30-minute Infusion Research Articles

Txagorrapid: Ultrarapid infusion in 30 minutes of the biosimilar of rituximab truxima—A cohort study.

e13638 Background: Rituximab (anti-CD20 Ab) is the cornerstone of the treatment of non-Hodgkin B lymphomas. Infusion-related reactions (IRR) are the most common adverse effects. To reduce them, intravenous premedication with antihistamine and acetaminophen is administered prior to rituximab. If no IRR after first infusion, subsequent infusions time takes 3-6 hours. Many centers use the rapid 90-minute infusion (off-label). Since 2017 subcutaneous rituximab formulation is available, that takes 5 minutes of administration. Nevertheless, in order to reduce cost, due to approval of biosimilars, some health providers continue using intravenous rituximab. On the other hand, with COVID pandemic, an effort to reduce visits and day-care hospitals stays has been made. In the current situation, it would be convenient to reduce day-care stay and the nursing care burden. We wanted to evaluate the safety of an ultrarapid infusion of biosimilar rituximab in a total time of 30 minutes by analyzing IRR and adverse events (AE). Methods: Since November 2021, 3 cohorts of ultrafast infusion have been studied as follows: One cohort (Cohort 1) with intravenous premedication with dexchlorpheniramine and acetaminophen, followed by rituximab infusion over 1 hour, and 2 cohorts with rituximab infusion over 30 minutes: Cohort 2: with intravenous premedication, and cohort 3 with oral premedication. IRR and adverse events have been independently reviewed and graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (November 27, 2017). Results: 34 patients have been included receiving 48 rituximab infusions (16 infusions in each cohort). Median age was 64 years old (range: 51-91). Diagnostic of NHL were as follows: large b cell: 10; follicular: 13; marginal: 7; mantle cell: 1, Waldeström: 1; Ritcher transformation: 2. Rituximab infusion was in monotherapy (21), and in combination (27) with: bendamustine: 9, CHOP: 17, GEMOX: 1. Considering safety, no IRR has been observed in cohort 1 (1 hour infusion), and 1 IRR grade II in cohort 3 (30 minutes, oral premedication). Other AE were: hypertension grade I and hypotension grade I, both in cohort 2. Conclusions: Ultrarapid rituximab infusion is safe. Oral premedication is feasibly allowing a total infusion time of 30 minutes. This infusion rate alleviates day-care burden saving between 75-90% of time in each rituximab infusion, reduce day-care stay and is comfortable for the patients. Clinical trial information: NCT05191225.

Treatment of osteoporosis in clinical practice: first experience with the Russian generic drug of zoledronic acid

Objective: to evaluate the effect of the generic drug of zoledronic acid on bone mineral density (BMD) and markers of bone metabolism in patients with osteoporosis (OP), as well as possible long-term adverse reactions (AR) 12 months after drug administration.Patients and methods. The study included 30 postmenopausal women with OP (mean age 64±8 years) who signed an informed consent of participance in clinical observation. Patients received a single dose of generic zoledronic acid (5 mg) as a 15-minute infusion. All patients additionally took calcium and vitamin D. The dynamics of BMD and bone metabolism markers, as well as the safety and tolerability of the drug, were evaluated. Fractures that might have occurred during follow-up should have been reported as ARs.Results and discussion. During treatment with generic zoledronic acid, the increase in BMD in the lumbar region was 4.9% (p<0.0001), in the femoral neck –2.7% (p<0.01), and in the femur as a whole – 3.0% (p<0.0001). Positive dynamics (increase in BMD>2%) in the spine was detected in 26 (86.7%) patients, in the proximal femur – in 20 (66.7%) patients. There was a decrease in the intensity of pain in both the thoracic (by 62%; p=0.038) and lumbar (by 29%; p=0.022) spine. Three months after the administration of the drug, a decrease in the level of bone metabolism markers was revealed: CTX – by an average of 29.7%, and P1NP – by an average of 25.5%. ARs were post-dose reactions that occurred within the first 48 hours after drug infusion. Remote ARs, fractures of peripheral bones and vertebrae were not recorded.Conclusion. The use of the generic drug of zoledronic acid has demonstrated its positive effect on BMD and markers of bone metabolism, as well as safety.

Stretch‐induced Myocardial Injury and Inflammation After Transient Vasopressin‐Mediated Left Ventricular Pressure Overload in Swine

ObjectiveUsing the α1‐adrenergic agonist phenylephrine (PE), we have previously demonstrated that an acute episode of transient pressure overload (TPO) elicits stretch‐induced myocardial injury and reversible left ventricular (LV) systolic dysfunction. Although this was accompanied by leukocyte mobilization, a rise in inflammatory cytokine levels, and increased pro‐inflammatory gene expression in the heart, the extent to which this resulted from direct activation of α1‐adrenergic receptors on immune cells vs. an inflammatory response to mechanical stretch‐induced myocardial injury is unclear. Accordingly, the present study was designed to determine if an inflammatory response to myocardial injury is evident when TPO is produced by vasopressin (VP), a vasoconstrictor without direct α1‐adrenergic agonist properties.MethodsHemodynamic and echocardiographic parameters were assessed in propofol‐anesthetized swine before, during, and after a 30‐minute infusion of VP (VP‐TPO; 0.04 U/kg/min, n=7) to increase LV end‐diastolic pressure (EDP) to ~30mmHg. Serial jugular venous blood sampling was performed to quantify circulating cardiac troponin I (cTnI), leukocytes, and inflammatory cytokines (TNF‐α and IL‐6) at baseline and 3‐hours after cessation of VP‐TPO. Leukocyte and cytokine levels were compared with those observed after PE‐mediated TPO in a separate group of animals (PE‐TPO; n=6).ResultsVP elicited a significant rise in mean arterial pressure (91±5 to 165±11 mmHg) and LV EDP (10±1 to 29±2 mmHg; both p<0.05 vs. baseline). This was accompanied by a significant rise in LV end‐diastolic volume (73±5 to 110±7 mL) and end‐systolic volume (20±3 to 53±6 mL), as well as a reduction in LV ejection fraction (EF; 72±3 to 52±3 %; all p<0.05 vs. baseline). One hour after cessation of VP‐TPO, LV EF remained depressed vs. baseline (60±3 %; p<0.05) and circulating cTnI levels began to rise, reaching a concentration that was ~10‐fold higher than baseline concentrations at the 3‐hour post‐TPO timepoint (18±5 to 118±21 ng/L; p<0.05). These changes were accompanied by a significant rise in circulating neutrophils, monocytes, TNF‐α, and IL‐6 that was similar to that observed after PE‐TPO (Figure).ConclusionsVP‐TPO elicits myocardial injury, leukocyte mobilization, and an acute rise in circulating pro‐inflammatory cytokines, thereby recapitulating several features of PE‐TPO in the absence of direct α1‐adrenergic stimulation. These findings suggest that stretch‐induced myocardial injury provokes an inflammatory response that may play an important role in promoting the development of cardiac fibrosis and diastolic dysfunction after exposure to repetitive episodes of TPO.

A Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP): Statistical analysis plan.

Background:Anaemia affectsmore than half ofAfrica'spregnancies.Standard care, with oral iron tablets,often fails to achieve results, with complianceandgastrointestinalside-effectsbeing a significant issue.In recent years,intravenousiron formulations havebecomesafe,effective,and quick to administer, allowingthecompleteiron requirementsofpregnancyto beprovidedin one15-minuteinfusion.The Randomized controlled trial of the Effect ofintraVenousiron on Anaemia in Malawian Pregnant women (REVAMP)will evaluate whethera modern intravenous ironformulation,ferriccarboxymaltose(FCM),given once during the second trimesteriseffective and safein improving maternal and neonatal outcomes for treatment of moderate to severe anaemiainsub-Saharan Africa. The objective was to publish the detailed statistical analysis plan for the REVAMP trial prior to unblinding the allocated treatments and performing the analysis. Methods:REVAMP is amulticentre, two-arm,open-label,parallel-grouprandomizedcontroltrial(RCT)in 862 pregnantwomen in their second trimester.The trial statistician developed the statistical analysis planin consultation with thetrial managementteambased on the protocol, data collection forms, and study outcomes available in the blinded study database. Results:The detailed statistical analysis plan will support the statistical analyses and reporting of the REVAMP trial after unblinding the treatment allocations. Conclusions:A statistical analysis planallows for transparency as well as reproducibility of reporting and statistical analyses.

A Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP): Statistical analysis plan

Background: Anaemia affects more than half of Africa’s pregnancies. Standard care, with oral iron tablets, often fails to achieve results, with compliance and gastrointestinal side-effects being a significant issue. In recent years, intravenous iron formulations have become safe, effective, and quick to administer, allowing the complete iron requirements of pregnancy to be provided in one 15-minute infusion. The Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP) will evaluate whether a modern intravenous iron formulation, ferric carboxymaltose (FCM), given once during the second trimester is effective and safe in improving maternal and neonatal outcomes for treatment of moderate to severe anaemia in sub-Saharan Africa. The objective was to publish the detailed statistical analysis plan for the REVAMP trial prior to unblinding the allocated treatments and performing the analysis. Methods: REVAMP is a multicentre, two-arm, open-label, parallel-group randomized control trial (RCT) in 862 pregnant women in their second trimester. The trial statistician developed the statistical analysis plan in consultation with the trial management team based on the protocol, data collection forms, and study outcomes available in the blinded study database. Results: The detailed statistical analysis plan will support the statistical analyses and reporting of the REVAMP trial after unblinding the treatment allocations. Conclusions: A statistical analysis plan allows for transparency as well as reproducibility of reporting and statistical analyses.

14P Flat-dose nivolumab (NIVO) as second-line (2L) treatment (tx) in Asian patients (pts) with advanced non-small cell lung cancer (NSCLC): CheckMate 870 long-term results

NIVO is approved in China as 2L tx for advanced NSCLC via weight-based 60-minute (min) infusion. We further investigated the safety and efficacy of the more convenient flat dosing via a 30-min infusion in pts with advanced NSCLC, including those with hepatis B virus (HBV) due to its prevalence in China. Asian (mostly Chinese) pts with previously treated advanced NSCLC received NIVO 240 mg over 30 min every 2 weeks (Q2W) for up to 2 years (y). High-grade (G3–5) select tx-related adverse events (sTRAE) were analysed by HBV infection status (primary endpoint). Secondary and exploratory endpoints included efficacy and patient-reported outcomes (PROs) among pt subgroups. Overall, 400 pts were treated: 383 non-HBV infected; 34 EGFR positive (+); 168 and 174 had PD-L1 ≥1% and <1%, respectively. Median (med) age was 61 y. Most pts were male (78.5%), had non-squamous histology (65.8%), and stage IV (77.3%) disease. Minimum follow-up (f/u) was 35.4 months (mo) and med tx duration was 3.24 mo. At a med f/u of 37.6 mo, occurrence of G3–4 sTRAE was low regardless of HBV status. No G5 sTRAEs were reported. Med overall survival was 14.2 (12.3–18.1) and 22.3 (10.0–NA) mo for non-HBV and HBV-infected, 19.3 (11.2–31.7) and 13.7 (11.5–18.1) mo for EGFR+ and negative, and 19.3 (12.9–23.5) and 13.3 (10.9–17.7) mo for PD-L1 ≥1% and <1% subgroups. No notable changes from baseline were observed in PROs among those subgroups.Table: 14PNon-HBVN=383HBVN=17G3−4 sTRAEs, n (%)Endocrine3 (0.8)1 (5.9)Gastrointestinal2 (0.5)0Hepatic8 (2.1)0Pulmonary5 (1.3)0Renal2 (0.5)0Skin7 (1.8)1 (5.9)Hypersensitivity00EfficacymOS, mo (95% CI)14.16 (12.25−18.07)22.31 (10.02−NA)2-year OS rate, % (95% CI)34 (29−39)44 (19−67)mPFS, mo (95% CI)3.61 (2.33−3.75)2.04 (1.64−10.22)2-year PFS rate, % (95% CI)10 (07−13)10 (01−34)ORR, % (95% CI)14.88 (11.47−18.85)17.65 (3.80−43.43)DOR, mo (95% CI)19.38 (11.04−24.97)NA (8.15−NA) Open table in a new tab NIVO 240 mg 30-min infusion Q2W was well-tolerated in Asian pts with previously treated advanced NSCLC, regardless of HBV, EGFR and PD-L1 status. Results were consistent with CheckMate 078 study. Data should be interpreted with caution given the small subgroup sample size.

Safety of Rapid Daratumumab Infusion: A Retrospective, Multicenter, Real-Life Analysis on 134 Patients With Multiple Myeloma.

BackgroundThe anti-CD38 monoclonal antibody daratumumab is the backbone of most anti-multiple myeloma (MM) regimens. To mitigate the risk of infusion-related reactions (IRRs), intravenous daratumumab administration requires 7 hours for the first infusion and 3.5-4 hours thereafter, thus making daratumumab-containing regimens burdensome for patients and health care resources. Preliminary data suggest that a rapid (90-minute) infusion of daratumumab is safe and does not increase IRRs. The rapid schedule was adopted by our centers since 2019.MethodsWe conducted an observational multi-center, real-life study to assess the safety of rapid daratumumab infusion protocol from the third administration in relapsed MM patients receiving daratumumab alone or in combination with lenalidomide-dexamethasone or bortezomib-dexamethasone. The primary endpoint was the safety of the rapid infusion protocol, particularly in terms of IRRs.ResultsA total of 134 MM patients were enrolled. IRRs occurred in 7 (5%) patients and were mostly mild (6/7 of grade 1-2), with only 1 patient experiencing a grade 3 IRR. Due to the IRRs, 5 (3.7%) patients discontinued the rapid infusions and resumed daratumumab at the standard infusion rate, while 1 patient permanently discontinued daratumumab. In 4/7 patients (57%), IRRs occurred while resuming rapid daratumumab infusions after a temporary interruption (2-4 months). No other adverse event was considered related to the rapid infusion protocol.ConclusionsOur findings confirmed the safety of rapid daratumumab infusions starting from the third administration. In case of prolonged daratumumab interruption, it is advisable to resume infusions at the standard rate (3.5 hours) before switching to the rapid infusion.

MANP (M-Atrial Natriuretic Peptide) Reduces Blood Pressure and Furosemide-Induced Increase in Aldosterone in Hypertension.

cGMP MANP (M-atrial natriuretic peptide) is a best-in-class activator of the pGC-A (particulate guanylyl cyclase A) receptor. Furosemide increases the effectiveness of antihypertensive agents, but activates renin-angiotensin-aldosterone system. We aimed to investigate for the first time cardiorenal and neurohumoral actions of MANP in a genetic model of hypertension in spontaneously hypertensive rats. We also assessed how MANP would potentiate the blood pressure (BP)-lowering actions of furosemide while reducing the production of aldosterone. Spontaneously hypertensive rats (N=60) were randomized in vehicle, MANP, furosemide, or MANP+furosemide groups. Furosemide (1, 5, 10 mg/kg) was given as a single bolus which in MANP+furosemide groups was followed by a 60-minute infusion of MANP. BP was reduced in MANP300 (300 pmol/[kg·min]) and MANP600 (600 pmol/[kg·min]) groups (P<0.05) and was accompanied by significant increase in plasma cyclic guanosine monophosphate. Furosemide alone reduced BP but less compared with MANP with no change in plasma cyclic guanosine monophosphate. MANP+furosemide resulted in the greatest BP reduction and significant increase in plasma cyclic guanosine monophosphate in Fs5+MANP300, Fs10+MANP300, and Fs10+MANP600. Plasma aldosterone increased in furosemide groups, which was significantly attenuated in MANP+furosemide groups. Natriuresis and diuresis increased in all treated groups (P<0.05) with no significant differences between furosemide and furosemide+MANP. In vitro, MANP increased cyclic guanosine monophosphate level in human vascular cells. We provide novel evidence that MANP potentiates the BP-lowering actions of furosemide, suppresses the activation of renin-angiotensin-aldosterone system, and preserves renal function. These data are highly relevant to clinical needs in the treatment of hypertension and heart failure.

Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

Sincalide-Stimulated Cholescintigraphy: A Retrospective Study and Proposal of a Modified Workflow.

Current guidelines for sincalide-stimulated cholescintigraphy (SSC) call for a 60-minute sincalide infusion, and a gallbladder ejection fraction (GBEF) ≥38% is considered normal. In this retrospective study, we hypothesize that most patients reach a normal GBEF by 30 minutes. Eligible patients had undergone a 60-minute SSC from January to December 2019. The clinical SSC data were previously processed on a Xeleris workstation (GE Healthcare). In subjects with GBEF ≥38% based on standard SSC, the GBEF at 20 minutes and 30 minutes were retrospectively calculated using manual pixel height measurements. Receiving operating characteristic was analyzed to determine the best GBEF cutoff at 30 minutes. Of 302 subjects, mean age of 46 ± 17 years, 33 (10.9%) showed an abnormal GBEF <38% suggestive of functional gallbladder disorder. In the remaining 269 patients (89.1%) with a normal GBEF, 60.6% and 86.6% reached a normal GBEF at 20 minutes and 30 minutes, respectively. Moreover, a GBEF threshold >29.1% at 30 minutes was associated with a negative predictive value of 99.6%, indicating that a 60-minute SSC was not necessary. The GBEF values were not associated with sex, age, patient symptoms, or type of referral. Manually calculated GBEFs on the time-activity curve showed excellent correlation with the primary values. We propose a modified workflow that splits the 60-minute SSC into two 30-minute image sets to allow for a screening GBEF at 30 minutes. If GBEF is >29.1% at 30 minutes, the second image set may be stopped, and the examination is complete. The majority of patients (77.2%) undergoing the standard 60-minute SSC reach a normal GBEF already by 30 minutes. The proposed workflow shortens the SCC procedure by 30 minutes, while maintaining high diagnostic accuracy and contributing to improved procedure efficiency and reduced patient discomfort as well as symptoms.

A Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP): Statistical analysis plan.

Background:Anaemia affectsmore than half ofAfrica'spregnancies.Standard care, with oral iron tablets,often fails to achieve results, with complianceandgastrointestinalside-effectsbeing a significant issue.In recent years,intravenousiron formulations havebecomesafe,effective,and quick to administer, allowingthecompleteiron requirementsofpregnancyto beprovidedin one15-minuteinfusion.The Randomized controlled trial of the Effect ofintraVenousiron on Anaemia in Malawian Pregnant women (REVAMP)will evaluate whethera modern intravenous ironformulation,ferriccarboxymaltose(FCM),given once during the second trimesteriseffective and safein improving maternal and neonatal outcomes for treatment of moderate to severe anaemiainsub-Saharan Africa. The objective was to publish the detailed statistical analysis plan for the REVAMP trial prior to unblinding the allocated treatments and performing the analysis. Methods:REVAMP is amulticentre, two-arm,open-label,parallel-grouprandomizedcontroltrial(RCT)in 862 pregnantwomen in their second trimester.The trial statistician developed the statistical analysis planin consultation with thetrial managementteambased on the protocol, data collection forms, and study outcomes available in the blinded study database. Results:The detailed statistical analysis plan will support the statistical analyses and reporting of the REVAMP trial after unblinding the treatment allocations. Conclusions:A statistical analysis planallows for transparency as well as reproducibility of reporting and statistical analyses.

1087. Imipenem-Cilastatin-Relebactam (I/R) Pharmacokinetics (PK) in Critically Ill Patients with Augmented Renal Clearance (ARC)

BackgroundImipenem (IMI) and relebactam (REL) are predominantly excreted via glomerular filtration. ARC is a common syndrome in critically ill patients with sepsis, whereby increased renal blood flow may result in enhanced solute clearance; therefore, sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the PK of I/R in critically-ill patients with confirmed ARC. MethodsInfected patients in the intensive care unit with ARC (CrCl ≥130 mL/min) received a single dose of I/R 1.25g as a 30min infusion. Blood samples were collected over 6 hours (hr) for IMI and REL concentration determination by a validated LC/MS/MS assay. Protein binding was assessed at 0.5hr by ultrafiltration (UF). An 8hr urine creatinine (UCr) collection was performed to confirm ARC. IMI and REL plasma concentrations were fitted to compartmental models in WinNonlin. Simulated concentration vs time profiles were used to assess attainment of pharmacodynamic (PD) targets for IMI (30%fT >MIC) and REL (fAUC:MIC 18) at the susceptibility breakpoint of 2 mg/L. ResultsFive patients (60% female) completed the study. Mean (SD) age, weight, and APACHE II were 43 (14) years, 90 (15) kg, and 16 (6), respectively. All patients had confirmed ARC with CrCl of 160.6 ± 47.0 mL/min (range: 135-244mL/min) based on UCr. Both IMI and REL concentrations fitted a 2-compartment better than 1-compartment model. IMI PK was: clearance, 17.9 ± 8.7 L/hr; volume of central compartment, 15.6 ± 11.2 L; volume of peripheral compartment, 10.6 ± 5.4 L; and intercompartmental clearance, 16.6 ± 14.5 L/hr. REL PK parameters were 11.9 ± 7.5 L/hr, 17.0 ± 11.3 L, 13.5 ± 9.9 L, and 13.4 ± 11.1 L/hr, respectively. Half-life was 1.5 ± 0.5 for IMI and 2.8 ± 2.2 hr for REL. Protein binding for IMI ranged from 0-10%, while REL was 0-14%. IMI fT >MIC ranged from 40-90%, and REL fAUC:MIC ranged from 22.6-59.0. ConclusionThese are the first data to describe IMI and REL PK in critically-ill infected patients with ARC. Despite plasma clearance values greater than those reported in healthy volunteers and patients in clinical trials, I/R 1.25g as a 30 minute infusion provided optimal exposure in all patients for isolates with MICs ≤2 mg/L. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)

Abstract PR-002: A phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: Effective therapy for the treatment of PDAC remains one of the greatest unmet oncology clinical needs. The addition of C to G and AP has shown 71% ORR in a previously reported study [JAMA Oncol. 2019 Oct 3;6(1):125-32]. In preclinical work, vitamin D (Vit D) analog therapy decreases myeloid derived suppressor cells and regulatory T cells, turning PDAC into a more immune favorable microenvironment. This trial combines AP/C/G with Vit D analog P and the anti-PD-1 antibody N as a combination therapy for patients with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in that patient population (NCT02754726). Methods: Eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70, and RECIST 1.1 measurable disease. Doses are AP 125 mg/m2, G 1000 mg/m2, each infused over 30 minutes with C 25 mg/m2 infused over 60 minutes on days 1, 8, 22, and 29 of a 42-day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV twice weekly. Primary objective was to determine the efficacy of the combination for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective was to evaluate safety in patients with previously untreated metastatic PDAC. Exploratory endpoints include evaluating tissue molecular profile as it relates to treatment outcomes. Results: Trial was conducted May 2016 with enrollment completed August 2020. 35 patients have been enrolled in the study and 32 are evaluable (baseline and ≥1 follow up CT scan). Most common drug-related grade (Gr) 3-4 adverse events (AE’s), are thrombocytopenia 76% (gr 3 = 34%, gr 4 = 28%) with no serious bleeding events, anemia 37% (gr 3 = 37%, gr 4 = 0%), and CIPN 11% (gr 3 = 11%, gr 4 = 0%). Immune Related Adverse Events &amp;gt;5% were colitis (gr 3=8.6%, gr 4= 0%) and dermatitis (gr 3=8.6%, gr 4= 0%). By RECIST 1.1 criteria, the best response is 1 CR, 26 PR, 4 SD, 1 PD, yielding an 84% ORR (95% CI = (67%, 95%). Median PFS is 6 months (95% CI = (5, 8)). Median OS is 18 months (95% CI = (13, 22)). Conclusions: Although a small study, the high response rate is encouraging. Evaluation of exploratory endpoints is ongoing. Pursuing this regimen in localized PDAC is warranted due to its high ORR. Supported by grants from the Seena Magowitz Foundation, Mattress Firm, Bristol Myers Squibb, and SU2C. Citation Format: Erkut Borazanci, Gayle S. Jameson, Sunil Sharma, Frank Tsai, Ronald L. Korn, Lana Caldwell, Karen Ansaldo, David T. Ting, Denise Roe, Anna Bermudez, Daniel D. Von Hoff. A phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-002.

PORT (OP-109): Phase 2, Randomized, Pharmacokinetic (PK), Cross-over Study of Peripheral Vs Central Intravenous Administration of Melflufen in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Melphalan flufenamide (melflufen) is a peptide-drug conjugate with unique PK properties that rapidly penetrates cells, where it is metabolized to melphalan either directly or through an intermediate metabolite, desethyl-melflufen. Melflufen has only been administered via central venous catheter (CVC); however, peripheral venous catheter (PVC) administration may be preferred by patients if safety and tolerability are acceptable. The ongoing PORT study (NCT04412707) aims to compare the PK of melphalan after central and peripheral administration of melflufen, and to assess the local tolerability of peripheral administration of melflufen. The overall efficacy and safety of melflufen in patients with RRMM will also be evaluated.Methods: Patients (following ≥2 lines of prior therapy) were randomized (1:1) to melflufen 40 mg (administered on Day 1 of each cycle; combined with weekly oral dexamethasone 40 mg [20 mg for patients aged ≥75 years] on Days 1, 8, 15, and 22) either via PVC in Cycle 1 then CVC in Cycle 2 (Arm A) or via CVC in Cycle 1 and then PVC in Cycle 2 (Arm B). From Cycle 2 (Arm A) or Cycle 3 (Arm B) onward, patients received melflufen via CVC. PK sampling was performed frequently during and after the 30-minute melflufen infusion. Primary endpoints were maximum observed concentration (C max), area under the concentration-time profile from start of infusion to both last measurable concentration (AUC 0-t) and infinity (AUC 0-inf) for melphalan, and frequency and severity of PVC-related local infusion-site reactions. Secondary endpoints included PK variables for melflufen and desethyl-melflufen and general safety and tolerability. PK parameters after CVC and PVC administration were compared using bioequivalence methods. Patient satisfaction and nurse convenience after CVC and PVC administration (Day 1 of Cycles 1 and 2) were also explored.Results: At data cutoff (June 2, 2021), 27 patients had received melflufen (median age 67 years; 48.1% male), of whom 19 patients received at least 2 doses and were evaluable for PK analysis. Melphalan C max, AUC 0-t, and AUC 0-inf met bioequivalence criteria for CVC and PVC administration, as demonstrated by a 90% confidence interval (CI) for the ratio of means within 80-125%. Geometric mean melphalan concentration over time by CVC vs PVC is shown in Figure 1. For melflufen, the ratio of means was 107-117% for the PK parameters, with all upper 90% CIs above 125%. For desethyl-melflufen, AUC 0-t and AUC 0-inf met bioequivalence criteria and the 90% CI for C max was marginally above the upper limit (127%). Melflufen disappeared rapidly from plasma after the end of infusion, with an average half-life of 5-7 minutes. Melphalan C max was observed on average 7-9 minutes after the end of melflufen infusion for both routes of administration, which reflects the delay in distribution of melphalan from tissues to plasma. Furthermore, there were no local or systemic tolerability issues reported, and patient-reported satisfaction and nurse-reported convenience were comparable for CVC and PVC melflufen administration. The overall melflufen safety profile was in line with previous studies.Conclusions: Systemic melphalan exposure is similar after melflufen PVC and CVC administration. Differences between PVC- and CVC-related PK parameters for melflufen and desethyl-melflufen are considered to have no clinical consequences because their plasma-exposure duration is short. There were no local reactions after melflufen PVC administration. [Display omitted] DisclosuresMinarik: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Micheva: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Andzhelini Farma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Usenko: AbbVie: Consultancy, Honoraria, Other: Clinical Trials Investigator; Janssen: Consultancy, Honoraria, Other: Clinical Trials Investigator; Pfizer: Consultancy, Honoraria; Acerta: Other: Clinical Trials Investigator; Ascentage: Other: Clinical Trials Investigator; Celgene: Other: Clinical Trials Investigator; Il-Yang: Other: Clinical Trials Investigator; Karyopharm: Other: Clinical Trials Investigator; Oncopeptides: Other: Clinical Trials Investigator; Rigel: Other: Clinical Trials Investigator; Takeda: Other: Clinical Trials Investigator; UCB: Other: Clinical Trials Investigator. Mikala: Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Thuresson: Oncopeptides AB: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jerling: Oncopeptides: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Xie: Oncopeptides: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Successful Treatment of Acute Myeloid Leukemia with CPX-351 in 2 Patients in the United Kingdom during the COVID-19 Pandemic

Introduction: The COVID-19 pandemic hit the United Kingdom in early 2020. High infection rates prompted concern for immunocompromised patients, including patients with AML receiving intensive chemotherapy. CPX-351 (Europe: Vyxeos ® Liposomal; US: Vyxeos ®), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults in Europe and in adults and pediatric patients aged ≥1 year in the United States. Despite concerns about intensive chemotherapy-related myelosuppression, the National Cancer Research Institute AML Working Group recommends that CPX-351 should continue to be administered in patients with adverse-risk cytogenetics and/or secondary AML during the pandemic. We report 2 patients with AML who were successfully treated with CPX-351 in the United Kingdom during the COVID-19 pandemic.Methods: The patients were diagnosed and managed per institutional guidelines. Two patients received CPX-351 induction (daunorubicin 44 mg/m 2 + cytarabine 100 mg/m 2) on Days 1, 3, and 5 (Days 1 and 3 for second induction) and CPX-351 consolidation (daunorubicin 29 mg/m 2 + cytarabine 65 mg/m 2) on Days 1 and 3, all by 90-minute IV infusion, during the pandemic.Results: The first patient was a 67-year-old male who presented with generalized fatigue in June 2020 with comorbidities of type 2 diabetes, diabetic nephropathy, and leg ulcers. Blood counts demonstrated a hemoglobin count of 79 g/L, white blood cell count of 0.7×10 9, platelet count of 58×10 9/L, and neutrophil count of 0.2×10 9/L. A bone marrow biopsy revealed AML-MRC with 40% blasts, and the patient had wild-type FLT3, NPM1, and SRSF2. The patient achieved morphologic and cytogenetic remission after 2 CPX-351 induction cycles. The patient then received 1 CPX-351 consolidation cycle but was not a candidate for transplant due to diabetic nephropathy. Tolerability improved with each cycle; the patient experienced neutropenic sepsis during the first induction, a flare up of leg ulcers and cellulitis during the second induction, and no tolerability concerns during the consolidation cycle. After the first induction, recovery of neutrophils and platelets occurred around Day 35 and Day 28, respectively (Figure 1), and counts recovered more quickly with each cycle. This patient was managed without contracting COVID-19 or experiencing any pandemic-related complications.The second patient was a 69-year-old female who presented with pancytopenia in February 2020 with no significant past medical or drug history. Her hemoglobin count was 66 g/L, white blood cell count was 0.6×10 9/L, platelet count was 17×10 9/L, and neutrophil count was 0.3×10 9/L. The patient was diagnosed with AML-MRC with mutated NPM1, SRSF2, IDH2, and JA2. During the first CPX-351 induction cycle, the patient contracted COVID-19. Some symptoms were present, but the patient did not become significantly unwell from COVID-19. Despite count recovery, the patient remained positive by nasal/oral PCR swab test for several weeks, delaying the delivery of the second CPX-351 induction cycle. After the second CPX-351 cycle began, the patient once again became positive for COVID-19 by PCR swab. The patient remained positive for longer than the first infection but was largely asymptomatic during the cycle (apart from a bout of sepsis). After a period of approximately 3 months from the previous CPX-351 cycle, the patient received a CPX-351 consolidation cycle and achieved complete remission with no measurable residual disease by NPM1 mutation in the bone marrow (Figure 2). The patient was eligible for transplant but declined.Conclusions: Two patients with AML-MRC were successfully treated with CPX-351 during the COVID-19 pandemic, despite one of the patients contracting and variably testing positive for the disease. During the pandemic, it is important to weigh the benefits of treating AML with curative intent versus the risks of immunosuppression and potential COVID-19 infection. Individualized decisions must be made for each patient based on disease, treatment, and COVID-19 risk factors through discussion with a multidisciplinary team. Although treating patients with AML with CPX-351 during the pandemic can be challenging, it remains an option for appropriate patients with newly diagnosed t-AML or AML-MRC. [Display omitted] DisclosuresMunisamy: Roche: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Choudhuri: AstraZeneca, Bristol-Myers Squibb, Jazz Pharmaceuticals, and Pfizer: Consultancy.

Clinical Characteristics and Responses of Patients with Relapsed or Refractory High-Grade B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Clinical Trial

Clinical Characteristics and Responses of Patients with Relapsed or Refractory High-Grade B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Clinical Trial

The Anti-CD19 Antibody-Drug Conjugate Loncastuximab Tesirine Achieved Responses in Patients with Diffuse Large B-Cell Lymphoma Who Relapsed after Anti-CD19 CAR T-Cell Therapy

The Anti-CD19 Antibody-Drug Conjugate Loncastuximab Tesirine Achieved Responses in Patients with Diffuse Large B-Cell Lymphoma Who Relapsed after Anti-CD19 CAR T-Cell Therapy

Safety and Early Efficacy of Obinutuzumab in Combination with Chemotherapy in Treatment Naive Patients with Follicular Lymphoma - Report of Polish Lymphoma Research Group (PLRG)

Safety and Early Efficacy of Obinutuzumab in Combination with Chemotherapy in Treatment Naive Patients with Follicular Lymphoma - Report of Polish Lymphoma Research Group (PLRG)

Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol.

We investigated the hemodynamic effects of 2 short-acting β1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 μg/kg/min esmolol or 10 μg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of β-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of β-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for β-blockers, whereas the blood pressure effects are likely due to direct and indirect β-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.