24-hour Infusion Research Articles

Safety of Cefazolin Test Dose in Patients With Penicillin Allergy Just Prior to Cardiac Device Implantation: A Single-Centre Experience

BackgroundCephalosporins are the cornerstone of cardiac device infection prophylaxis. Owing to fears of cross-reactivity, penicillin-allergic patients are exposed to potentially more-toxic drugs, with decreased efficacy. We evaluated the safety of a cefazolin test dose (CTD) in self-reported penicillin-allergic patients. MethodsIn this single-centre study, we evaluated consecutive patients with chart documentation of penicillin allergy undergoing cardiac device implantation, over a 2-year period. A CTD was performed if no cephalosporin allergy or severe anaphylactic reaction to penicillin had been documented. Patients were given 2 doses of 100 mg IV cefazolin, and if no allergic reaction occurred after 5 minutes, the full dose (1800 mg) was administered in the electrophysiology laboratory just before the implantation procedure. ResultsA total of 2200 patients were included. The frequency of reported penicillin allergy was 9.3% (n = 204). In 80% of cases, the type of allergic reaction was not reported in medical notes or was unknown by the patient. A CTD was performed in 67.6% of patients with a penicillin allergy (n = 138). A total of 5 adverse events occurred (3.6% of patients [95% confidence interval, 1.1%-6.1%]) — 4 skin rashes and 1 tongue edema. These 5 patients became asymptomatic after antihistaminic and corticosteroid IV treatment. Even if the test dose was negative, 79% of patients also were administered vancomycin before the procedure, as it requires a 1-hour infusion prior to the CTD in the implantation procedure room. ConclusionA CTD in most penicillin-allergic patients appears to be safe and allows its use per recommended guidelines.

Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney replacement therapy

ObjectivesDespite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment. MethodsFour hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population. ResultsPiperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs. DiscussionIn children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.

Tranexamic acid is not inferior to placebo with respect to adverse events in suspected traumatic brain injury patients not in shock with a normal head computed tomography scan: A retrospective study of a randomized trial.

A 2-g bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a randomized controlled trial. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected traumatic brain injury (TBI) when intracranial hemorrhage (ICH) is absent on initial computed tomography. This study used data from a 2015 to 2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-g bolus, 1-g bolus plus 1-g infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial computed tomography negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: myocardial infarction, deep vein thrombosis, seizure, pulmonary embolism, acute respiratory distress syndrome, cardiac failure, liver failure, renal failure, cerebrovascular accident, cardiac arrest, cerebral vasospasm, "any thromboembolism," hypernatremia, acute kidney injury, and infection. Other unfavorable outcomes analyzed include mortality at 28 days and 6 months, Glasgow Outcome Scale-Extended score of ≤4 at discharge and 6 months, intensive care unit-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups, the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared with placebo. No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury, which were overrepresented in the 1-g TXA bolus plus 1-g TXA infusion. Administration of either a 2-g TXA bolus or a 1-g TXA bolus plus 1-g TXA 8-hour infusion in suspected TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-g bolus is associated with a mortality benefit, it should be administered in suspected TBI. Therapeutic/Care Management; Level II.

Abstract WP134: Association Between Hyperacute Blood Pressure Variability And Hematoma Expansion In Patients With Intracerebral Hemorrhage: Secondary Analysis Of The Field Administration Of Stroke Therapy - Magnesium Database

Background: Blood pressure variability (BPV) has emerged as a significant factor associated with clinical outcomes after intracerebral hemorrhage (ICH). While hematoma expansion (HE) is also associated with clinical outcomes, the relationship between BPV and HE has not been established. In this secondary database analysis, we aim to describe the association between BPV and HE. We hypothesized that BPV was positively associated with HE. Methods: Among 1,690 enrolled in the NIH-funded Field Administration of Stroke Therapy - Magnesium (FAST-MAG) study, 268 patients sustained ICH and received repeat CT or MRI head imaging within 6 to 48 hours of arrival. BPV was calculated by standard deviation (SD) and coefficient of variation (CV) of the hyperacute, prehospital data using the systolic blood pressure (SBP) measurements taken on ED arrival, 15min-post maintenance infusion start, 1-hour post maintenance infusion start, 4-hours after ED arrival. HE was defined by hematoma volume expansion greater than 6ml. Multivariate logistic regression was used for presence of HE in quintiles of SD and CV of SBP. Results: Of the 268 patients from the FAST-MAG study who had follow up head imaging, 116 (43%) had HE. Proportions of patients with HE was not statistically significant in the higher quintiles of the SD and CV of SBP for either hyperacute or acute period. Conclusions: HE was not found to be associated with higher quintiles of BPV using SD and CV of SBP in the hyperacute or the acute period. Expanded inclusion criteria or new statistical markers for BPV incorporating temporality for SBP could help in future studies.

Abstract TP20: Intravenous Glibenclamide For Large Hemispheric Infarction: Baseline Data From Initial Enrollees In The Charm Phase 3 Study

Objective: To present baseline data from initially enrolled participants in CHARM, a Phase 3 study evaluating whether intravenous (IV) glibenclamide (BIIB093) improves functional outcomes at 90 days in individuals with large hemispheric infarction (LHI) compared with placebo. Background: In preclinical models, glibenclamide reduces cerebral edema due to LHI by inhibiting the SUR1/TRPM4 cation channel. Phase 2 trial data suggested that glibenclamide compared with placebo may reduce 30-day mortality and increase rates of favorable functional outcomes. Design/Methods: CHARM is a global, randomized, double-blind, placebo-controlled trial (NCT02864953). Eligible participants (planned enrollment: 768) are 18-85 years old, with a diagnosis of acute ischemic stroke of the middle cerebral artery territory, and study drug treatment initiated within 10 hours of last known normal (LKN) time. Randomization is (1:1) to a 72-hour continuous infusion of glibenclamide or placebo and may receive standard of care reperfusion therapy. The primary endpoint is ordinal analysis of the modified Rankin Scale at 90 days in participants ≤70 years of age. Results: As of January 2021, 264 participants were randomized and 249 were dosed. Mean (SD) age 64 (12.4) years (n=249). Median time from LKN to dosing was 9.3 hours. At baseline, mean (SD) National Institute of Health Stroke Scale score was 20.4 (5.09); IQR (17-23). Participants with baseline imaging data (n=259) had documented qualifying LHI on MRI (38.6%), computed tomography perfusion (CTP; 35.1%), or non-contrast computed tomography (26.3%). Site investigator-read median infarct size on MRI/CTP was 135 mL (IQR 99 - 174 mL, n=249). Conclusions: Initially enrolled CHARM participants have imaging evidence of LHI and moderate-to-severe neurologic deficits. Ages 71-85 years have completed enrollment; remaining enrollees in CHARM will be ≤70 years of age. Enrollment is ongoing.

Tenecteplase use in the management of acute ischemic stroke: Literature review and clinical considerations.

Several research articles have been published within the last decade comparing the use of tenecteplase to alteplase in ischemic stroke management. Prior reporting on the comparative therapeutic efficacy and safety profiles of tenecteplase and alteplase is reviewed. Tenecteplase is a variant of native tissue-type plasminogen activator, which rapidly promotes thrombolysis by catalyzing formation of the serine protease plasmin. Tenecteplase has theoretical advantages over alteplase as it has greater fibrin specificity and has a longer half-life than alteplase. This allows the administration of a single bolus over 5 to 10 seconds, as opposed to a bolus followed by a 1-hour infusion with alteplase. While currently approved by the Food and Drug Administration for the treatment of ST-segment elevation myocardial infarction, tenecteplase has also been studied in the treatment of acute ischemic stroke and has extensive data for this off-label indication. The most comprehensive trials to date evaluating the use of tenecteplase in acute ischemic stroke include the TNK-S2B, Australian TNK, ATTEST, Nor-Test, and EXTEND-IA TNK trials. Findings from these randomized controlled studies suggest that tenecteplase is at least as efficacious as alteplase in terms of neurological outcomes. The majority of these studies also reported a trend toward improved safety profiles with the use of tenecteplase. Current clinical evidence shows that tenecteplase is not inferior to alteplase for the treatment of ischemic stroke and suggests that tenecteplase may have a superior safety profile. Furthermore, tenecteplase also has practical advantages in terms of its administration. This can potentially lead to a decrease in medication errors and improvement in door to thrombolytic time.

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban.

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population ( n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Ceftobiprole medocaril.

Ceftobiprole medocaril is a broad-spectrum 5th-generation cephalosporin with activity against Gram-positives such as methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae, and against Gram-negatives such as Pseudomonas aeruginosa. The recommended dose is 500 mg every 8 h in 2-hour infusions. Various clinical trials have demonstrated its usefulness in the treatment of community-acquired pneumonia and nosocomial pneumonia, with the exception of ventilator-associated pneumonia. In summary, it is a very useful antibiotic for the treatment of pneumonia.

Does the Computed Tomography Hounsfield Units Change Predict Response to Perioperative Chemotherapy in Patients with Gastric Adenocarcinoma.

Purpose: We aimed to investigate whether Computed Tomography (CT) attenuation change is predictive of poor pathological response in patients with gastric cancer (GC) and gastroesophageal junction (GEJ) adenocarcinoma who received perioperative fluorouracil (FU), leucovorin (LV), oxaliplatin, and docetaxel (FLOT) regimen.Methods: This trial was planned as a retrospective single-center study. In the neoadjuvant setting, patients received a regimen that includes docetaxel (50 mg/m2), oxaliplatin (85 mg/m2), and LV (200 mg/m2) with short-term infusional FU (2600 mg/m2 as a 24-hour infusion), on day 1 and administered every two weeks for four cycles. Patients were classified as response rates according to the CAP-TRG system (0-1 response or 2-3 response) after completing four cycles of the FLOT regimen.Results: In total, 108 patients with GC and GEJ adenocarcinoma were included in the study. In a univariate analysis, age, histologic grade, T stage, N stage, and change in attenuation were found to be the statistically significant factors (p = 0.034, p =0.038, p = 0.001, p =0.029, and p = 0.022, respectively). In a multivariate analysis, T4 tumors and a higher change in attenuation were found to be important factors associated with poor pathologic response (p = 0.027 and p = 0.038, respectively).Conclusion: Our results demonstrate that a higher decrease in CT attenuation and T4 tumors is associated with a poor response to perioperative FLOT chemotherapy in patients with GC and GEJ adenocarcinoma.

Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding.

There are currently no drug therapies modifying the natural history of patients suffering Alzheimer's disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

Levosimendan and heart failure: A retrospective case series

Levosimendan is characterized with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance. The aim of our study was to describe the clinical, biological and echocardiographic efficacy of this molecule according to the experience of our cardiology department. This is a monocentric, retrospective, descriptive study about patients hospitalized in the cardiology department of Sahloul hospital between January and December 2019 and who received a Levosimendan treatment. Six levosimendan cures were administered to six patients. The average age was 49.6 ± 17 years. Three patients received an initial bolus followed by a 24-hour infusion. We did not report any side effects that led to discontinuation of treatment. Inotropic agents’withdrawal was possible in 3 of the 4 patients who were on inotropic support. Death occurred in one patient. After levosimendan infusion, mean diuresis increased from 0.63cc/kg/hour to 1.51cc/Kg/hour ( P = 0.007). The mean heart rate before the start of the treatment and 48 hours afterwards were 97 and 85.6bpm respectively ( P = 0.4). Mean Systolic blood pressure increased from 89 mmHg to 92 mmHg 48 hours after the start of the treatment ( P = 0.42). Biologically, mean lactatemia levels decreased from 5 mmol/L to 3.24 mmol/L by day 2 after levosimendan treatment. There was a significant improvement in mean left ventricule ejection fraction from 21.6% to 25.5% ( P = 0.05) after 48 hours. Systolic pulmonary arterial pressures decreased significantly after the same period from 64 mmHg to 50 mmHg ( P = 0.007). The mean value of S’ measured at the tricuspid annulus in tissue Doppler mode, increased from 7.6 cm/s to 8.8 cm/s on the second day of levosimendan treatment ( P = 0.03) Although our sample size was small, our results are consistent with the literature regarding the efficacy of Levosimendan in cardiogenic shock. Its high cost limits its use in our daily practice.

Mechanical Mitral Valve Thrombosis – A Twenty-Five-Hour Alteplase Protocol

There is compelling observational data regarding the efficacy and safety of fibrinolytic therapy for mechanical valve thrombosis. The available data support use of alteplase (25 mg) infused over 25 hours with no bolus followed by a 6-hour infusion of unfractionated heparin. We present our experience with this protocol.

982. Effect of Hepatic Impairment on the Safety and Pharmacokinetics of Rezafungin

BackgroundRezafungin (RZF) is a novel echinocandin antifungal being developed for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases among immunosuppressed patients. In the Phase 2 and Phase 3 treatment trials of rezafungin compared with caspofungin (STRIVE [NCT02734862] and ReSTORE [NCT03667690], respectively), patients with severe hepatic impairment (HI) were not included due to lack of caspofungin data in this population. Rezafungin was previously evaluated in patients with moderate hepatic impairment. Here we report an open-label, single-dose study on rezafungin in patients with HI (Child-Pugh class C).MethodsTo investigate the safety, tolerability, and pharmacokinetics (PK) of RZF in subjects with HI and healthy subjects (HS), 8 subjects with HI and 8 HS matched for age, sex, and body mass index (BMI) were enrolled and received a single 400-mg intravenous 1-hour infusion of RZF. Plasma PK sampling was performed at various time points through 336 hours postdose. RZF PK parameters were derived using non-compartmental analysis. Safety was assessed throughout the study. ResultsThe majority of the HI subjects were White (87.5%) and male (75%) while equal distribution between White and Black or African American was observed among HS (50%) and 75% were male. The mean age of HI subjects was 58 years (range, 41–68 years) and 56.6 years (range, 50–61 years) for the HS. Mean BMI was 29.7 kg/m2 (range, 24.5–34.3 kg/m2) for HI subjects and 29.7 kg/m2 (range, 25.4–34.2 kg/m2) for the HS. RZF exposure (Cmax and AUC) in subjects with HI was ~30% lower than that in HS (Table 1), while half-life was generally similar (HI: 121 h, HS:124 h; Figure 1). Three HI subjects had one adverse event (AE) each (bronchitis, worsening hepatic encephalopathy, hyponatremia), all moderate in severity; one HS had 1 AE of infusion site infiltration mild in severity. No AEs were considered related to RZF, and all were resolved or resolving by the end of the study.Table 1. Plasma Rezafungin PK Parameter Estimates in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400 mg IV Infusion of Rezafungin Figure 1. Mean (+SD) Plasma Rezafungin Concentration-Time Profiles in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400-mg IV Infusion of Rezafungin (Semi-Logarithmic Scale)ConclusionRZF was well tolerated in HI subjects and showed modestly reduced exposure that was within the range observed in matched HS. These findings support no RZF dose adjustment in subjects with severe hepatic impairment. Disclosures Voon Ong, PhD, Cidara Therapeutics (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics (Employee, Shareholder) Rebeca M. Melara, M.S., Altasciences (contract research organization) (Employee) Thomas C. Marbury, MD, Orlando Clinical Research Center (Employee, Other Financial or Material Support, Equity owner of Orlando Clinical Research Center) Alena Jandourek, MD, Cidara therapeutics (Consultant) Shawn Flanagan, PhD, Cidara Therapeutics (Employee, Shareholder)

LB12. Exebacase Shows Rapid Symptom Resolution in a Phase 2 Study in Adult Patients with Staphylococcus aureus bacteremia

BackgroundExebacase (EXB), a recombinantly-produced lysin (cell wall hydrolase), is the first direct lytic agent to advance into Phase 3 of clinical development for the treatment of bacteremia including infective endocarditis due to Staphylococcus aureus. The microbiologic attributes of EXB, including pathogen-targeted rapid bacteriolysis, and biofilm eradication are distinct from and synergistic with those of traditional antibiotics and underpin the therapeutic potential for EXB.MethodsThe Phase 2 trial was a randomized, double-blind, placebo-controlled multinational study. Patients were randomized (2:1) to receive a single 2-hour infusion of EXB or placebo (PBO) in addition to standard of care antibiotics. Time to resolution of symptoms (shortness of breath, sweating, fatigue and confusion) attributable to the bacteremia was analyzed using Kaplan-Meier methods. Time to resolution was defined as the number of days until all attributable symptoms were absent. If a new (not present at baseline) attributable symptom was present before the baseline symptoms resolved, this new symptom also had to be absent for symptoms to be considered resolved.ResultsA total of 86 patients (53 EXB and 33 PBO) had at least one attributable symptom present at baseline. Of these, symptoms resolved in 94.3% and 87.9% of EXB and PBO patients, respectively. The median time to resolution was 3 days for EXB and 6 days for PBO patients. Median days to symptom resolution in the MRSA group was 3 and 7 days for EXB and PBO patients, respectively, and 3 and 5 days for EXB and PBO patients in the MSSA group, respectively. Time to symptom resolution in MRSA patients in presented in Figure 1.Figure 1. Time to Resolution of Symptoms in Patients with MRSA Bacteremia including Infective Endocarditis ConclusionThe majority of EXB and PBO patients had symptom resolution. However, EXE patients achieved symptom resolution in 3 days compared with 6 days for PBO patients overall, and 7 days for PBO patients with MRSA. These data suggest that rapid bacteriolysis may translate to a clinical benefit for patients receiving EXB and aligns with a median length of hospital stay of 6 and 10 days among US MRSA patients that received EXE and PBO patients, respectively. (Fowler, et al, 2020).Disclosures Cara Cassino, MD, ContraFect Corporation (Employee) Anita F. Das, PhD, Adagio (Consultant)AN2 (Consultant)Cidara (Consultant)ContraFect (Consultant)Iterum (Consultant)MicuRx (Consultant)Paratek (Consultant)Union (Consultant) Joy Lipka, MS, ContraFect Corporation (Consultant)

Laparoscopic-Guided Ropivacaine Trocar-Site Infiltration Can Improve Post-Operative Pain Control after Laparoscopic Adrenalectomy.

There is no consensus on pain control in patients undergoing laparoscopy; nowadays, conventional therapy may be improved by transversus abdominis plane block. The aim of this evaluation is to investigate the role of laparoscopic-assisted trocar-site ropivacaine infiltration during adrenalectomy in pain control. This is a retrospective evaluation of a prospectively maintained database including patients undergoing adrenalectomy. Patients were divided into 2 groups: Group A patients received laparoscopic-assisted trocar-site infiltration of 7.5mg/mL ropivacaine and Group B patients did not receive any infiltration. All patients received a 24-hour infusion of 20mg morphine; pain was checked at 6, 24, and 48hours after surgery by Visual Analogue Scale (VAS) score. A rescue analgesia by was given if VAS score was > 4 or on patient request. No differences in operative time, complications, and post-operative stay and no complications related to trocar-site infiltration were found. 6-hour and 48-hour VAS scores were not found to be significantly different between groups, even if a slight decrease in VAS score in Group A was reported. Group A showed significant reduction in VAS score at 24hours (2.44 +/- .41 vs 3.01 +/- .78, P < .005) and in the number of patients requiring further analgesic drugs administration (40.6% vs 57.8%, P < .005). Laparoscopic-guided trocar-site ropivacaine infiltration can be considered safe and effective in the management of post-operative pain and in the reduction of analgesic need in patients undergoing laparoscopic adrenalectomy. The retrospective nature of the study and the lack of a consistent series of patients require further evaluations.

Abstract P047: A phase 1/2 trial of CBX-12, an alphalexTM peptide drug conjugate, in patients with advanced or metastatic refractory solid tumors

Abstract Background Tumor-targeted drug delivery technologies are urgently needed to overcome the lack of tumor selectivity, a major drawback of conventional chemotherapy. In addition, the acidic intercellular microenvironment in solid tumors traps weak acid/base chemotherapy agents, preventing necessary intracellular concentrations in tumour cells. An alphalex conjugate, which contains a low-pH insertion peptide, a linker, and a payload, is designed to overcome these limitations. Unlike antibody drug conjugates, these peptide drug conjugates target tumors in an antigen-agnostic manner. At pH ≥7.0, the peptide is unstructured. In the low-pH tumor microenvironment, the peptide forms an alpha helix, inserts directionally in the cell membrane delivering the linker and payload intracellularly where the linker is cleaved. CBX-12 consists of the pH-sensitive peptide, a self-immolating linker, and the topoisomerase 1 (TOP1) inhibitor exatecan. Methods CBX-12-101 is a first-in-human, open-label, dose-escalation, safety, pharmacokinetics (PK), and biomarker study of CBX-12 in patients with advanced or metastatic refractory solid tumors. CBX-12 is administered as a 1-hour intravenous infusion. Two dosing schedules, daily x 5 every 3 weeks (Part A) and daily x 3 every 3 weeks (Part B), are being evaluated. The starting dose in Part A is 0.25 mg/kg. Single-patient cohorts will be enrolled initially, with dose-escalations up to 100% of the prior dose, until a patient has a ≥ Grade 2 adverse event (AE) considered possibly related to CBX-12 during Cycle 1 (the DLT period), at which time 2 additional patients will be enrolled in that cohort, and a 3 + 3 design will subsequently be utilized. Further dose escalations may be no more than 50% of the prior dose. After at least 2 cohorts have been evaluated in Part A, Part B will open for accrual. Maximum tolerated doses and recommended phase 2 doses will be determined for each dosing schedule. The PK of the CBX-12 conjugate and free exatecan will be determined. The stability of the conjugate in circulation will be evaluated by the ratio of CBX-12 to free exatecan. Pre- and on-treatment tumor biopsies are required. Biomarker and pharmacodynamic evaluations including measuring intratumor exatecan levels, TOP1, gamma H2AX and schlafen-11 are planned. Antitumor activity will be assessed per RECIST v 1.1. Phase 2 expansion cohorts are planned in patients with platinum-resistant ovarian and small cell lung cancer. As of July 2021, patients are enrolling in Part A Cohort 2 at a dose of 0.50 mg/kg. Citation Format: Anthony Tolcher, Joseph Paul Eder, David Sommerhalder, Sophia Gayle, Paul Pearson, Deb Chapman, Arthur P. DeCillis, Anish Thomas, Funda Meric-Bernstam. A phase 1/2 trial of CBX-12, an alphalexTM peptide drug conjugate, in patients with advanced or metastatic refractory solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P047.

Abstract P031: MANTRA: A randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan (RAIN-32) versus trabectedin in patients with de-differentiated liposarcoma

Abstract Background: p53 plays a central role in tumor suppression and maintenance of genome integrity. Murine double minute 2 (MDM2) is a ubiquitin ligase that inhibits p53 transcriptional activity and induces p53 degradation through ubiquitination. MDM2 amplification occurs in many cancers but is universal in well-differentiated (WD) or de-differentiated (DD) liposarcomas (100% of cases) [Cancer Genome Atlas Research Network. Cell 2017]. Current therapies for WD/DD liposarcomas include anthracycline-based chemotherapy, eribulin, and trabectedin. Inhibition of the MDM2-p53 interaction is a promising therapeutic approach to restore p53 tumor suppressor activity in liposarcomas. Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor that inhibits the MDM2-p53 interaction and restores p53 function at nanomolar concentrations. In a phase 1 study, milademetan showed promising efficacy in patients with WD/DD liposarcoma when administered on an intermittent schedule (260 mg on Days 1–3 and 15–17 every 28 days), with a median progression-free survival (PFS) of 7.4 months [Gounder et al. AACR-NCI-EORTC 2020]. MANTRA (RAIN-3201) is a randomized, multicenter, open-label, phase 3 registration study designed to evaluate the efficacy and safety of milademetan versus trabectedin in patients with unresectable or metastatic DD liposarcoma with disease progression on ≥1 prior systemic therapies, including ≥1 anthracycline-based regimen (EudraCT: 2021-001394-23). Methods: Eligible patients are ≥18 years of age with histologically confirmed unresectable and/or metastatic DD liposarcoma, with or without a WD component, who have received ≥1 prior systemic therapies, including ≥1 anthracycline-based regimen, with radiographic evidence of progression within 6 months before study entry. Prior treatment with trabectedin or an MDM2 inhibitor is not permitted. Patients will be randomly assigned (1:1) to receive milademetan (260 mg once daily orally Days 1–3 and 15–17 on a 28-day cycle) or trabectedin (1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks). Randomization is stratified by Eastern Cooperative Oncology Group performance status (0 or 1) and number of prior treatments for liposarcoma (≤2 or &amp;gt;2). Tumor response will be evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: PFS by blinded independent central review. Secondary endpoints: overall survival; disease control rate; objective response rate; duration of response; PFS by investigator assessment; safety; health-related quality of life. Exploratory endpoints: molecular markers in peripheral blood and/or tumor tissue; milademetan pharmacokinetics. To demonstrate a 3-month increase in PFS (from 3 to 6 months) corresponding to a hazard ratio of 0.5, approximately 160 patients will be required to observe 105 events with 93.9% power and 2-sided significance level of 5%. MANTRA is currently open to enrollment. Citation Format: Mrinal Gounder, Gary Schwartz, Robin Jones, Shreyaskumar Patel, Silvia Stacchiotti, Andrew Wagner, Vijaya Tirunagaru, Naisargee Shah, Richard Bryce, Robert Doebele. MANTRA: A randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan (RAIN-32) versus trabectedin in patients with de-differentiated liposarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P031.

Population Pharmacokinetics of Meropenem in Preterm Infants

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

Postoperative Chemoradiotherapy With Capecitabine and Oxaliplatin vs Capecitabine for Stage II to III Rectal Cancer

Several studies have explored the efficacy and toxic effects of concurrent 5-fluorouracil (5-FU)- or capecitabine-based chemoradiotherapy (CRT) with or without oxaliplatin in the neoadjuvant setting. Addition of oxaliplatin to 5-FU or capecitabine elicited similar outcomes but with significantly increased toxic effects; however, there is a need for randomized clinical trials comparing 2 CRT regimens for patients receiving CRT in the adjuvant setting. To explore the efficacy and toxic effects of oxaliplatin combined with postoperative concurrent capecitabine and radiotherapy (RT) for pathological stage II and III rectal cancer. This multicenter randomized clinical trial enrolled patients from 7 centers in China between April 1, 2008, and December 30, 2015. Patients with pathologically confirmed stage II and III rectal cancer were randomized (1:1) to receive concurrent CRT with capecitabine or capecitabine plus oxaliplatin. Analysis was conducted from December 31, 2019, to March 15, 2020. RT comprised 45 to 50 Gy in 25 fractions of 1.8 to 2.0 Gy over 5 weeks. In the capecitabine with RT group, concurrent chemotherapy included 2 cycles of capecitabine (1600 mg/m2) on days 1 to 14 and 22 to 35. The capecitabine and oxaliplatin with RT group received identical postoperative RT to that in the capecitabine with RT group combined with capecitabine (1300 mg/m2) on days 1 to 14 and 22 to 35 and a 2-hour infusion of oxaliplatin (60 mg/m2) on weeks 1, 2, 4, and 5. Patients in both groups received adjuvant chemotherapy (capecitabine or fluorouracil and oxaliplatin) after CRT. The primary end point was 3-year disease-free survival (DFS). A total of 589 patients (median [IQR] age, 55 [47-52] years; 375 [63.7%] men and 214 [36.3%] women) were enrolled, including 294 patients randomized to the capecitabine with RT group and 295 patients randomized to the capecitabine and oxaliplatin with RT group. Median (IQR) follow-up was 68 (45-96) months. Most patients had stage III disease (574 patients [75.9%]). Three-year DFS was 76.3% for the capecitabine with RT group and 74.1% for the capecitabine and oxaliplatin with RT group, and 5-year DFS was 72.0% for the capecitabine with RT group and 71.1% for the capecitabine and oxaliplatin with RT group (hazard ratio [HR], 1.07; 95% CI, 0.79-1.44; P = .68). There was no significant difference between groups in overall survival (HR, 0.93; 95% CI, 0.64-1.34; P = .70) or local recurrence (HR, 0.61; 95% CI, 0.31-1.22; P = .16). More grade 3 and 4 acute toxic effects were observed in the capecitabine and oxaliplatin with RT group than in the capecitabine with RT group (114 patients [38.6%] vs 84 patients [28.6%]; P = .01). This randomized clinical trial found that addition of oxaliplatin to capecitabine-based postoperative CRT did not improve the efficacy of treatment but increased the risk of severe acute toxic effects. This finding highlights the basic role of postoperative capecitabine with RT for patients with locally advanced rectal cancer. ClinicalTrials.gov Identifier: NCT00714077.

Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial.

RationaleThe mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who require mechanical ventilation remains high, and endotheliopathy has been implicated.ObjectivesTo determine the effect of prostacyclin infusion in mechanically ventilated patients infected with SARS-CoV-2 with severe endotheliopathy.MethodsWe conducted a multicenter, randomized clinical trial in adults infected with coronavirus disease (COVID-19) who required mechanical ventilation and had a plasma level of thrombomodulin >4 ng/ml; patients were randomized to 72-hour infusion of prostacyclin 1 ng/kg/min or placebo.Measurements and Main ResultsThe main outcome was the number of days alive and without mechanical ventilation within 28 days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Eighty patients were randomized (41 prostacyclin and 39 placebo). The median number of days alive without mechanical ventilation at 28 days was 16.0 days (SD, 12) versus 5.0 days (SD, 10) (difference of the medians, 10.96 days; 95% confidence interval [CI], −5 to 21; P = 0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio, 0.50; 95% CI, 0.24 to 0.96; P = 0.06). The incidence of serious adverse events within 7 days was 2.4% versus 12.8% (risk ratio, 0.19; 95% CI, 0.001 to 1.11; P = 0.10) in the prostacyclin and the placebo groups, respectively.ConclusionsProstacyclin was not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28 days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials.Clinical trial registered with www.clinicaltrials.gov (NCT 04420741); EudraCT Identifier: 2020-001296-33.