.

Determination of the effective dose of a novel oral formulation of sarolaner (Simparica™) for the treatment and month-long control of fleas and ticks on dogs

Three laboratory studies were conducted to determine the appropriate dose of sarolaner, a novel isoxazoline, for the treatment and month-long control of infestations of fleas and ticks on dogs. In the first study, dogs were treated orally with sarolaner suspension formulations at 1.25, 2.5 or 5.0mg/kg, and infested with Dermacentor reticulatus, Rhipicephalus sanguineus ticks and with Ctenocephalides felis felis (cat flea) prior to treatment and then weekly for up to 8 weeks. Fleas and ticks were counted 48h after treatment and after each subsequent infestation at 24h for fleas and 48h for ticks. The lowest dose of sarolaner (1.25mg/kg) provided 100% efficacy against fleas from treatment through Day 35 and 98.4% at Day 56. This dose of sarolaner resulted in 99.7–100% control of both species of ticks through Day 28. In Study 2, dogs were dosed orally with placebo or sarolaner suspension formulations at 0.625, 1.25 or 2.5mg/kg and infested with Ixodes scapularis prior to treatment and weekly for 6 weeks, Amblyomma americanum (pretreatment and Day 26), Dermacentor variabilis (Day 33) and A. maculatum (Day 41). Ixodes scapularis was the most susceptible; the lowest dose (0.625mg/kg) providing>95% efficacy through Day 43. Efficacy against D. variabilis on Day 35 was>95% at 1.25 and 2.5mg/kg, whereas the 0.625mg/kg dose gave only 61.4% efficacy. Amblyomma spp. were the least susceptible ticks; efficacy of the 1.25mg/kg dose at Day 28 for A. americanum was markedly lower (88.5%) than achieved for D. reticulatus (100%) at Day 28 and also lower than for D. variabilis at Day 35 (96.2%). In Study 3, dogs were dosed orally with placebo or sarolaner in the proposed commercial tablet (Simparica™) at 1.0, 2.0 or 4.0mg/kg, and infested with A. maculatum, one of the ticks determined to be dose limiting, prior to treatment and then weekly for 5 weeks. All doses gave 100% control of the existing infestation. The two highest dosages resulted in >93% control of subsequent challenges for 5 weeks. There was no significant improvement in efficacy provided by the 4.0 mg/kg dose over the 2.0mg/kg dose (P>0.05) at any time point. The 2.0mg/kg dose was superior to the 1.0mg/kg on Day 14 (P=0.0086) and as efficacy for 1.0mg/kg declined below 90% at Day 28, a single 1mg/kg dose would not provide a full month of tick control. Thus, 2.0mg/kg was selected as the sarolaner dose rate to provide flea and tick control for at least one month following a single oral treatment.

Targeted Therapies for Lung Cancer.

Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting. In patients with NSCLC with anaplastic lymphoma kinase (ALK) rearrangements, phase III trials of crizotinib have demonstrated superior efficacy compared to platinum-pemetrexed in the first-line setting and standard chemotherapy in the second-line setting. A second-generation ALK inhibitor, ceritinib, is available for patients who have progressed after or were intolerant of crizotinib. Crizotinib has also demonstrated activity on patients with ROS1 rearrangements, and BRAF inhibitors (dabrafenib, vemurafenib) have demonstrated activity in patients with NSCLC with BRAF V600E mutation. The oncogenic mutations that are susceptible to targeted therapy are mainly found in non-squamous NSCLC. The development of targeted therapy in patients with squamous NSCLC has been more challenging due to the genomic complexity observed in the squamous histology and the low prevalence of EGFR, ALK, and ROS1 molecular alterations. A phase III trial of cisplatin and gemcitabine with and without necitumumab in patients with advanced NSCLC with squamous histology demonstrated a statistically significant improvement in progression-free and overall survival.

A randomized prospective comparative study of efficacy of asenapine, iloperidone and zotepine in patients with psychosis

Background: Antipsychotic drugs constitute the mainstay in the treatment of schizophrenia and other psychotic disorders. For these medications to be maximally beneficial, they must be efficacious, with an acceptable side effect profile and be taken as prescribed. The objective of the study was to compare the efficacy of iloperidone, asenapine and zotepinein subjects with psychotic disorders. Methods: Randomized prospective study was conducted in the Department of Psychiatry of a tertiary care hospital, at Mysore, India. Sixty Patients who met the criteria for acute psychosis and schizophrenia according to ICD 10 were recruited. Atypical antipsychotics-asenapine, iloperidone and zotepine were administered and their efficacy was monitored by brief psychiatric rating scale (BPRS), which was administered on day one, week 1, week 3 and week 6. Results: Out of 60 recruited subjects 31 (51.7%) completed all four visits of the study. Iloperidone and asenapine showed significant improvement in efficacy than zotepine at week 6. Among the total dropouts 55.2% subjects didn’t come for follow-up and 44.8% were dropped due to development of side effects. Conclusions: In patients with acute psychosis and schizophrenia, iloperidone appears more effective and tolerated than the other two. Asenapine was effective but less tolerated and zotepine was less efficacious and produced poor response. Asenapine and zotepine have more dropouts and showed few uncommon extrapyramidal side effects.

Phase II Trial of Ofatumumab (OFA) in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL): CALGB 50901 (Alliance)

Background: Rituximab has proven safety and efficacy in untreated patients with advanced stage follicular lymphoma (FL) with response rates upward of 67% (Ghielmini et al., Blood 2004). OFA is a fully humanized anti-CD20 mAb with higher CD20 antigen affinity and increased complement dependent cytotoxicity compared to rituximab. OFA has demonstrated activity in relapsed/refractory FL and high risk untreated FL in combination with chemotherapy. We therefore investigated OFA monotherapy as initial treatment for low/intermediate (int) risk, advanced stage FL in order to determine single agent efficacy as a platform for future studies. Methods: We conducted a randomized, multicenter phase II study in which previously untreated CD20+, grade (gr) 1- 3a FL patients (pts) and low/int FLIPI scores in stages III, IV or bulky stage II were randomized to either 500 mg (n=15) or 1000 mg (n=36) OFA dose. Induction consisted of 4 weekly doses followed by an extended induction schedule every 8 weeks for 4 additional doses. The primary endpoint was overall response rate (ORR) with an ORR of 60% or lower considered inadequate, and 80% or higher of strong interest. Secondary endpoints included progression-free survival (PFS) and safety. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2 and extended induction infusions 5-8). Pts with gr 3/4 infusion reactions during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. Due to slower than anticipated accrual, the 500 mg arm was stopped in Oct 2013 in order to meet the primary endpoint in at least one dosing arm; pts enrolled on 500 mg prior to that date continued treatment at that dose. Results: Fifty-one pts were accrued. The median age was 60 years (range 40-85). 86.3% were Caucasian; 54.9% were male. The majority had FL gr 1 (45.1%) or gr 2 (41.2%) and Stage III-IVA (84.3%). Five pts had B-symptoms. The majority of pts were int risk (72.5% FLIPI 2; 70.6% FLIPI2 1-2) or low risk (21.6% FLIPI 0-1; 19.6% FLIPI2 0). Of 36 pts allocated to the 1000 mg arm, 32 were evaluable for response. Four pts are excluded from response analysis: ineligible (n=3) and insufficient data (n=1). Two additional pts had no response assessment as therapy was stopped after the first dose; one withdrew consent and the other received alternative therapy per treating physician. The best response was CR (13.3%), PR (73.3%) and SD (10%). One pt progressed on treatment. The ORR of evaluable pts with evaluable defined as having at least one response assessed was 86.7% [95% CI (69.3%-96.2%)]. The ITT response rate was 81.3% [95% CI (63.6%- 92.8%)]. With a median (med) follow-up of 15.6 months (mo) ( Conclusions: OFA when given as a single agent in an extended induction dosing schedule is well tolerated and active as front line therapy in patients with low/int risk FLIPI, advanced stage FL in this multicenter study. Activity appears to be in a range comparable to that reported with other anti-CD20 antibodies in this setting, suggesting that significant improvements in efficacy will require novel combinations. NCT01190449. Support: U10CA180821, U10CA180882 Disclosures Rosenbaum:Celgene: Speakers Bureau. Off Label Use: Ofatumumab is an anti CD20 monoclonal antibody not approved for use in follicular lymphoma.. Bartlett:Genentech: Research Funding; Pfizer: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding; Gilead: Consultancy, Research Funding; Insight: Research Funding; Janssen: Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Hsi:Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau; Cellerant Therapeutics: Research Funding; Eli Lilly: Research Funding; Abbvie: Research Funding. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:Roche/Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Consultancy, Research Funding; MedImmune: Research Funding; Astellas: Consultancy; Ascenta: Research Funding; Teva: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Spectrum: Consultancy.

Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria

Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs.Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs.These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.

Fabrication of aceclofenac nanocrystals for improved dissolution: Process optimization and physicochemical characterization

The purpose of the study is to optimize process variables and fabricate nanocrystals to improve dissolution rate of aceclofenac. Particle engineering was carried out to obtain pure drug nanocrystals of aceclofenac to overcome its poor dissolution behavior using different polymeric stabilizers. A Box-Behnken design was used to study the influence of process variables and further optimization was carried out. The physicochemical properties were evaluated including particle size distribution, powder X-ray diffractometry, scanning electron microscopy and dissolution studies. Preclinical investigation was also carried out in Wistar rats. All the identified process variables influenced the particle size and dissolution velocity of aceclofenac. Methyl cellulose (MC) and hydroxypropyl methyl cellulose (HPMC) were found very effective in preventing growth of crystals and improving the dissolution of aceclofenac. The optimized process variables predicted were 0.47%, 25 °C and 1070 rpm for stabilizer concentration, processing temperature and mixing speed respectively using MC as stabilizer. The optimized aceclofenac nanocrystals showed improved dissolution and reduced particle size (Q = 87.27 ± 0.83% and Mz = 54.23 ± 3.24 nm). Preclinical investigation using Wistar rats revealed statistically significant improvement of efficacy of optimized nanocrystals in terms of percentage inhibition of paw edema induced by carrageenan challenge indicating enhanced bioavailability through improved dissolution of aceclofenac nanocrystals.

Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC).

8006 Background: In 78 BRAF V600E mut NSCLC pts, single agent D induced an overall response rate (ORR) of 32%. The combination of D and T (DT) has demonstrated significant improvements in efficacy ...

Novel Approach for NK Cell Therapy for Cancer

Novel therapeutic approaches are urgently needed for many malignancies such as Acute Myeloid Leukemia (AML). We have developed a new therapeutic strategy based upon NK cell immunotherapy that exhibits high clinical potential based upon cell and animal studies. While the harnessing of NK cells for cellular therapy against malignancies has been a topic of interest for several decades, our approach overcomes a major hurdle of insufficient NK cell cytotoxic activity. We have identified that targeting the kinase GSK3 through pharmacologic and genetic approaches leads to the hyperactivation of human blood derived NK cells and a significant improvement in efficacy as compared to traditionally used activated NK cells or chemotherapy in our mouse AML model systems. Importantly this GSK3 inhibition can be achieved through a short ex-vivo incubation of NK cells with a GSK3 inhibitor paving the way for a rapid implementation into a clinical trial. Utilizing both in vitro studies with AML cell lines (ex. OCI-AML3 and HL-60)) and primary human AML cells we observe approximately a 50% increase in efficacy with GSK3 inhibited NK cells as compared to untreated NK cells. Further, we demonstrate significant efficacy of GSK3 inhibited NK cells in a mouse model of circulating human AML. After 4 weekly injections of human NK cells, there is a 50% greater reduction in human AML cells present in the mouse bone marrow with GSK3 inhibited NK cells as compared to vehicle treated NK cells.Besides efficacy studies, our work has led a model of how GSK3-inhibition enhances NK cell activity as depicted in figure 1. GSK3 inhibition leads to a dramatic increase in adhesion of NK cells to target cells as demonstrated by a flow cytometric adhesion assay (49% vs 83% after 20 min incubation) as well as live cell imaging. Consistent with the increased adhesion, GSK3 inhibited NK cells as well as target cells (after co-incubation) exhibit increased expression of essential NK cell-target adhesion molecules including L-selectin (on NK cells) and ICAM (on target cells). The induction of ICAM on target cells is due to a marked induction in TNFa production from the NK cells upon incubation with target cells (>7 fold increase in TNFa production). TNFa neutralization impairs the NK activity of the GSK3 inhibited NK cells (~30%) but not vehicle treated cells. Finally, GSK3 inhibition also leads to changes in the NK cells that enhance activity such as increased expression of granzyme and perforin and secretion of IFNg. Overall, our work has a revealed a novel strategy for NK cell therapy that holds high clinical potential. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract NG02: Rational drug combinations to improve anti-EGFR targeted therapies in metastatic colorectal cancer

Abstract NG02: Rational drug combinations to improve anti-EGFR targeted therapies in metastatic colorectal cancer

Advances in stent technologies and their effect on clinical efficacy and safety.

The introduction of intracoronary stents represented a major advance in interventional cardiology. While bare metal stents set the benchmark for improved safety over angioplasty, intimal hyperplasia and subsequent restenosis were important limitations. First-generation drug-eluting stents demonstrated significant improvements in efficacy, but not necessarily safety, and further technologic developments have focused on optimizing both. Current advances and understanding in stent design continue to improve on these concepts. This review summarizes past and present technology with particular emphasis on the principles underlying the efficacy and safety of drug-eluting stents, and offers a glimpse into the next generations of stents aimed at treating symptomatic coronary artery disease.

Dextran-Based Doxorubicin Nanocarriers with Improved Tumor Penetration

Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nanocarrier system with aldehyde functionalities capable of forming an acid labile linkage with the chemotherapy drug doxorubicin was developed. Aldehyde dextran nanocarriers (ald-dex-dox) demonstrated efficacy as delivery vehicles with an IC50 of ∼300 nM against two-dimensional (2D) SK-N-BE(2) monolayers. Confocal imaging showed that the ald-dex-dox nanocarriers were rapidly internalized by SK-N-BE(2) cells. Fluorescence lifetime imaging microscopy (FLIM) analysis indicated that ald-dex-dox particles were internalized as intact complexes with the majority of the doxorubicin released from the particle four hours post uptake. Accumulation of the ald-dex-dox particles was significantly enhanced by ∼30% in the absence of glucose indicating a role for glucose and its receptors in their endocytosis. However, inhibition of clathrin dependent and independent endocytosis and macropinocytosis as well as membrane cholesterol depletion had no effect on ald-dex-dox particle accumulation. In three-dimensional (3D) SK-N-BE(2) tumor spheroids, which more closely resemble a solid tumor, the ald-dex-dox nanoparticles showed a significant improvement in efficacy over free doxorubicin, as evidenced by decreased spheroid outgrowth. Drug penetration studies in 3D demonstrated the ability of the ald-dex-dox nanocarriers to fully penetrate into a SK-N-BE(2) tumor spheroids, while doxorubicin only penetrates to a maximum distance of 50 μM. The ald-dex-dox nanocarriers represent a promising therapeutic delivery system for the treatment of solid tumors due to their unique enhanced penetration ability combined with their improved efficacy over the parent drug in 3D.

In the rat liver, Adenoviral gene transfer efficiency is comparable to AAV

Adenoviral (AdV) and Adenovirus-associated viral (AAV) vectors both are used for in vivo gene therapy of inherited liver disorders, such as Crigler-Najjar syndrome type 1. In a relevant animal model, the Gunn rat, both vectors efficiently correct the severe hyperbilirubinemia characteristic of this liver disorder. Although the clinical use of AAV is more advanced, as demonstrated by the successful phase 1 trial in hemophilia B patients, because of its large cloning capacity AdV remains an attractive option. A direct comparison of the efficacy of these two vectors in the liver in a relevant disease model has not been reported. Aim of this study was to compare the efficiency of clinically applicable doses of both vectors in the Gunn rat. AdV or scAAV (self-complimentary AAV) ferrying identical liver-specific expression cassettes of the therapeutic gene, UGT1A1, were injected into the tail vein. As the titration methods of these two vectors are very different, a comparison based on vector titers is not valid. Therefore, their efficacy was compared by determining the amount of vector genomes delivered to the liver required for therapeutic correction of serum bilirubin. Like AAV, the liver-specific first-generation AdV also provided sustained correction in this relevant disease model. UGT1A1 mRNA expression provided per genome was comparable for both vectors. Flanking the expression cassette in AdV with AAV-ITRs (inverted terminal repeats), increased UGT1A1 mRNA expression eightfold which resulted in a significant improvement of efficacy. Compared with AAV, less AdV genomes were needed for complete correction of hyperbilirubinemia.