24-hour Infusion Research Articles

Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodysplastic syndrome.

Trabectedin is an FDA-approved DNA minor groove binder that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6mg on days 1 and 8 or 2, 3, 1, or 1.5mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs 8±8% (n=16), respectively (P=.04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients.

The Impact of Pediatric Outpatient Parenteral Antibiotic Therapy Implementation at a Tertiary Children's Hospital in the United Kingdom.

Recent advances in outpatient parenteral antibiotic therapy (OPAT) have largely focused on adult practice, and there are few published data on the safety and effectiveness of pediatric OPAT (p-OPAT). During a 3-year period (2012 to 2015), data were prospectively collected on patients managed within the p-OPAT service at Southampton Children's Hospital, a tertiary pediatric hospital in the South of England. A total of 130 p-OPAT episodes were managed during this period. The most frequently managed pathologies were bone and joint infections (44.6%), followed by ear, nose and throat (10.7%), respiratory (10.0%) and central nervous system (10.0%) infections. The most frequently used antimicrobial agent was ceftriaxone (n = 103; 79.2%). For the majority of p-OPAT episodes, antimicrobials were delivered in prefilled syringes (n = 109; 83.8%); 24-hour infusions administered by elastomeric devices were used less commonly (n = 16; 12.3%). The median duration of p-OPAT treatment was 9.2 days (interquartile range: 7.6-19.0 days). With regard to patient outcomes, 113 (86.9%) p-OPAT episodes resulted in cure and 12 (9.2%) in improvement; treatment failure occurred in 5 (3.9%) episodes. Intravenous catheter-related complications were rare. A total of 1683 bed days were saved over the 3-year period. Our data suggest that p-OPAT is safe and effective, with the potential to offer considerable savings for the healthcare economy through reduced length of inpatient stay.

Improved Survival of Patients with AML By Addition of Cladribine to Standard DA3+7 Induction Chemotherapy (DAC) - Single Center Experience at University Medical Centre Ljubljana, Slovenia

Background: Polish Adult Leukemia group demonstrated that addition of cladribine to standard daunorubicin + cytarabine (DAC) induction chemotherapy for acute myeloid leukaemia (AML) increases remission rate and prolongs overall survival. The approach was subsequently included in NCCN guidelines. At University Medical Centre Ljubljana, Slovenia we started using DAC induction regimen in May 2014 for all patients up to 60 years of age, eligible for intensive chemotherapy. We compared the outcome of patients treated with DA3+7 (in use from January 2012 until April 2014) with the outcome of patients treated with DAC in the period from May 2014 to December 2017.Methods: We retrospectively analyzed all consecutive patients diagnosed with AML between January 2012 and December 2017, aged 60 or less, who were eligible for intensive chemotherapy according to ECOG performance status, echocardiography and spirometry results. Exclusion criteria were severe organ impairment and acute promyelocytic leukaemia. The induction regimen in the period January 2012 -April 2014 consisted of daunorubicin 60 mg/m2 on days 1,3 and 5 and continuous infusion of cytarabine 200 mg/m2 from day 1 to 7 (DA3+7) while in the period May 2014 - December 2017 cladribine 5 mg/m2 in a 3-hour infusion on days 1 through 5 was added to DA3+7. Consolidation treatment was the same for both groups and consisted of 2 or 3 courses of cytarabine. Eligible patients with unfavorable characteristics (monosomal /complex kariotype, FLT3 ITD or KMT2A rearrangements, therapy-related AML) proceeded to alogenic bone marrow transplantation (BMT). Patients who did not achieve remission after induction chemotherapy received rescue chemotherapy and also proceeded to alogenic BMT. The efficacy of induction treatment was assessed by bone marrow aspiration in the aplasia between days 7 and 10 after the last day of induction chemotherapy, and before the first consolidation therapy.Results: 50 patients with AML (27 women, 23 men) were treated with DA3+7. 58 patients (31 women, 27 men) were treated with DAC. There were no significant differences in the median age of the patients in both groups (54,4 years in the DA group vs 54,5 years in the DAC group; p=0,853). There were also no significant differences in the proportion of patients with unfavorable cytogenetics or therapy-related AML (50% in the DA group vs 51,7% in the DAC group; p= 0,858). Remission after induction chemotherapy was achieved in a significantly higher proportion of patients in the DAC group (47/58= 81,0%) compared to the DA group (30/50 =60%; p=0,016). Survival was significantly higher in the DAC group compared to the DA group (p=0,034) with a median survival of 18 months in the DA group, while in the DAC group the median survival was not reached. No diferences in toxicity between the DA and DAC regimen were observed.Conclusions: We confirmed results from other research groups by demonstrating improved remisssion induction rate and improved overall survival of AML patients aged 60 years or less treated with DAC induction compared to the standard DA3+7 induction chemotherapy. For evaluating the long-term overall survival further follow up is needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Therapeutic Manipulation of Cancer Cell Metabolism with the Mitochondrial Metabolism Inhibitor Cpi-613 in Addition to Chemotherapy Abrogates the Adverse Prognostic Effect of Age in Relapsed and Refractory AML

Background: Acute myeloid leukemia is an aggressive malignancy with poor outcomes especially in patients 60 years of age or older. This thought to be in part from increased resistance to chemotherapy in AML cells arising in an older host. One of the nine recognized biological hallmarks of aging is a decline in mitochondrial quality. The effect of exploiting this age-related metabolic vulnerability in relapsed AML has not been previously established. CPI-613 is a first-in-class agent that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, effectively impairing the TCA cycle. We have combined CPI-613 with high dose cytarabine and mitoxantrone in phase I and II clinical trials in over 100 patients with relapsed or refractory AML.Methods: To determine the effect of the addition of CPI-613 in older patients, the phase I and II datasets were combined and outcomes by age were analyzed and compared to age related outcomes in a historical dataset of patients treated with a high dose cytarabine, mitoxantrone and L-asparaginase but without CPI-613. In both trials, patients were given CPI-613 as a 2-hour infusion on days 1 through 5. Cytarabine was dosed at 3,000 mg/m² (if younger than 60) or at 1,500 mg/m² (if 60 years of age or older), given every 12 hours for 5 doses, starting on day 3 following the CPI-613 infusion. The mitoxantrone was dosed at 6 mg/m² and is given once daily following the first, third and fifth cytarabine doses. At day 14, nadir marrow was evaluated, and patients with residual disease could be re-treated as above or with an abbreviated 3-day cycle. Responding patients were eligible to receive up to 2 abbreviated 3-day consolidation cycles. The historical cohort was treated identically without CPI-613, except L-Asparaginase was given at a dose of 6,000 units/m2 following the last dose of cytarabine.Results: Patient characteristics are summarized in Table 1. In the historical dataset younger patients had a highly significant increase in median overall survival when compared to patients ≥60 years of age (figure 1A). In contrast, older and younger patients treated with CPI-613 in addition to the chemotherapy had no significant difference in median survival (figure 1B). Additionally, when outcome by dose of CPI-613 was analyzed, older but not younger patients had a significant improvement in survival when given a dose of 2,000 mg/m2 compared to those given 1,500 mg/m2 (figure 1C+D). Patients 60 years of age or older had a response rate of 55% and a median overall survival of 12.4 months when treated with a dose of CPI-613 of 2,000 mg/m2.Conclusions: Targeting mitochondrial metabolism exploits an age-related metabolic vulnerability in AML arising in older patients. These results have led to a randomized phase III trial of CPI-613 at 2,000 mg/m2 in combination with high dose cytarabine and mitoxantrone compared to high dose cytarabine and mitoxantrone alone in relapsed or refractory AML patients 60 years of age or older. [Display omitted] DisclosuresPardee:Amgen: Speakers Bureau; Karyopharm: Research Funding; Celgene: Speakers Bureau; Rafael Pharmaceuticals: Employment; Novartis: Speakers Bureau. Ellis:Alexion: Speakers Bureau. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

The CDK9 Inhibitor, Alvocidib, Potentiates the Non-Clinical Activity of Azacytidine or Decitabine in an MCL-1-Dependent Fashion, Supporting Clinical Exploration of a Decitabine and Alvocidib Combination

The hypomethylating agents (HMAs) azacytidine and decitabine exert biological activity via two distinct mechanisms, namely, DNA damage and inhibition of DNA methyltransferases. Azacytidine and decitabine are indicated in the treatment of patients with myelodysplastic syndromes (MDS). As a result of DNA methyltransferase inhibition, it is hypothesized that HMAs may function by inducing re-expression of key pro-apoptotic proteins such as NOXA, which sequesters the anti-apoptotic protein MCL-1, preventing its association with the mitochondrial pore-forming proteins BAX/BAK. Activity of the potent CDK9 inhibitor, alvocidib, is largely driven by targeting of CDK9-dependent MCL-1 expression. Alvocidib is under active clinical investigation, but has also has demonstrated high complete response rates in newly diagnosed AML patients, particularly when administered as part of a cytarabine and mitoxantrone containing regimen (ACM regimen). Given the dual NOXA/MCL-1-targeting ability of combining alvocidib and azacytidine or decitabine, the combination may synergize therapeutically in the treatment of non-clinical models of AML or MDS by means of transcriptional induction of NOXA and repression of MCL-1 expression.Cell viability and induction of apoptosis was assessed following treatment with alvocidib, azacytidine, and decitabine in cells using the Celltiter-Glo and Caspase-Glo assays. Gene expression changes following treatment were assessed using quantitative RT-PCR. Protein expression changes with treatment were also measured using standard immunoblotting technique. To assess the in vivo anti-tumor activity of these compounds, xenograft studies in the MOLM13 and additional models of MDS, exploring sequencing and scheduling of alvocidib administration with HMAs, were performed. Treatment of AML cell lines with alvocidib inhibited both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion. Pre-treatment of cells with alvocidib, to repress MCL-1 expression prior to azacytidine treatment, reduced the azacytidine cell viability EC50 more than 2.5-fold, from 1.8 µM to 0.6 µM in MV4-11 cells. The alvocidib/azacytidine combination also resulted in synergistic increases in caspase activity relative to either single agent within the combination, at multiple dose levels. The combination of azacytidine or decitabine with alvocidib was active in the MOLM13 xenograft model, yielding up to 65.7 or 91.1% tumor growth inhibition (%TGI) in the azacytidine or decitabine combination, respectively. Taken together, the in vitro and in vivo studies indicated that decitabine was more effective at re-expressing NOXA and potentiating alvocidib activity compared to azacytidine.These non-clinical data suggest that an alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Based on these non-clinical results, a Phase 1b/2 clinical study of alvocidib administered in sequence after decitabine in patients with intermediate to high risk MDS is being conducted (Zella 102). Patients will be enrolled in cohorts of 3-6 patients with decitabine administered as a 1-hour IV infusion daily on days 1 to 5 at a dose of 20 mg/m2 followed by a single alvocidib treatment on day 8 as a loading dose over 30 minutes followed by a 4-hour infusion. Treatment will be repeated every 28 days until disease progression or unacceptable toxicity. Enrollment will include MDS patients (Phase 1b) with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs, as well as (Phase 2) untreated patients with de novo or secondary MDS. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose of alvocidib when administered in sequence with decitabine. Key Phase 2 endpoints will include complete response rate and improvement in transfusion dependency. DisclosuresKim:Tolero Pharmaceuticals, Inc: Employment. Whatcott:Tolero Pharmaceuticals, Inc: Employment. Siddiqui-Jain:Tolero Pharmaceuticals, Inc: Employment. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment. Warner:Tolero Pharmaceuticals: Employment.

Safety and Efficacy of Adct-402 (Loncastuximab Tesirine), a Novel Antibody Drug Conjugate, in Relapsed/Refractory Follicular Lymphoma and Mantle Cell Lymphoma: Interim Results from the Phase 1 First-in-Human Study

Safety and Efficacy of Adct-402 (Loncastuximab Tesirine), a Novel Antibody Drug Conjugate, in Relapsed/Refractory Follicular Lymphoma and Mantle Cell Lymphoma: Interim Results from the Phase 1 First-in-Human Study

Safety and Tolerability of Lurbinectedin (PM01183) in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Safety and Tolerability of Lurbinectedin (PM01183) in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Comparison of Second and First Generation of Andexanet Alfa in a Porcine Polytrauma Model with Apixaban Anticoagulation

Background Andexanet alfa (AnXa; Andexxa) was developed as a specific antidote for direct and indirect factor Xa (FXa) inhibitors. It has been approved in the US for the reversal of apixaban and rivaroxaban anticoagulation when necessary due to life-threatening or uncontrolled bleeding. Generation 2 manufacturing process of AnXa is promising for providing adequate global supply of AnXa and awaits comprehensive regulatory evaluation for comparability to the current commercial process.Purpose: In this ongoing porcine polytrauma study, we investigated and compared efficacy and safety of the first and second generation AnXa product for the reversal of apixaban anticoagulation.Method: In 35 anesthetized male pigs, a polytrauma consisting of bilateral femur fractures and a standardized blunt liver injury was inflicted after 3 days of apixaban intake (20 mg/day). 12 min after the polytrauma, pigs were randomly allocated to receive (n=7 per group) either 1000 mg bolus of 2nd generation AnXa followed by 2-hour (h) infusion of normal saline (2nd G AnXa B) or 1000 mg bolus immediately followed by infusion of 1200 mg 2nd generation AnXa in 2 h (2nd G AnXa B+). These two groups that received 2nd generation AnXa were compared with the cohorts from our previous study following precisely the same protocol with bolus and 2 h infusion of normal saline (Control group), 1000 mg bolus of 1st generation AnXa followed by 2 h infusion of normal saline (1st G AnXa B), and 1000 mg bolus immediately followed by 2 h 1200 mg infusion of 1st generation AnXa (1st G AnXa B+). Animals were then observed for 5 h or until death. The blood loss (BL) was the primary outcome. Hemodynamics and coagulation profile comprised apixaban (anti FXa activity and rotational thromboelastometry (ROTEM). Further D-dimer levels and thrombin generation (TG) were measured. Right after the premature death or at the end of the observation period, internal organs were obtained and examined for the occurrence of thromboembolic incidents. Two-way ANOVA (mean ± SD) and log-rank tests were performed to analyze the data, and the statistical significance was set at p <0.05.Results: Three days of oral apixaban administration resulted in comparable anti-FXa activity levels before the trauma (195.4 ± 90.9 ng/mL, Figure 1). The increased anti-FXa activity also prolonged the clotting time (CT) on extrinsically activated ROTEM channel EXTEM (43.6 ± 5.5 to 110.1 ± 28.2 sec). BL at 12 min after the trauma was similar among the study groups (856 ± 118 mL). Anticoagulation with apixaban in control group resulted in a total BL of 3403 ± 766 mL (p<0.01 vs. all other groups) with 100 % mortality (survival time: 92-193 min; p<0.01 vs. all other groups), whereas all animals treated with AnXa survived. Both regimens with 2nd generation AnXa (2nd G AnXa B and 2nd G AnXa B+) resulted in a significant reduction in total BL (1148 ± 58 mL and 1116 ± 128 mL, respectively). The decrease in total BL was similar to both therapy regimes of previous cohorts of 1st G AnXa B and 1st G AnXa B+ (1264 ± 205 and 1202 ± 95 mL, respectively). All AnXa treatments similarly reversed anti-FXa activity more than 90% (19.8 ± 15 ng/mL) within 5 min after the bolus. Similarly, in both bolus regimens (1st and 2nd G AnXa B) 30 and 56% of the initial anti-FXa activity respectively re-emerged at 60 and 120 min after the trauma due to the short half-life of AnXa (~1.6 h) and continued absorptionof apixaban. With the infusion regimens (1st G and 2nd G AnXa B+), 34 and 48% reappearance of anti-FXa activity were postponed to 240 and 300 min after the trauma, respectively. However, the return of FXa inhibition had no influence on total BL post trauma. AnXa restored EXTEM CT (45.3 ± 6 sec) within 5 min corresponding to the neutralization of apixaban. With the gradual reemergence of anti-FXa activity, EXTEM CT values were also prolonged. Compared to the control group, D-dimer levels increased significantly after the treatment with AnXa indicating activation of coagulation and in line with the restoration of impaired TG induced by apixaban. Neither clinical observations nor histopathologic examinations showed any sign of hypercoagulopathy.Conclusion: This animal polytrauma model is the first to show that 2nd generation AnXa is as effective and well tolerated as the 1st generation in reducing blood loss and improving survival in apixaban anticoagulated pigs with massive hemorrhage. [Display omitted] DisclosuresGrottke:Boehringer Ingelheim: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Portola: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; Sanofi: Honoraria; Pfizer: Honoraria. Conley:Portola: Employment. Rossaint:CSL Behring: Honoraria; Boehringer Ingelheim: Honoraria.

Prospective Evaluation of Prognostic Relevance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: Results from the JALSG CBF-AML209-KIT Study

Prospective Evaluation of Prognostic Relevance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: Results from the JALSG CBF-AML209-KIT Study

1422. Comparative Monte-Carlo Analysis of Aztreonam-Avibactam vs. Ceftazidime–Avibactam Against Carbapenem-Resistant Gram-Negative Pathogens

BackgroundThe new β-lactamase inhibitor, avibactam (AVI), has recently been combined with ceftazidime (CAZ) as CAZ-AVI. AVI is also in Phase 3 clinical trials combined with aztreonam as ATM-AVI. Both drug combinations have similar in vitro activity against some organisms, but ATM-AVI is more potent against metallo-β-lactamase (MBL) producing organisms. However, against P. aeruginosa (PA), CAZ-AVI is more potent. Since these compounds have similar pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and there is a need for drugs for the treatment of resistant microorganisms, a Monte-Carlo analysis (MCA) was used to assess their potential efficacy against carbapenem-resistant pathogens.MethodsMCA (n = 10,000) was performed for ATM-AVI and CAZ-AVI using PK parameters, CrCl vs. Cl regression, PD targets, and recent MICs from peer-reviewed literature against five carbapenem-resistant (CR) organisms: P. aeruginosa (CR-PA), E. cloacae (CR-EC), K. pneumoniae (CR-KP), Enterobacteriaceae (CR-ENT), and MBL producing Enterobacteriaceae (MBL-ENT). Only MIC studies that directly evaluated both combinations were utilized. Our institution’s inpatient CrCl distribution (range: 10–120 mL/minute) was used to assess drug clearance. The ATM-AVI regimen was 1.5 g q6h with a 3 hours infusion and adjusted for renal function) and the CAZ-AVI regimen was 2 g q8h with a 2-hour infusion and adjusted for renal function). PD targets (%fT>MIC) for ATM-AVI were 40 and 60% and for CAZ-AVI were 40 and 70%.ResultsTarget attainment (TA%) for each regimen and organism was:DrugATM-AVICAZ-AVIRegimen1.5 g q6h (3h infusion)2 g q8h (2h infusion)fT>MIC (% of interval)40604070CR-PA48439387CR-EC100100100100CR-KP100100100100CR-ENT1001009696MBL-ENT1009922ConclusionBoth ATM-AVI and CAZ-AVI displayed very high TA% (>95%) for CR-EC, CR-KP, and CR-ENT at both PD targets. However, TA% for MBL-ENT was very low for CAZ-AVI and ≥99% for ATM-AVI. Against CR-PA, CAZ-AVI was had much higher TA% than ATM-AVI (87–93% vs. 43–48%). These differences suggest different roles for each drug combination in clinical practice.Disclosures All authors: No reported disclosures.

1719. Pharmacokinetics (PK) of Oritavancin in Children: The ORKIDS Trial

BackgroundOritavancin (ORI) is a lipoglycopeptide antibiotic approved in adults as a single 1,200 mg intravenous (IV) dose for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive organisms, including methicillin-resistant Staphylococcus aureus. The objective in children is to achieve a PK profile that is similar to that attained in adults. PK and safety data from the first 3 age-specified cohorts are presented.MethodsThe ORKIDS trial is a Phase 1 open-label, sequential, dose-finding study evaluating the PK, safety and tolerability of a single-dose 15 mg/kg (max 1,200 mg) IV infusion of oritavancin in children under 18 years. The first 3 age cohorts (12 to <18 years, 6 to <12 years, 2 to < 6 years) with 8 subjects in each cohort have completed the study. Subjects were required to have a suspected or confirmed Gram-positive bacterial infection for which they received standard-of-care antibiotic therapy. Following a single dose of ORI, PK samples were obtained at 3, 4, 9, 24, 48, 72, and 336 hours after the start of the 3-hour infusion. Plasma concentrations were analyzed by noncompartmental Methods. Subjects were evaluated for safety through Day 60. An independent data safety monitoring board evaluated the safety and PK data of each cohort prior to dosing the subsequent cohort.ResultsPK in children compared with adult data from the SOLO Phase 3 ABSSSI studies (Table 1).Table 1:Mean PK Parameters from Cohorts 1–3 and AdultsCohort 1, 12 to <18 years (n = 8)Cohort 2, 6 to <12 years (n = 8)Cohort 3, 2 to <6 years (n = 8)Range from Pooled Adult SOLO TrialsCmax (μg/mL)12713684106–170AUC0-inf (h μg/mL)4,0143,7091,9631,999–3,600ConclusionIn subjects 6 to <18 years, a single 15 mg/kg dose of ORI appears to be well tolerated and provides a PK profile similar to a single 1,200 mg dose in adults. Mean AUC0-inf of 1,963 h μg/mL in subjects 2 to <6 years is lower than the targeted exposure range in adults. A higher dose of ORI is currently being studied in this cohort.Disclosures J. Bradley, Melinta Therapeutics: Investigator, Research support. A. Arrieta, Melinta Therapeutics: Investigator, Research support. P. Bokesch, Melinta Therapeutics: Consultant, Consulting fee. K. Fusaro, Melinta Therapeutics: Employee, Salary. D. C. Griffith, Melinta Therapeutics: Consultant, Consulting fee. J. S. Loutit, Melinta Therapeutics: Consultant, Consulting fee.

The Efficacy, Safety, and Tolerability of Additional Serelaxin Administration to Standard Therapy in Asian Patients with Acute Heart Failure: The RELAX-AHF-ASIA trial

Background Acute heart failure (AHF) is associated with a high risk of post-discharge rehospitalisation and mortality. Existing evidence suggested potential therapeutic benefits of serelaxin in patients with AHF, although corresponding data in Asian patients remained scarce. RELAX-AHF-ASIA, a multinational, randomised, double-blind, placebo-controlled, Phase III trial, evaluated the effects of serelaxin on symptom relief and clinical outcomes in Asian AHF patients. Methods Patients diagnosed with AHF based on clinical criteria regardless of ejection fraction, with a systolic blood pressure ≥125 mmHg and mild-to-moderate renal dysfunction were randomised within 16 hours of presentation to receive 48-hour intravenous infusion of 30 μg/kg/day serelaxin or placebo in addition to standard therapy. The patients were followed-up for up to 180 days. A novel trichotomous primary endpoint was used in the RELAX-AHF-ASIA trial. It included: (1) treatment success (moderate/marked improvement in patient-reported dyspnoea and physician-assessed signs of congestion on Day 2); (2) treatment failure (in-hospital worsening of signs and/or symptoms of heart failure [HF] requiring intensification of intravenous HF therapy or mechanical ventilation, renal/circulatory support, rehospitalisation due to HF/renal failure or death through Day 5) and (3) unchanged status. Secondary endpoints included time to in-hospital worsening HF through Day 5 and all-cause and cardiovascular deaths through Day 180. Results Although the trial aimed to randomise 1520 AHF patients, it was prematurely terminated following the neutral read-out of the large phase III RELAX-AHF-2 trial. A total of 876 patients were randomised in the RELAX-AHF-ASIA trial and the final analysis was performed with 870 patients (serelaxin, 437; placebo, 433). The trial was conducted at 127 centres in 11 countries: (China, 15; India, 7; Japan, 50; Republic of Korea, 14; Malaysia, 7; Philippines, 9; Singapore, 2; Jordan, 3; Lebanon, 4; Taiwan, 10; Thailand, 6). The mean age was 70 years and 64% of patients were men. The demographics and baseline characteristics were well balanced between treatment groups. Due to premature termination of this trial, only exploratory analysis for primary and secondary endpoints was performed. The proportion of patients with treatment failure was less in the serelaxin group (4.1%) than in the placebo group (8.3%), but the primary endpoint failed to achieve statistical significance. Serelaxin significantly reduced in-hospital worsening HF through Day 5 with a hazard ratio of 0.41 (95% confidence interval: 0.20, 0.84; P=0.0119), using a Cox-regression model. There was no difference in time to cardiovascular mortality and all-cause mortality through Day 180. No new or unexpected safety findings were reported in this trial. The frequency of serious adverse events was similar between groups, and serelaxin infusion was well tolerated. Conclusion The RELAX-AHF-ASIA as the first randomised clinical trial specifically in Asian AHF patients represents a landmark trial in Asia. Although the trial was prematurely terminated, it demonstrated that serelaxin was well tolerated and that it improved a novel trichotomous primary endpoint, albeit not statistically, compared with placebo. Exploratory analysis revealed that worsening HF significantly improved with serelaxin treatment. Although RELAX-AHF-ASIA could not confirm the primary endpoint, it demonstrated that future clinical trials of AHF could be successfully conducted in Asian countries.

Comparison of two minimally invasive enilconazole perendoscopic infusion protocols for the treatment of canine sinonasal aspergillosis.

To compare two minimally invasive enilconazole infusion protocols for the treatment of canine sinonasal aspergillosis and evaluate the importance of complete endoscopic debridement in determining first treatment success rate. Data for 48 dogs with confirmed sinonasal aspergillosis treated with endoscopic debridement followed by per-endoscopic enilconazole infusion were collected. Twenty-four dogs were treated according to the previously published 1-hour infusion protocol and 24 dogs underwent a simplified 15-minute infusion protocol. Completeness of debridement, evaluated as partial or complete at the end of the procedure and outcome after one or several treatments were assessed in all dogs. Multi-variable analysis was performed to derive odds ratios and 95% confidence intervals. The median duration of the simplified protocol - 92∙3 minutes (range 40 to 140) - was substantially shorter than the duration of the previous protocol - 201∙3 minutes (range 120 to 265). First treatment success rates were 58 and 62∙5% for the previous and simplified protocol, respectively. Overall treatment success rate was similar in both groups (96%). Complete debridement was associated with an improved first treatment success rate compared to partial debridement. The simplified protocol is a valid alternative approach to the treatment of sinonasal aspergillosis. Completeness of endoscopic debridement before infusion is an important step for the success of treatment in canine sinonasal aspergillosis.

Creating value: Institution of outpatient infusional EPOCH-based chemotherapy at a safety-net hospital.

128 Background: EPOCH-based chemotherapy regimens are traditionally administered inpatient because they include a continuous 96-hour infusion. These admissions are costly, and disruptive to patients’ lives. We transitioned EPOCH-based chemotherapy regimens to an ambulatory infusion model at our safety-net hospital (Parkland Health and Hospital System, Dallas, TX), where patients visit the infusion center daily for 5 days. Methods: Guidelines for chemotherapy administration and educational materials were developed through a multidisciplinary collaboration with physicians, nursing, and pharmacy. Data were collected through chart review and the finance department. Project costs included purchase of portable infusion pumps and increasing outpatient infusion clinic capacity. Patient satisfaction with home infusions compared to hospitalization was measured on a Likert-type scale via direct-to-patient survey. Results: From 1/30/2017 through 1/30/2018, a total of 87 cycles of EPOCH-based chemotherapy were administered to 23 unique patients. 61 (70%) of these cycles were administered in the outpatient setting to 18 unique patients. There was a 58% reduction in drug costs in the outpatient setting due to lower drug acquisition cost. An estimated 336 days of hospital stay were avoided. There were no inappropriate prophylactic antimicrobial prescriptions and daily blood draws in the outpatient setting. 88% of survey responders reported &gt; 3 (scale, 1 to 5) on a Likert-type scale for both overall experience with home infusions, and likelihood they would use home infusions again. No chemotherapy spills or extravasation occurred; 1 cycle was complicated by pump failure where chemotherapy was given at a slower rate than intended. Conclusions: Multiday EPOCH-based regimens were successfully and safely administered in an ambulatory setting at our safety net urban hospital. Patients reported satisfaction with the experience, and received less unnecessary interventions in the outpatient setting. Significant cost savings from avoided hospitalization and decreased drug acquisition cost were demonstrated.

The difference between hematocrit and plasma albumin in the course of systemic capillary leak syndrome: a systematic review

To investigate the changes of the difference between hematocrit (Hct) and plasma albumin (Alb) in the course of patients with systemic capillary leak syndrome (SCLS). 281 case reports on human vascular leaking from the PubMed database from January 1st, 1996 to September 30th, 2015 were screened by systematic review method. Studies related to intracranial vascular leakage or intraocular vascular leakage were excluded. 213 articles related to SCLS were identified (164 in English, 16 in French, 8 in Japanese, 7 in German, 7 in Spanish, 4 in Italian, 2 in Chinese, 2 in Danish, 2 in Dutch, and 1 in Swedish). Due to the unavailable full text, 40 articles were excluded. A total of 173 articles related to SCLS were screened, of which 84 patients were enrolled. The data of Alb, Hct, age, gender, weight change, the length of hospital stay and 24-hour fluid infusion volume in SCLS patients were recorded, and the difference between Hct and plasma Alb (Hct-Alb) was calculated. According to the time when accurate Hct and Alb data were collected, they were divided into three groups: basic value group before onset, value group at onset and value group at recovery/discharge after onset. The levels of Hct and Alb and Hct-Alb at different time points in the course of the disease were compared. Pearson test was used to analyze the correlation between Hct-Alb and 24-hour fluid infusion volume. (1) A total of 12 cases with both exact values of Alb and Hct [or hemoglobin (Hb)] at the time of onset and recovery after treatment were selected from 84 cases of SCLS. It was shown that the Hct-Alb at the time of onset was significantly higher than that after treatment (26.33±16.36 vs. 0.55±8.81, P < 0.001). (2) A total of 17 cases with both the pre-onset baseline value and the exact values of Alb and Hct (or Hb) at the time of onset were selected from 84 cases of SCLS. It was shown that the Hct-Alb at the time of onset was significantly higher than that of the pre-onset basic value (15.83±11.37 vs. 1.82±7.97, P < 0.001). (3) A total of 14 cases with both exact values of Alb, Hct and 24-hour fluid infusion volume at the time of onset were selected from 84 cases of SCLS. It was shown that the Hct-Alb was 35.45±19.58 at the time of onset. The average 24-hour fluid infusion volume was (9.82±4.95) L, and the maximum volume of fluid infusion was 20 L. Pearson correlation analysis showed that the Hct-Alb at the time of onset was significantly positively correlated with 24-hour fluid infusion volume (r = 0.578, P < 0.05). In the analysis of SCLS cases published with adequate data available from 1996 to 2015, it was revealed that: (1) the difference in Hct-Alb levels at the onset of SCLS was 32.06±17.41. (2) The greater the difference between Hct and plasma Alb, the more amount of fluid required to maintain normal blood pressure.

Safety and Feasibility of Argatroban, Recombinant Tissue Plasminogen Activator, and Intra-Arterial Therapy in Stroke (ARTSS-IA Study)

BackgroundA randomized trial of concurrent recombinant tissue-type plasminogen activator (r-tPA) + thrombin-inhibition with Argatroban in stroke patients recently demonstrated safety and signal of efficacy compared to r-tPA alone, but patients having endovascular therapy (EVT) were excluded. The current study intended to study feasibility and safety of concurrent r-tPA and Argatroban in patients undergoing EVT. MethodsWe conducted a single-arm, feasibility, and safety study of patients that received standard-dose r-tPA, had intracranial large vessel occlusions, and underwent EVT within 6 hours of stroke onset. During r-tPA, a 100 μg/kg Argatroban bolus, followed by 12-hour infusion, targeted an activated Partial Thromboplastin Time (aPTT) 2.25 timesbaseline. Feasibility was defined as ability to combine treatments without EVT time-metric delays, compared to cotemporaneous r-tPA + EVT treatments. Safety was incidence of symptomatic intracerebral hemorrhage (sICH), systemic hemorrhage, or EVT complications. ResultsAll preplanned 10 patients were enrolled. Arterial occlusions were middle cerebral artery (n = 8), internal carotid artery (n = 1), and posterior cerebral artery (n = 1). All received Argatroban before EVT and completed infusions. There were no delays in time-metrics compared to nonstudy patients during the same period. Nine patients achieved excellent angiographic reperfusion (Thrombolysis In Cerebral Ischemia [TICI] ≥2b); with 7 complete (TICI = 3). There were no sICH, systemic hemorrhage, or EVT complications. At 90 days, 6 (60%) patients had a modified Rankin Scale of 0-2 and none died. ConclusionsIn patients treated with r-tPA and EVT, concomitant Argatroban is feasible, does not delay EVT provision, produces high rates of recanalization, is probably safe, and warrants further study.

Assessment of the stability of citrate-buffered flucloxacillin for injection when stored in two commercially available ambulatory elastomeric devices: INfusor LV (Baxter) and Accufuser (Woo Young Medical): a study compliant with the NHS Yellow Cover Document (YCD) requirements

ObjectivesTo investigate the effect of pH and buffers on the degradation rate of flucloxacillin and to determine if flucloxacillin can be stabilised using a buffered diluent for up to 14...

PS02.102: RESULTS FROM MULTICENTER, RANDOMIZED PHASE 3 FLOT4-AIO-TRIAL

Abstract Background The MAGIC trial established perioperative (periop) epirubicin, cisplatin, and 5-FU (ECF) as a standard treatment for patients (pts) with operable esophagogastric cancer, but survival continues to remain poor. FLOT4 (NCT01216644) is a multicenter, randomized, investigator-initiated, phase 3 trial (AIO-trial). It compares the docetaxel-based triplet FLOT with the anthracycline-based triplet ECF/ECX as a periop treatment for pts with resectable gastric or GEJ adenocarcinoma. Methods Eligible pts of stage ≥ cT2 and/or cN + were randomized to either 3 preoperative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2, cisplatin 60 mg/m², both d1, and 5-FU 200 mg/m² as continuous infusion or capecitabine 1250 mg/m2 orally d1–21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-FU 2600 mg/m² as 24-hour infusion, all d1). The primary endpoint was overall survival (OS; 80% power; HR of 0.76; 2-sided log-rank test at 5% type I error). Results Between Aug 2010 and Feb 2015, 716 pts (360 ECF/ECX; 356 FLOT) were randomly allocated. Baseline characteristics were similar between arms (overall, male 74%; median age 62; cT3/T4 81%; cN + 80%; GEJ 56%). 91% and 37% of pts with ECF/ECX and 90% and 50% with FLOT completed planned pre-operative and post-operative cycles, respectively. Median follow-up was 43 mon. 369 pts died (203 ECF/ECX; 166 FLOT). FLOT improved OS (mOS, 35 mon with ECX/ECF vs. 50 mon with FLOT; HR 0.77 [0.63 - 0.94]; P = 0.012). 3y OS rate was 48% with ECF/ECX and 57% with FLOT. FLOT also improved PFS (mPFS, 18 mon with ECX/ECF vs. 30 mon with FLOT; HR 0.75 [0.62 - 0.91]; P = 0.004). Periop complications were 50% with ECF/ECX and 51% with FLOT. 30- and 90-day mortality was 3% and 8% with ECF/ECX and 2% and 5% with FLOT. There was more G3/4 nausea and vomiting with ECF/ECX and more G3/4 neutropenia with FLOT. Conclusion Periop FLOT improved outcome in patients with resectable gastric and GEJ cancer compared to periop ECF/ECX. Disclosure All authors have declared no conflicts of interest.

Scheduled intermittent inotropes for Ambulatory Advanced Heart Failure. The RELEVANT-HF multicentre collaboration

BackgroundAmbulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients. Methods185 AAHF NYHA class III–IV patients, with ≥2 HF hospitalizations/emergency visits in the previous 6 months and systolic dysfunction, were treated with LEVO at tailored doses (0.05–0.2 μg/kg/min) without prior bolus every 3–4 weeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6 months before and after treatment start. ResultsInfusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6 months before to the 6 months after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, p < 0.0001), cumulative number (1.3 (0.6) vs 1.8 (0.8), p = 0.0001) and length of HF admissions (17.4 (15.6) vs 21.6 (13.4) days, p = 0.0001). One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant. ConclusionsIn AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients.

In vitro and in vivo activity of liposome-encapsulated curcumin for naturally occurring canine cancers.

Curcumin has well-established anti-cancer properties in vitro, however, its therapeutic potential has been hindered by its poor bioavailability. Lipocurc is a proprietary liposome-encapsulated curcumin formulation that enables intravenous delivery and has been shown to reach its highest concentration within lung tissue. The goal of this study was to characterize the anti-cancer and anti-angiogenic activity of Lipocurc in vitro, in addition to evaluating Lipocurc infusions in dogs with naturally occurring cancer. We therefore evaluated the effect of Lipocurc, relative to free curcumin, on the viability of canine osteosarcoma, melanoma and mammary carcinoma cell lines, as well as the ability of Lipocurc to inhibit endothelial cell viability, migration and tube formation. We also undertook a pilot clinical trial consisting of four weekly 8-hour Lipocurc infusions in 10 cancer-bearing dogs. Tumour cell proliferation was inhibited by curcumin at concentrations exceeding those achievable in the lung tissue of dogs. Similarly, equivalent high concentrations of Lipocurc and curcumin also inhibited endothelial cell viability, migration and tube formation. Four out of six dogs completing planned infusions of Lipocurc experienced stable disease; however, no radiographic responses were detected.