Shorter Infusion Time Research Articles

Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants

PurposeFacilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically.MethodsThis phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint.ResultsOf 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms.ConclusionThe favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Hypoxic environment of wounds and photosynthesis-based oxygen therapy.

The hypoxic environment is among the most important factors that complicates the healing of chronic wounds, such as venous leg ulcers, pressure injuries and diabetic foot ulcers, which seriously affects the quality of life of patients. Various oxygen supply treatments are used in clinical practice to improve the hypoxic environment at the wound site. However, problems still occur, such as insufficient oxygen supply, short oxygen infusion time and potential biosafety risks. In recent years, artificial photosynthetic systems have become a research hotspot in the fields of materials and energy. Photosynthesis is expected to improve the oxygen level at wound sites and promote wound healing because the method provides a continuous oxygen supply and has good biosafety. In this paper, oxygen treatment methods for wounds are reviewed, and the oxygen supply principle and construction of artificial photosynthesis systems are described. Finally, research progress on the photosynthetic oxygen production system to promote wound healing is summarized.

Phase 1/2 Trial to Jointly Optimize Dose and Administration Schedule of Evomela in Newly Diagnosed Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Background: Eligible patients with multiple myeloma (MM) are offered autologous hematopoietic cell transplantation (auto-HCT) in their first remission. The usual conditioning regimen consists of melphalan (Alkeran) 200 mg/m 2 infused over ~ 30 minutes due to its limited stability. Evomela is a newer formulation of melphalan, which is stable at room temperature for ~ 24 hours. The current trial studied the dose escalation and compared the short versus extended infusion time of evomela used as a conditioning regimen before auto-HCT. Methods: Patients with newly diagnosed MM, age ≤ 70, were eligible. Two dose levels, 200 and 225 mg/m 2 were studied. Patients were randomized between two infusion schedules: 30-60 minutes (short) and an extended infusion of 8-9 hours. Disease response was measured using IMWG criteria. Minimal residual disease (MRD) was measured by flow cytometry at 10 -5. Results: Sixty patients were enrolled. The first 3 patients in each arm were treated at evomela 200 mg/m 2. Since no dose-limiting toxicity (DLT) was observed, all subsequent patients (n=54; 27 in each arm) were treated at evomela 225 mg/m 2. The results are presented for patients treated at evomela 225 mg/m 2. Patient characteristics were evenly distributed (Table 1). The median age was 58.6 years (range: 42.6 -70.3). Twelve (22%) patients had high-risk cytogenetics (4 [15%] in the short infusion; 8 [30%] in the extended infusion arm), p-value 0.19. There were no deaths, and no patient experienced grade > 3 adverse events (AE). Grade 2-3 AEs were seen in 53 (98%) patients (26 [96%] in the short infusion; 27 [100%] in the extended infusion). Twenty-four (44%) patients experience grade 2-3 diarrhea (16 [60%] in the short infusion; 8 [30%] in the extended infusion). Grade 2-3 esophagitis was seen in 3 (6%) patients overall (0 in the short infusion; 3 [11%] in the extended infusion). Atrial fibrillation was seen in one patient (grade 2, extended infusion). Before transplant, six (22%) patients were in stringent complete remission (sCR) or CR in the short infusion arm vs. 4 (15%) patients in the extended infusion arm. At day-90 post-transplant, 13 (48%) patients in each arm were in sCR/CR, and 17 (63%) patients in each arm achieved MRD-negative status. Overall, 23 (43%) patients achieved MRD-negative plus sCR/CR status at day-90 (11 [41%] in short and 12 [50%] in the extended infusion arm). The median follow-up was 14.5 (range: 6-40) months (13.8 months in the short infusion and 14.8 months in the extended infusion arm). The median progression-free survival (PFS) was not reached in the overall trial population (Figure). The median PFS in the short infusion arm was not reached vs. 28.2 months in the extended infusion arm. The 2-year progression-free survival (PFS) was 91% in the short infusion arm vs. 77% in the extended infusion arm (hazard ratio (HR)=9.5 with 95% CI: 1- 91.2), p-value=0.022. On multivariate analysis, controlling for age and cytogenetic risk category, the extended infusion arm was associated with a shorter PFS (HR 10.96; 95% CI 1.18 - 102.02), p-value 0.0355, although the range for HR was notably wide, which could be attributed to a small number of events in each arm. Conclusions: Dose escalation of evomela to 225 mg/m 2 is safe and associated with an acceptable toxicity profile and a high response rate. Short and extended infusions of evomela are well-tolerated and associated with high response rates. The PFS is longer with the short infusion schedule, however, to affirm these preliminary observations, additional follow-up is needed.

Clinical Pharmacokinetics and Pharmacodynamics of Daratumumab.

Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6-9 weeks followed by a less frequent dosing regimen, once every 2-4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure-efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg of daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related reactions are frequently observed in patients given daratumumab, particularly with the first infusion, thus prompting long durations of infusion (~ 7 h) and splitting of the first dose across 2 days. This led to the development of a subcutaneous delivery formulation for daratumumab (Dara-SC). Dara-SC provides a similar efficacy and safety profile to intravenous daratumumab (Dara-IV) but has a much lower rate of infusion-related reactions and a shorter infusion time. Exposure-response relationships for efficacy and safety endpoints were similar between Dara-SC and Dara-IV, and co-administered drugs with either Dara-IV or Dara-SC do not significantly affect daratumumab PK. Except for baseline myeloma type and albumin level, none of the other investigated disease and patient characteristics (renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group performance status) was identified to have clinically relevant effects on exposure to daratumumab monotherapy or combination therapy regimens. Dara-IV exposure was significantly lower in patients with immunoglobulin G myeloma compared with patients with non-immunoglobulin G myeloma (p < 0.0001) and in patients with a lower albumin level, whereas the overall response rate was similar regardless of the myeloma type and albumin level. Daratumumab dose adjustment is not currently recommended based on disease and patient characteristics.

Infusion-Related Reactions With Ocrelizumab: Risk Factors, Symptom Management and Patient Choices in the ENSEMBLE PLUS Study (P7-3.003)

Infusion-Related Reactions With Ocrelizumab: Risk Factors, Symptom Management and Patient Choices in the ENSEMBLE PLUS Study (P7-3.003)

611. Meropenem Dosage Optimization in Critically Ill Patients Based on a Population Pharmacokinetic Approach.

Abstract Background Meropenem (MRP) is commonly used to treat serious infections and displays wide variability in plasma concentrations after administration of the same dose in critically ill patients due to factors that affect MRP volume of distribution (V) and clearance (CL) (e.g. edema, sepsis, kidney failure). These alterations could lead to not achieve the pharmacokinetic/pharmacodinamic (PK/PD) target with the consequent failure of antibacterial therapy. The aim of this study was to describe MRP pharmacokinetic parameters in critically ill patients in order to establish safe and effective initial dosing regimens adapted to patients characteristics. Methods This prospective observational study enrolled 78 critically ill patients receiving MRP based on the clinical, biochemical and microbiological findings. Blood sampling occurred at pre-dose, 1, 3 and 6h post-dose. MRP plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modelling and Monte Carlo simulations were executed with NONMEM. Several regimen dosages of MRP under different scenarios were simulated in order to achieve high probability of target attainment (PTA &amp;gt; 90%) for PK/PD targets of %t &amp;gt; CMI 50% and 100%. Results In critically-ill Mexican patients, MRP PK were best described by a one compartment model. The final population model was: CL (L/h) = 11.9 ∗ (CLCr/102.23) and V (L) = 25.2. Final model was internally validated proving that it was stable and showed an adequate estimation of variability. Precision and bias fit were assessed through external validation comparing the predictive performance of the base and final models. Different initial dosage regimens were found for CLCr values in which the clinician can choose between a lower dose, a longer dosage interval or a shorter infusion time. However, for patients with augmented renal clearance or PK/PD target 100%t &amp;gt; MIC it was observed that no regimen complied PTA &amp;gt; 90%, suggesting a continuous infusion would be more appropriate. Conclusion This study demonstrates the wide variability in MRP pharmacokinetics and enhances the need to include therapeutic drug monitoring as part of stewardships interventions in critically ill patients to maximize bacteriological and clinical responses. Disclosures All Authors: No reported disclosures.

Ketamine as potential treatment for postpartum depression: A narrative review.

Postpartum depression (PPD) is a severe, debilitating mood disorder with consequences for both mothers and children, highlighting the need for rapid-acting and effective treatments for PPD. The aim of this narrative review is to synthesize the available literature on the administration of ketamine for PPD and propose ketamine as a viable and advantageous treatment. A search was conducted on MEDLINE/PubMed, PsycInfo, and Embase databases from inception to October 10, 2021 for preclinical studies, interventional studies (ie, open-label and randomized controlled trials), as well as systematic reviews and meta-analyses evaluating the use of ketamine in postpartum populations. Completed and ongoing clinical trials were identified on ClinicalTrials.gov. Four clinical trials were identified. Results from this review support additional investigation into ketamine as a potential treatment for PPD. Ketamine may be a favorable option for treating PPD due to its antidepressive and analgesic effects, short infusion time, and rapid clearance from the maternal bloodstream. However, there is insufficient evidence to support its use in this population, underscoring the importance of additional clinical research investigating ketamine for PPD.

Burden of cremophor-related paclitaxel therapy on patients with ovarian cancer: A patient focused study from the United Kingdom, Germany, and Spain.

e17576 Background: Cremophor EL (CrEL) is a solubilizer used in paclitaxel and is associated with side effects (i.e., hypersensitivity reactions, peripheral neuropathy). Current CrEL-containing therapies require long infusion times (2-4 hours) and pre-medication with steroids to manage these side-effects. However, the holistic burden of CrEL on patients is not well studied. This study aimed to characterize the burden associated with CrEL-paclitaxel treatment on patients with ovarian cancer, including clinical, safety, and quality of life (QoL) implications. Methods: This quantitative, Institutional Review Board (IRB) approved, cross-sectional survey of patients (≥18 years) who received ≥3 cycles of CrEL-containing paclitaxel within the prior 6 months was conducted in UK, Germany, and Spain in 2021. Data were collected via a web-enabled instrument including a screener, questionnaire, and validated Functional Assessment of Cancer Therapy (FACT)-Taxane scale. Results are reported overall for the 3 countries. Results: Of the 90 patients surveyed, the mean age was 38.8 years. Most patients reported improvement of QoL (77%), treatment effectiveness (77%), less need for pre-medications (74%), and manageable/less disruptive infusion times and schedules (71%) as extremely desirable treatment attributes. Prior to or during chemotherapy, 41% of patients reported receiving steroids. Most patients (71%) experienced 3-6 side effects related to ovarian cancer treatment. Of the patients that experienced neuropathy (27%), the side effect lasted for up to 1 week for 54% of patients, and over multiple cycles of treatment (&gt; 3 weeks) for 13% of patients. Of the 82% of patients eligible to complete the FACT-Taxane scale, 62% were somewhat to very much bothered by the side effects of paclitaxel. Half of these patients reported tingling/numbness in their hands/feet, moderately or very often. Patients reported an average of 4.8 hours as the time taken for their travels to/from the infusion center and receive their medication. Additionally, 91% of patients needed caregiver support for an average of 16 hours per week. 51% of patients reduced their work hours due to treatment and 58% reported a substantial impact on work productivity. To cover treatment costs, 63% purchased supplemental insurance. Conclusions: The patient-reported burden of treatment associated with CrEL-containing paclitaxel is significant and complex. Multiple treatment side effects occur in most patients which are burdensome and can recur and/or persist with future treatment cycles. There is an unmet need for an effective therapy that reduces treatment burden for patients and improves tolerability through fewer side effects, a reduced need for premedication, and shorter infusion time.

Safety of rapid intravenous paracetamol infusion in paediatric patients

PurposeParacetamol is recommended as a first-line treatment for pain and fever in paediatric patients. Intravenous (IV) infusions are recommended to be administered as a 15-min infusion to minimize local tissue trauma and related pain. The purpose of this study was to demonstrate that IV paracetamol could be administered during 5 ​min or less in paediatric patients without causing related adverse reactions. MethodsProspective, observational safety study including children aged <18 years who received IV paracetamol. Pain scores before and after the paracetamol infusions were obtained using VAS, FLACC, COMFORT neo, or COMFORT behaviour scales with scores from 0 to 10 representing no pain to worst pain. Further, objective signs of inflammation at the infusion site were registered. FindingsWe included 44 patients (median age 2.8 years, range 0.01–17.0 years) who received paracetamol in a peripheral venous catheter (n ​= ​22) or central venous catheter (n ​= ​22). In total, the 93 paracetamol infusions had a median infusion time of 3:00 ​min, range 0:40 to 5:00 ​min. After infusions, pain scores were lower, compared to before infusions (mean change −0.26, 95% confidence interval −0.45 to −0.07, P ​= ​0.007), and no objective signs of inflammation were reported. ImplicationsThis safety study indicates that IV paracetamol can be administered in paediatric patients with a shorter infusion time than recommended without causing adverse reactions. The results may contribute to a more efficient workflow at paediatric departments.

Anti-D immunoglobulin versus immunoglobulin G for the treatment of acute immune thrombocytopenia in children: a 10-year retrospective study

BackgroundAnti-D immunoglobulin (anti-D) therapy is cheaper and has a shorter infusion time than intravenous immunoglobulin G (IgG), but their comparative effects in the treatment of acute immune thrombocytopenia (ITP) have not been studied thoroughly. The aim of this study was to compare the effect of anti-D and intravenous IgG in the treatment of acute ITP in children. MethodsThe medical records of children diagnosed with acute ITP between January, 2008, and January, 2018, at Al-Rantisy Specialized Pediatric Hospital (a tertiary care centre) in Gaza were reviewed. Patients who received either intravenous anti-D (75 μg/kg, single dose) or intravenous IgG (2 g/kg, divided doses) as initial treatment for ITP were included in this retrospective study. Data on patient demographics, hospital stay period, and adverse drug reactions were collected for analysis. Laboratory results, including platelet counts and haemoglobin levels, were evaluated before treatment, and after 1, 3, 5, and 7 days of treatment. The therapy response was defined as the time taken to increase the platelet count to at least 20,000 platelets per μL. FindingsData from 134 patients (mean age, 5·8 years; range, 1·1–10·4 years) were included for analysis. 32% of patients (43 of 134) received anti-D and 68% of patients (91) received intravenous IgG. Mean pre-treatment platelet counts were 6420 platelets per μL and 8750 platelets per μL for anti-D and intravenous IgG groups, respectively. The platelet count increased significantly after 1, 3, 5, and 7 days of treatment in both groups (p<0·001). After 24 h of treatment, 58% of patients (25 of 43) in the anti-D group and 55% of patients (50 of 91) in the intravenous IgG group had platelet counts of over 20 000 platelets per μL. Moreover, all of the patients in both groups had more than 20 000 platelets per μL after 7 days of therapy. There were no significant differences in platelet count after treatment between the two groups. Haemoglobin levels decreased during the 72 h after treatment (anti-D group, mean 0·8 g/dL, range, 0·1–1·4 g/dL; intravenous IgG group, mean 0·5 g/dL, range, 0·2–1·2 g/dL; p=0·237), but increased on days 5 and 7 in both groups. The changes in haemoglobin after treatment were similar in both study groups. No patient developed severe anaemia requiring medical intervention. The average length of hospital stay was significantly shorter in the anti-D group than in the intravenous IgG group (1·8 days and 3·2 days, respectively; p<0·0001). Fewer adverse effects (headache, vomiting, chills) were reported in children who received anti-D therapy. InterpretationIn this analysis, anti-D was as effective as intravenous IgG in the treatment of children with acute ITP. Given that patients in the anti-D group experienced fewer adverse effects and shorter hospitalisation times than patients in the intravenous IgG group, this suggests that anti-D is a good substitute for intravenous IgG in the treatment of children with acute ITP. FundingNone.

Phase II trial of atezolizumab (A) + carboplatin (C) + pemetrexed (P) + bevacizumab (B) in pts with stage IV non-squamous non-small cell lung cancer (NSq-NSCLC): Big Ten Cancer Research Consortium Study LUN 17-139.

9034 Background: The addition of A to C+ Paclitaxel (Pac) + plus B improved progression free survival (PFS) and overall survival (OS) compared with C + Pac + B alone in pts with metastatic NS-NSCLC. However, C + Pem is more commonly used for this patient population with a shorter infusion time and favorable toxicity profile compared with Pac. Methods: Multicenter single arm phase II clinical trial of chemo and immunotherapy-naïve pts with stage IV NSq-NSCLC. All pts received A (1200 mg, D1) + C (AUC 5, D1) + P (500 mg/m2, D1) + B (15mg/kg D1) q3 week x4. If non-PD, pts could receive maintenance APB until PD or intolerable side effects. The primary endpoint was 1 yr. PFS. Sample size of 42 planned with 87% power and two-sided type I error of 0.05 for 1 yr PFS. Secondary endpoints included ORR, disease control rate (DCR) [defined by CR + PR + SD], and toxicity. Results: 30 pts were enrolled from 11/15/2018 to 10/5/2020. The study was closed early due to 3 patient deaths, possibly related to treatment (VTE, Febrile neutropenia, colonic perforation). Median age 64 (range 38-83); M/F 20/10; mutations in EGFR/ALK/KRAS/BRAF (5/1/4/2); PD-L1 TPS &lt; 1%/1-49%/ &gt; 50% (9/14/6) and one pt did not have PDL-1 status. Median f/u was11.6 mos (range 1-20). ORR 35.71% (95% CI: 18.64%-55.95%), DCR 92.85% (95% CI: 83%-100%). 1yr PFS and OS were 55.27% and 82.90% respectively. The most common G III and G II toxicity were HTN (20%) and fatigue (33.3%).3 pts had G IV toxicity (Anemia, Febrile neutropenia and colonic perforation) and 2 pts had Grade (G) V toxicity (VTE, Hypoxia/Sepsis). Conclusions: Atezolizumab + Carboplatin + Pemetrexed + Bevacizumab was associated with longer DCR, PFS, and OS than historical controls. 3 on-treatment deaths, possibly related to therapy (more likely bevacizumab), prompted early closure. A phase 3 study evaluating this regimen is ongoing by another group NCT03786692. Clinical trial information: NCT03713944.

Incidence of ifosfamide induced encephalopathy in patients receiving concomitant fosaprepitant.

The incidence of Ifosfamide-induced encephalopathy (IIE) ranges from 5-30%. Aprepitant and fosaprepitant may increase the risk of IIE; however, data is limited. The objective of this study was to characterize the incidence of IIE in patients receiving concomitant fosaprepitant. This single-center, retrospective chart review included adult patients diagnosed with sarcoma who received at least one administration of high dose ifosfamide (≥1800mg/m2) and fosaprepitant between January 2017 and June 2018. The primary endpoint was the percentage of patient cycles in which IIE was experienced. Secondary endpoints included characterization of IIE management strategies, time to IIE resolution, and the incidence of IIE upon ifosfamide re-challenge. Subgroup analyses were performed to assess whether the following variables predisposed a patient to neurotoxicity: elevated serum creatinine, hypoalbuminemia, metabolic acidosis, hyperbilirubinemia, shorter infusion time, and higher body mass index. The role of CYP2B6 inhibitors and prior cisplatin use were also examined. Fifty-one patients who received 215 total cycles of ifosfamide were included. Twenty (9.3%) patient cycles included documented evidence of IIE. The most common management strategies were to prolong the infusion time and administer methylene blue. The mean time to resolution of IIE was 2.58 days. The incidence of secondary IIE upon re-challenge was 26.3%. Baseline albumin <3.5 g/dL (p<0.001) was statistically associated with the development of IIE. Co-administration of fosaprepitant and ifosfamide in sarcoma appears to be safe. Hypoalbuminemia was a notable risk factor confirmed in this study. Further research is needed to delineate IIE risk factors.

Daratumumab subcutaneous formulation for the treatment of multiple myeloma

ABSTRACT Introduction Intravenous daratumumab has shown unprecedented anti-myeloma activity when used as a single agent or in combination with other myeloma therapies. Recently, a subcutaneous formulation of daratumumab was approved for use in both the United States and European Union based on data which showed shorter infusion times and decreased rate of infusion reactions while maintaining non-inferior efficacy. Areas covered We cover the physiology behind subcutaneous daratumumab and summarize the relevant clinical data with a particular focus on the pharmacokinetics, pharmacodynamics, safety, and clinical efficacy. Articles used to generate this review were obtained by searching pubmed (https://pubmed.ncbi.nlm.nih.gov/) with the search terms ‘subcutaneous daratumumab’ and ‘daratumumab hyaluronidase’. Expert opinion Subcutaneous daratumumab is associated with lower risk of infusion reactions and decreased administration time while maintaining non-inferior efficacy. We support the use of subcutaneous daratumumab for all approved indications and for investigational use moving forward.

Abstract CT218: Flat-dose nivolumab (NIVO) as second-line (2L) treatment (tx) for Asian patients (pts) with advanced non-small cell lung cancer (NSCLC): CheckMate 870

Abstract Introduction: Weight-based dosing of NIVO over 60 minutes is approved in China for 2L NSCLC tx; however, more convenient flat dosing over a shorter infusion time has yet to be fully assessed in Asian pts. In addition, the benefit of NIVO in Asian pts with NSCLC and EGFR or ALK mutations, or hepatitis B virus (HBV) infection, has yet to be evaluated. CheckMate 870 (NCT03195491) is a phase 3b trial assessing a flat dose of NIVO infused over 30 minutes for previously treated NSCLC in Asian pts. Methods: Eligible pts had stage IIIB/IV NSCLC with 1-2 prior systemic tx and ECOG PS 0-1. Pts with HBV had to have a viral titer &amp;lt; 500 IU/mL. Pts received NIVO 240 mg over a 30-minute infusion, Q2W, until progression, unacceptable toxicity, or for ≤ 2 years. The primary endpoint was high-grade (G; G3-5) tx-related select adverse events (AEs) in non-HBV infected pts. Results: Of 400 treated pts, 394 were from China; 34 pts had EGFR mutations, and 383 were non-HBV infected. Median (range) age was 61 (27-80) y and 78% were male. Clinical data cutoff was May 30, 2019, median duration of tx was 3 mo. The most common categories for G3-4 tx-related select AEs in non-HBV infected pts were hepatic (2%), skin (2%), pulmonary and endocrine (1% each). There were no G5 tx-related select AEs reported in non-HBV infected pts. No G3-5 tx-related select AEs were reported in HBV-infected pts (n = 17). There were 2 tx-related deaths, due to myocarditis (non-HBV infected pt) and lung infection (HBV-infected pt). G3-4 treatment-related AEs (TRAEs) were reported in 13% of all treated pts, and 2% had G3-4 TRAEs leading to discontinuation. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) are shown in the Table. Conclusions: Flat-dosing of NIVO 240 mg over 30 minutes was well tolerated and active in a predominantly Chinese pt population with previously treated NSCLC, including pts with EGFR mutations or HBV infection. These results are similar to pivotal trials of NIVO for previously treated NSCLC. No new safety signals were reported. Table.OS, PFS, and ORR among subgroups in CheckMate 870OSMedian PFSa,mo (95% CI)ORRaMedian,mo (95% CI)6-mo rates (%)n (%)All treated (N = 400)NR (11.7–NR)753.7 (3.1–3.9)62 (16)HBV statusbNo HBV (n = 383)NR (11.6–NR)753.7 (3.1–3.9)59 (15)With HBV (n = 17)NR (10.0–NR)822.0 (1.6–NR)3 (18)EGFR mutation statuscPositive (n = 34)NR (9.6–NR)851.9 (1.7–3.6)5 (15)Not detected (n = 261)NR (11.4–NR)743.6 (2.7–3.9)37 (14)Tumor histologyNon-squamous (n = 264)NR (11.5–NR)763.4 (2.1–3.8)37 (14)Squamous (n = 136)NR (10.5–NR)724.7 (3.1–5.6)25 (18)Tumor PD-L1 expressiond≥ 1% (n = 169)NR (11.7–NR)745.4 (3.7–5.6)42 (25)&amp;lt; 1% (n = 174)13.2 (10.9–NR)773.1 (2.0–3.8)15 (9)Minimum follow up was 10 mo.aPer investigator;bHBV status is a protocol pre-specified enrollment cohort; the number of pts with HBV entering the study was capped at 60 (15% of the total population);cThe number of pts entering the study with EGFR mutations was capped at 40;dOf all treated patients, 343 (86%) were evaluable for tumor PD-L1 expression level. NR, not reached. Citation Format: Shun Lu, Ying Cheng, Jianying Zhou, Mengzhao Wang, Jun Zhao, Gongyan Chen, Baocheng Wang, Jifeng Feng, Zhiyong Ma, Lin Wu, Changli Wang, Shucai Zhang, Kewei Ma, Jun Liang, Yong Song, Jie Wang, Yi-Long Wu, Ang Li, Ting Ma, Jianhua Chang. Flat-dose nivolumab (NIVO) as second-line (2L) treatment (tx) for Asian patients (pts) with advanced non-small cell lung cancer (NSCLC): CheckMate 870 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT218.

Is intra-arterial hepatic chemotherapy painful?

Liver metastases are mainly supplied by the hepatic artery, allowing the administration of intra-arterial hepatic chemotherapy (IAHC) while preserving normal parenchyma. The progression-free survival and response rate are prolonged by IAHC which can improve the rate of secondary resectability. Severe abdominal pain requiring high-dose opioids can appear during HIAC administration. This pain is related to extrahepatic infusion and gastroduodenal ulceration. However, intense abdominal pain was observed under oxaliplatin IAHC specifically without any extrahepatic infusion. We retrospectively reviewed the charts of 68 patients who received IAHC in our center between 2011 and 2015. Patient's demographics and disease characteristics were collected. Other variables such as the type, duration, and dosage of the chemotherapy administered, as well as the usage of painkillers before, during, or after intra-arterial administration, were also registered. The mean age of the patients was 59years. 61.7% were male (n = 42). The mean dose of oxaliplatin administered was 162mg per cure over 6.7-h course. Fifty percent were diagnosed with a left colon cancer, and 85.2% had synchronous liver metastasis. While 47% of patients received IAHC as a third-line therapy, the main chemotherapeutic drug was oxaliplatin (85.2% of cases; n = 58), then OPTILIV protocol (5FU, irinotecan, oxaliplatin) (13.3%; n = 9), and mitomycin C (1.5%; n = 1). A dose reduction of 23.6% had been noted in 58.8% (n = 40) cases due to adverse effects. Among patients who received opioids during IAHC (n = 40), 20% required opioids in intercure. Before, during, and after IAHC administration, patients complained of abdominal pain in 8.8%, 58.8%, and 19.1%, and opioids were used in 10.2%, 57.3%, and 19.1%, respectively. The main onset of pain occurs during the third cycle of chemotherapy. Among our patients, 11.7% and 22% had ulcer and extrahepatic perfusion, respectively, while 7.3% of them were asymptomatic. The mean occurrence of these signs was during the fourth cycle of IAHC. 33.8% and 52.9% of patients had abdominal pain while an extended and short infusion time, respectively. Lengthening of the infusion time did not prevent the occurrence of abdominal pain significantly but was nonetheless decreased compared with patients undergoing short infusion durations. Pain was more common in patients who did not have a dose reduction and who presented with ulcer and extrahepatic perfusion. Abdominal pain occurred on average one cycle before ulcer or extrahepatic perfusion diagnosis. In current practice, pain should be an alarming indicator in patients receiving IAHC, as it may be associated with ulcer or extrahepatic perfusion and thus requiring opioids.

Systematic analysis of chemotherapy agents for home-based administration.

e14012 Background: Improvement in supportive care medications, feasibility of outpatient management, and regulatory changes have led to a dramatic shift in the primary location of chemotherapy delivery from the inpatient setting to outpatient infusion centers. Over the last decade, centers in Europe and Canada have taken the next logical step – home based chemotherapy infusion. To our knowledge there is no systematic large scale initiative that has transitioned chemotherapy to the home in the United States. In order to implement a home based chemotherapy infusion program, we systematically scored anti-neoplastic agents for ease of administration. Methods: We reviewed all anti-neoplastic agents administered at our infusion center. Characteristics of each medication that could be a barrier to home infusion were identified. These included route and duration of administration, vesicant status, emetogenic potential, and duration of stability at room temperature. Scoring was determined by a multi-disciplinary team of pharmacists and oncologists (see Table). Higher scores indicated greater potential for home administration. Results: We reviewed 100 medications. The highest possible score was 8; the lowest possible score was -4. Agents ranged with scores from 8 (fulvestrant) to -1 (dactinomycin), with a median score of 4. The mode score was 3 (24 medications). The largest factor lowering the ease of administration score was stability at room temperature; score of -2 and -1 in 19 and 18 medications respectively. Conclusions: It is feasible to administer the majority of our chemotherapeutic agents in the home setting. The biggest barrier to administration at home is stability of medications at room temperature. This issue can be addressed by transporting and storing the medication in a refrigerated container. Expectedly, injectable drugs and medications with short infusion times that are stable at room temperature would be the easiest to administer in the home. Further analysis in ongoing to assess the financial feasibility and establishment of our home based program. [Table: see text]

Phase II expansion cohort in colorectal cancer to evaluate the safety and tolerability of RRx-001 blood mix.

e16144 Background: In a 34 patient randomized Phase 2 trial in 3rd/4th line colorectal cancer called ROCKET (NCT02096354) of RRx-001 + irinotecan versus regorafenib + irinotecan, RRx-001 + irinotecan demonstrated improved overall survival (OS) (8.6 vs 4.7 months) and progression free survival 2 (PFS2) (7.5 vs. 1.7 months) compared to the regorafenib control arm. The main adverse event attributed to RRx-001 treatment, which involved once weekly peripheral or central infusion, was a painful infusion-related superficial phlebitis in 80% of patients. Following the randomized portion of the ROCKET trial, another 18 colorectal patients were enrolled in an expansion cohort to evaluate the safety and tolerability of an RRx-001 “blood mix”, the objective of which was mitigation of the phlebitic complications of direct RRx-001 infusion. Methods: Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly via blood mix until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle. Results: The median OS and PFS2 were 6.3 and 5.2 months, respectively, which was similar to that of RRx-001 administered by direct infusion in the randomized part of the trial. No patients experienced phlebitis. The adverse event profile was otherwise unchanged compared with direct IV infusion of RRx-001. Conclusions: The results of this expansion cohort demonstrate similar activity of RRx-001 given by blood mix followed by irinotecan to RRx-001 given by direct IV infusion followed by irinotecan.RRx-001 alleviated the pain that had been observed in the direct IV infusion and therefore allowed for a shorter infusion time without any apparent compromise in activity (based on OS/PFS2 comparability to earlier results). Finally, since phlebitis in theory may progress to deep venous thrombosis or suppurative thrombophlebitis in hypercoagulable and immunosuppressed cancer patients, blood mix RRx-001 is the preferred method of infusion. Clinical trial information: NCT02096354 .

Safety of two-hour intermittent intravenous infusions of tacrolimus in the allogeneic hematopoietic stem cell transplantation unit.

At our institution, tacrolimus is used as a second-line agent for the prevention and treatment of graft-versus-host-disease in the allogeneic hematopoietic stem cell transplantation (HSCT) unit after patients have experienced a serious or intolerable adverse event to cyclosporine. As per our standard practice, tacrolimus is administered via 2-h intermittent IV infusions (IIVs) every 12 h rather than continuous IV infusion. Shorter infusion times are cautioned due to concerns of higher rates of nephrotoxicity, neurotoxicity and infusion-related reactions, although there is a paucity of data to support this claim. Our primary objective was to evaluate the safety of a 2-h IIV of tacrolimus in an adult HSCT population. We retrospectively reviewed the charts of 104 patients who received tacrolimus by IIV (3574 doses; median = 22, range 1-158, IQR = 28) from 2002 to 2016. Primary outcomes collected include rates of nephrotoxicity, neurotoxicity and infusion-related reactions. One (0.9%) grade 2 infusion-related reaction occurred and resolved without discontinuation of tacrolimus. Of 16 incidences (13.6%) of nephrotoxicity, all but 10 (8.5%) cases resolved. Precipitating factors for nephrotoxicity unrelated to tacrolimus were identified in all 10 cases. There were 41 incidences (35%) of neurotoxicity, of which, 8 (6.8%) were considered serious. All neurotoxicity reverted to baseline or resolved completely. We propose that a 2-h IIV of tacrolimus is a safe method of administration in the adult HSCT setting.

Abstract P1-18-04: Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results

Abstract Background: Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T) and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both the 158V (high-binding) and 158F (low-binding) allotypes of the activating Fc receptor CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, and does so more effectively than T in vitro. Based on ex vivo experiments with cells collected from patients (pts) before and after treatment, M induces adaptive immunity, including enhanced T-cell clonality and induction of HER2-specific T- and B-cell responses. The SOPHIA trial (NCT02492711) showed that in pts with pretreated HER2+ metastatic breast cancer (MBC), M+chemotherapy improved progression-free survival vs T+chemotherapy, with comparable safety. M is intended to be dosed at 15 mg/kg every 3 weeks, with infusions over 120 min at every cycle (C). A substudy of SOPHIA was conducted to evaluate the safety and tolerability of reduced infusion times from C2 onward. Methods: Eligible pts had HER2+ MBC after ≥4 lines of prior therapy for MBC, including prior T, pertuzumab, and ado-T emtansine. Enrolled pts received a 120-min M infusion, with or without chemotherapy, in C1, then either 60- or 30-min infusions in C2 and beyond. This single-arm substudy was unblinded, with no comparator. The primary objective was incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end of C2. Incidence of all IRRs was a secondary objective. Results: Of 88 pts enrolled, 69 received M+chemotherapy and 19 received M alone. Mean age was 54.5 years; 99% were female and 71% white. The median number of cycles of M received was 3 (range 1-17). Overall, 7 pts were assigned to received 60-min M infusions starting at C2 (range 1-17 cycles), and 76 pts were assigned to received 30-min M infusions starting at C2 (range 1-14 cycles). Five pts did not receive C2 treatment due to non-radiologic progressive disease, unrelated adverse event (AE), patient or physician decision, or loss to follow-up. Eighty (91%) pts had premedication for IRRs. No pt had Grade ≥3 IRR. Overall, 18 (21%) had IRRs (2 Grade 1, 16 Grade 2), all but 1 of which occurred in C1 (120 min). Of the 18 pts with IRRs, 17 (94%) were premedicated and 10 (56%) were treated for IRRs. The overall rate of IRRs in premedicated pts was 21% (17/80) and in non-premedicated pts was 13% (1/8). One pt experienced IRRs in both C1 and C2 (Grade 2 in C1 and Grade 1 in C2); the same patient then received 6 additional cycles of M (30 min) with no IRRs after C2 (C3-8) and had no premedication after C1. No pt discontinued treatment due to an IRR. Of 88 pts enrolled, 85 (97%) pts experienced an AE, and 7 (8%) had Grade ≥3 AEs. Fifty (57%) pts had M-related AEs. The most common (&amp;gt;5% of pts) M-related AEs were IRRs in 17 (19%), fatigue in 9 (10%), diarrhea in 5 (6%), and aspartate aminotransferase increase in 5 (6%). Serious AEs occurred in 13/88 pts (15%), none of which were considered M-related by the investigator. Conclusions: In this heavily pretreated population, shorter M infusion times did not lead to an increase in IRRs. IRRs were most likely to occur during C1 when the infusion time was 120 min. No Grade ≥3 IRRs were observed. Of 18 pts with Grade 1-2 IRRs, only 1 had an IRR after C1. These results showed that the acceptable safety and tolerability profile of M was maintained even after infusion time is reduced to 30-min from C2 onward. Shorter infusion times may reduce the burden of chronic M therapy on pts, caregivers, and clinic staff. Citation Format: William J. Gradishar, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Rosanna Berardi, Michelino De Laurentiis, Shakeela W. Bahadur, Young-Hyuck Im, Cynthia Lynch, Yelena Novik, Sutton Edlich, Edwin Rock, Shengyan Hong, Hope S. Rugo, SOPHIA Study Group. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-04.

The Role of EkoSonic Endovascular System or EKOS® in Pulmonary Embolism.

Pulmonary embolism has become a cause of great concern to health care professionals. Despite strides in research and availability of sensitive diagnostic tests, the mortality and morbidity related to this entity continues to cause tremendous economic burden. Patients present with an array of symptoms ranging from mild dyspnea to hemodynamic instability and even death. Prompt recognition of symptoms along with early risk stratification can be lifesaving. Management focuses on achieving hemodynamic stability and reducing clot burden. Approved treatment modalities include anticoagulation, systemic or catheter directed thrombolytic therapy and surgical embolectomy. In this article we will review catheter-directed thrombolytic therapy, specifically the EKOS® or the EkoSonic endovascular system. EKOS® uses ultrasound-facilitated catheter-directed thrombolysis. The rationale behind this therapy is using shorter infusion times and lower dosage of the thrombolytic therapy, thereby reducing the complications associated with their use.