4th Dose Research Articles

Initiation of Vancomycin Therapy and the First Therapeutic Drug Monitoring

Abstract There have been a limited number of studies in Latvia that were focused on vancomycin therapeutic drug monitoring (TDM), especially during the initiation phase of the therapy. The aim of this study was to investigate details of vancomycin therapy in its initiation phase and to analyse the results of the first therapeutic drug monitoring within a multidisciplinary hospital in Latvia. A retrospective observational study was performed in a multidisciplinary hospital in Latvia. Adult patients hospitalised in an intensive care unit and undergoing vancomycin therapy with at least one concentration measurement were included in this study. Data about patients included demographic and clinical data, renal function prior to initiation of vancomycin therapy, data about vancomycin therapy, data about the first TDM, and details about the first measurement of vancomycin concentration according to determined reference range — subtherapeutic, therapeutic and supratherapeutic levels. A total of 60 intensive care unit patients who received vancomycin with at least one concentration measurement were included in this study. Fifty-eight patients received vancomycin as intermittent intravenous infusion. The first measurement of concentration was taken before the 3rd–4th vancomycin dose in 38.3% cases, and in 33.3% cases — before the 2nd dose. Sampling to determine the concentration within 30 minutes before vancomycin administration was performed in zero cases. In 35% cases, sampling was done within 2–5 hours before vancomycin administration and in 23.3% — immediately after or within a few hours after vancomycin infusion. Twelve (20%) patients had a concentration in the subtherapeutic level, and 14 (23.3%) patients had concentrations above the therapeutic level. In 42.8% of patients who had concentrations in supratherapeutic level, sampling had been performed immediately after or within several hours after vancomycin administration. The first concentration measurement was performed more than one hour before an infusion in all cases. Data on concentrations and timing were not adequate to perform appropriate therapy modification. Interpretation of dosing regime and concentration results were not adequate, and therefore correct modification of vancomycin therapy was often not possible. Routines of correct dosing regime and the 1st TDM during the initiation phase of vancomycin therapy can be improved.

A new respiratory scoring system for evaluation of respiratory outcomes in children with spinal muscular atrophy type1 (SMA1) on SMN enhancing drugs

Nusinersen (NUS), the first treatment approved for Spinal Muscular Atrophy type 1 (SMA1), was made available in the UK for SMA1 through the Expanded Access Program (EAP) in 2017. The Great Ormond Street Respiratory (GSR) score was developed as an objective respiratory assessment for children with SMA1 during their treatment. Aims: Track respiratory status of SMA1 children over the course of Nusinersen treatment and compare GSR scores amongst SMA1 sub-types. Single centre study on SMA1 patients using the GSR score at set time points: prior to first NUS dose; 2 weeks post end of loading doses; 2 weeks post-subsequent doses. GSR score ranges 1–28, being 1–9 = Stable minimal support, thorough to 23–28 = Poor reserve with maximum support. 20 SMA1 children underwent NUS treatment between January 2017 - November 2018. Median age of diagnosis was 5.0 months. NUS started at median of 9.57 months. From 5th dose onwards, GSR scores were significantly lower for Type 1C patients compared to Type 1B By month 18, irrespective of subtypes, the whole cohort appears to stabilise GSR Scores. As treatment duration increases, an overall stabilisation of respiratory status across the cohort was observed. Further longitudinal studies are needed to validate the GSR.

PENYULUHAN TENTANG KHASIAT DAUN BANDOTAN TERHADAP PENURUNAN KADAR GULA DARAH DI PUSKESMAS TALUN KENAS

Background: Diabetes mellitus is a metabolic disease with chronic characteristics of hyperglycemia with metabolic disorders of carb, fats, and proteins. Therapies using synthetic drugs require a substantial amount of money and are having these side effects that encourage people to begin shifting into the traditional treatment of bandotan leaves.
 Purpose: To determine the effectiveness of bandotan leaf ethanol extract can reduce blood sugar levels compared to glibenclamide drugs.
 Method: The method used is the experimental method. The sample was extracted by maceration method using 70% ethanol sailor. Testing for antidiabetic effects was carried out on 15 male white rats divided into 5 treatment groups, namely the first group negative control (CMC Na 0.5%), the second group positive control (glibenclamide), the third group dose 126 mg / BB Kg, 4th group dose 252 mg / Kg BB, and group 5 dose 378 mg / Kg BB. The results were tested using the ANOVA method.
 Result: Based on this study, the ethanol extract of bandotan leaves at a dose of 126 mg / Kg BB, 252 mg / Kg, and 378 mg / Kg BB gave a decrease in blood sugar levels. the administration of bandotan leaf extract with a dose of 378 mg / Kg BB gave the same effective results as the glibenclamide drug while the negative control group (CMC Na 0.5%) was not effective in lowering blood sugar levels.
 Conclusion: Bandotan leaf ethanol extract has the effect of decreasing blood sugar levels which are almost the same as glibenclamide drugs in male white mice induced with alloxan.

Vancomycin pharmacokinetic parameters in patients undergoing hematopoietic stem cell transplantation.

Current guidelines on vancomycin dosing lack specific recommendations about its dosing in hematopoietic stem cell transplant (HSCT) patients, the objective of the current study was to compare vancomycin pharmacokinetic variables in this population with those of general population. A prospective study was designed and the calculated parameters of vancomycin pharmacokinetic were compared with individualized parameters. Two trough levels before 4th and 5th doses and a peak level after the 4th dose, were taken. All patients received a dose of 15 mg/kg of vancomycin two or three times a day. Pharmacokinetic parameters were calculated using a one compartmental model. The association between different variables and of acute kidney injury (AKI) development and achievement of target levels were also evaluated. A significant difference was observed between population Volume of distribution (Vd) and individualized Vd (mean 57.33 L vs 162.86 L, p value 0.019) and trough and peak levels (p values 0.0001 and 0.001; for mean trough and peak levels respectively). The achievement of the recommended trough levels and area under the concentration time curve per minimum inhibitory concentration (AUC24/MIC) was very low (5/71 and 24/71 patients respectively). No significant differences were observed between population and individualized clearance and rate of elimination of vancomycin (p values of 0.092 and 0.55 respectively). Concomitant receipt of cyclosporine was significantly related with development of AKI (p value 0.046). The dosing methods which use population-based pharmacokinetic variables does not result in desired therapeutic levels in HSCT patients, mainly because of larger vancomycin volume of distribution.

Improving the efficiency of poultry meat production by feeding ultrafine silicon

The article presents the results of a study on the effect of various doses of ultrafine silicon on the microbial content of the intestines and blood parameters of poultry. The microbiology of digestion is very complex and poorly understood. It was found that ultrafine silicon particles selectively affected the intestinal micro flora of chickens, reduced the number of pathogenic microorganisms, thereby increasing the number of lactobacilli in the total mass. Useful microorganisms can significantly increase the bioavailability of the feed used. It also has a positive effect on the content of red blood cells and by the middle of the experiment, their number was significantly higher in the experimental groups by 4.74–7.79 %, and by the end of the experiment-by 4.38–9.04% compared to the same indicator in the control group. The hemoglobin content in the blood of chickens also increases in comparison with the beginning of the experiment. By the end of the accounting period, in the 1st (dose of 100 mg/kg of feed from ultrafine si particles), 2nd (dose of 200 mg/kg of feed from ultrafine Si particles) experimental groups, the level of hemoglobin decreased by 4.78–5.06%, in the 3rd (dose of 300 mg/kg of feed from ultrafine Si particles) and 4th (dose of 400 mg/kg of feed from ultrafine Si particles) experimental groups, where the highest concentration of silicon in the feed was observed, increased by 12.0 %. There was also an increase in the total protein in the blood of the experimental bird by 3.05–5.45% by the middle of the experiment and by 10.08-11.58% by the end of the experiment. The albumin fraction content also increases by 10.48-3.10 %. Thus, the data obtained during the study reflect the body’s response to various doses of ultrafine silicon used in poultry feeding. The obtained result shows the possibility of using these forms in the industrial production of animal feed.

A comparison of post vaccination hepatitis B surface antibody level on the large and appropriate for gestational age infants.

PurposeThe aim of this study was to compare the hepatitis B surface antibody (HBs Ab) titer 1 month after the 4th dose of hepatitis B vaccine administration on the large and appropriate for gestational age infants.Materials and MethodsThis cross-sectional study was conducted on 7-month-old cases (n=132) divided into two groups of 2–4 kg (group 1: appropriate for gestational age, 63 cases) and >4 kg (group 2: large for gestational age, 69 cases), whom were vaccinated with a four-dose schedule of hepatitis B vaccine in 2016, Tehran, Iran.ResultsMean birth weight of the groups was 2.98±0.528 and 4.19±0.190 kg, respectively. Hepatitis B surface antigen and hepatitis B core antibody were negative in all cases. HBs Ab level in group 1 and 2 was 13,701.00±11,744.439 and 8,997.15±2,827.191, respectively (95% confidence interval of difference, −7,607.44 to −1,800.25). There was a significant difference between the two groups in antibody titration and antibody logarithm level (p=0.002, p=0.0001).ConclusionBirth weight may affect the response to the hepatitis B virus vaccine administration.

An unusual case of fatal rabies encephalitis despite completing postexposure prophylaxis

Rabies continues to be a major health scourge in many developing countries including India. It can be effectively prevented by providing postexposure prophylactic treatment. Failure of Rabies postexposure prophylaxis (PEP) is a rare occurrence. Our patient, a 39-year-old Male, was bitten by stray dog on the left hand. It was Category III dog bite for which proper wound care and PEP 5 doses of antirabies cell culture vaccine and Human Rabies Immunoglobulin was given. Two days after completing the 5th dose of PEP, he presented with fever, neck rigidity, drooling of saliva, pain, and numbness in the left hand along with auditory and visual hallucinations without hydrophobia and aerophobia. On 2nd say of hospitalization, he developed progressive respiratory difficulty and decreased oxygen saturation for which he was intubated and put on invasive ventilator support. However, he suffered fatal cardiac arrest and succumbed to his illness. Based on his symptoms, a clinical diagnosis of febrile encephalopathy with differential diagnosis of acute rabies encephalitis was made. On autopsy, his brain was markedly congested and histopathological examination was suggestive of acute rabies encephalitis. However, no Negri bodies were seen. Further examination of brain tissue by immunohistochemical labeling revealed numerous Negri bodies and confirmed the diagnosis of rabies encephalitis.

636. Immunogenicity, Safety and Tolerability of a Booster Dose of Clostridium difficile Vaccine and 4 Year Antibody Persistence

BackgroundClostroidides difficile (C difficile) is a common cause of antibiotic-associated diarrhea. To date, there is no vaccine to prevent C. difficile infection (CDI). This extension of a phase 2 study explores the immunogenicity, safety, and tolerability of a 4th dose, and antibody persistence of a three-dose regimen of a toxoid-based C difficile vaccine in 300 healthy adults 65 to 85 years of age in the United States.MethodsThe first stage of this study was conducted from 16 July 2015 to 7 March 2017, in which subjects were enrolled and randomized to receive one of two antigen dose levels (100µg or 200µg total toxoid A and B) or placebo, administered in one of two three-dose regimens: Days 1, 8 & 30 or Months 0, 1 & 6. Immunogenicity testing was conducted on samples obtained at each of nine study visits through 12 months post dose 3. In this extension stage, subjects who had received vaccine in the first stage were re-randomized at 12 months post dose 3 to receive either a booster dose or placebo in a 1:1 ratio. Subjects were followed for immunogenicity three (3) years post booster (four years post dose #3)ResultsPeak antibody response to vaccination was observed between day 8 and 30 following booster administration. Both regimens demonstrated robust anamnestic responses with peak levels above the three-dose peak (stage 1). Toxin A geometric mean concentrations (GMCs) remained above pre-booster GMCs, 3 years post booster for both dose levels and regimens. Antibody persistence for both groups demonstrated stable antibody levels four years after the primary vaccination series among subjects who did not receive a booster dose. No Grade 4 reactogenicity was reported during the study. Pain was the most common local reaction. Adverse event rates per subject were similar between both regimens and placebo. There were no Serious Adverse Events (SAEs) considered related to the investigational product at any dose or regimen. The safety profile was consistent with what was seen in the first stage of the study.ConclusionA booster dose of Clostroidides difficile vaccine candidate is highly immunogenic, well tolerated and demonstrates an acceptable safety profile in both dose groups for the Day and the Month regimens. Antibody persistence remains stable from 12 months to 4-year post dose 3.DisclosuresNicholas Kitchin, MD, Pfizer, Inc (Employee) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Annaliesa S. Anderson, PhD, Pfizer (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder)

Pharmacokinetics of single and repeated oral doses of esomeprazole and gastrin elevation in healthy males and females

Objective Gastrin elevation secondary to proton pump inhibitor (PPI) therapy is well documented. Recent studies have demonstrated a sex-related difference where females on PPIs have significantly higher baseline gastrin levels than males. The aim of the study was to analyse the pharmacokinetics of esomeprazole and short-term effect on serum gastrin levels and evaluate potential sex-related difference. Materials and methods Healthy volunteers received 40 mg of esomeprazole daily for five days. After the 1st and 5th dose blood samples for fasting gastrin and pharmacokinetic analysis were collected at scheduled time-points for eight hours. Esomeprazole was analysed by liquid chromatography and gastrin concentrations were measured using radioimmunoassay. Results A total of 30 volunteers were enrolled. Females had higher median baseline gastrin (pM) than males 12 (IQR 10–15) vs. 7 (IQR 4–11) (p = .03). In the study cohort, median gastrin levels rose from 10 (IQR 6–14) to 15 (IQR 13–20) (p = .0002). The serum levels for esomeprazole increased by an average of 299.8 ng/mL (p < .001) from day 1 to day 5. Comparison of the esomeprazole pharmacokinetic parameters between males and females revealed no significant sex-related differences. No significant correlation was found between the AUC and the gastrin level on day 5 (p = .15). Conclusions In healthy volunteers, serum gastrin increased significantly after a four-day PPI-therapy. There was also a significant increase in serum esomeprazole from day 1 to day 5. The increase in gastrin and esomeprazole concentration was not related to sex and no significant sex-related difference was found in terms of pharmacokinetic parameters. European Clinical Trial Database (2015-002230-41).

Cael-101 Is Well-Tolerated in AL Amyloidosis Patients Receiving Concomitant Cyclophosphamide-Bortezomib-Dexamethasone (CyborD): A Phase 2 Dose-Finding Study (NCT04304144)

Immunoglobulin light Chain (AL) amyloidosis is the most common form of systemic amyloidosis, accounting for approximately 70% of the diagnosed cases in developed countries. There are no approved treatments for AL amyloidosis, and currently autologous stem cell transplants and/or chemotherapy targeted to eradicate the underlying plasma-cell dyscrasia (PCD) to stop the production of misfolded light chains are used. No therapies are available to remove existing amyloid deposits, improve and/or reverse organ dysfunction. CAEL-101 is a chimeric immunoglobulin G1 kappa isotype that reacts specifically with light chain fibrils, irrespective of their κ or λ isotype but, notably, not with the native forms. CAEL-101 was shown to bind to a cryptic epitope at the N-terminal of light chain proteins that adopt a non-native b-sheet structure, which is conserved in κ and λ mis-folded light chains. It is hypothesized that CAEL-101 will modify the disease course of AL amyloidosis by facilitating the removal of amyloid fibrils deposited in tissues. CAEL-101 was previously studied as monotherapy in an open label dose escalation Phase 1 study where it was shown to be safe, tolerable up to 500 mg/m2 and associated with an early organ response. No DLT were seen and the PK profile appeared not to reach linearity. The current multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage I, II and IIIa AL amyloidosis patients was to define the safety and tolerability of CAEL-101 in combination with Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) as the standard of care (SOC) PCD therapy during a 27-day treatment period and to determine the recommended dose for the subsequent Phase 3 studies. Patients had measurable hematologic disease, as defined by at least one of:involved/uninvolved free light chain (FLC) difference (dFLC) &amp;gt; 5mg/dL orFLC &amp;gt;5mg/dL with abnormal ratio orserum protein electrophoresis (SPEP) m- spike &amp;gt; 0.5 g/dL Patients were seen in the clinic every week for 4 weeks to receive CAEL-101 2-HR IV infusions, and for safety and tolerability assessments. Subsequently, patients have been receiving CAEL-101 infusions approximately every other week. Actual dose was determined by patient body surface area in meters squared. When administered on the same day, CAEL-101 was administered first before CyBorD chemotherapy. The study employed a 3+3 dose escalation design, starting with a 500 mg/m2 dose. Patients were followed for dose-limiting toxicities (DLTs). The DLT observation period for the first cohort was through 14 days following the first infusion. For subsequent cohorts, this was through 27 days. At least 3 patients were enrolled in each dose cohort. Enrollment into a new cohort with the next higher dose of CAEL-101 did not begin until the DLT observation period had been completed for the last patient enrolled in the previous cohort, with further dosing cohorts at 750 and 1000 mg/m2. Safety assessment included vital signs, physical examinations, electrocardiograms (ECGs), clinical laboratory parameters (hematology, serum chemistry, urinalysis), and TEAEs. The pharmacokinetic (PK) profile of CAEL-101 was also assessed. The 13 patients averaging 65.2 years (range 47.6 to 79.6 years). The majority were male (76.9%), white (84.6%), and non-Hispanic (100%). Mayo staging I (7.7%), II (69.2%), and III (23.1%) reflected a wide range of disease severity in the patients enrolled. All patients were treated successfully through their 4th dose, the highest (1000 mg/m2) cohort enrolling 6 patients. No DLT was observed, and CAEL-101 was well-tolerated by all patients. The most common TEAEs were diarrhea and nausea (each 30.8%). Dose-normalized PK concentrations were best described by a linear two-compartment model, with terminal half-life of 28 days. This study demonstrated that CAEL-101 at doses up to 1000 mg/m2, given with CyBorD, was well-tolerated in the AL amyloidosis population. Two Phase 3 efficacy/safety studies, one enrolling Mayo Stage IIIa and the other Stage IIIb patients, have been initiated, and based on the findings from this Phase 2 study, the 1000 mg/m2 dose of CAEL-101 is being used for treatment in those studies. Figure 1 Disclosures Valent: Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau. Silowsky:Caelum Biosciences: Current Employment, Current equity holder in private company. Kurman:Caelum Biosciences: Consultancy. Daniel:Caelum Biosciences: Current Employment, Current equity holder in private company. Jobes:Caelum Biosciences: Current Employment, Current equity holder in private company. Harnett:Caelum Biosciences: Consultancy, Current equity holder in private company. Ziola:Caelum Biosciences: Consultancy. Roviwong:Caelum Biosciences: Current Employment, Current equity holder in private company. Spector:Caelum Biosciences: Current Employment, Current equity holder in private company. Sobolov:Caelum Biosciences: Current Employment, Current equity holder in private company.

A Phase I Study of Lintuzumab Ac225 in Combination with CLAG-M Chemotherapy in Relapsed/Refractory AML

Background: Lintuzumab Ac225 is a radiolabeled anti-CD33 antibody, composed of an alpha emitting isotope, Ac225, conjugated with the humanized anti-CD33 monoclonal antibody lintuzumab. As monotherapy, lintuzumab Ac225 was studied as upfront therapy for unfit AML, and nearly 70% of pts achieved a CR/CRi at the highest dose level (2uCi/kg) without significant non-hematologic toxicity. Therefore, we hypothesized that lintuzumab Ac225, when added to the salvage chemotherapy regimen CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone), would be tolerable and would improve remission rates in the treatment of relapsed/refractory AML (RR-AML). This investigator-initiated phase I study is the first study to combine radioimmunotherapy with salvage chemotherapy in pts with RR-AML. Patients and Methods: Medically fit pts with RR-AML, aged 18 years and older were eligible. Eligibility also required that more than 25% of leukemic blasts must have been CD33 positive by flow cytometry. Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Lintuzumab Ac225 was administered as a single dose on either day 7, 8, or 9. This trial had three cohorts, administering lintuzumab Ac225 at a dose of 0.25uCi/kg, 0.50uCi/kg, or 0.75uCi/kg. Treatment consisted of one induction cycle, with subsequent therapy up to physician discretion. Results: Fifteen pts were evaluable, with a median age of 61 yrs (Figure 1). Slightly less than half of the pts had previously received venetoclax/HMA and slightly more than half had previously had allogeneic HCT. Three pts enrolled into cohort 1 (0.25uCi/kg), nine pts enrolled into cohort 2 (0.5uCi/kg), and three pts enrolled into cohort 3 (0.75uCi/kg). Grade 3 or greater AEs irrespective of causality included febrile neutropenia (n=12), infection (n=8), maculopapular rash (n=2), nausea (n=2), and one patient each with QTc prolongation and tumor lysis syndrome. Of 15 pts, CR/CRi was observed in 10 (67%) pts. Excluding pts receiving &amp;gt;3 prior lines of therapy, 10/12 (83%) achieved CR/CRi. In cohort 1, 1 patient (33%) achieved remission (1 CR). In cohort 2, 6 pts (67%) achieved remission (3 CR, 2 CRp, 1 CRi). In cohort 3, 3 pts (100%) achieved remission (1 CR, 2 CRp). 7 pts of the 10 with CR/CRi (70%) achieved MRD negativity by flow (Table 2). Two of the 3 patients in cohort 3 were MRD- after therapy and the third had a small number of AML cells detected (0.2%). All pts who were independent for platelet transfusions pre-treatment recovered platelets. Overall, median time to ANC recovery ≥500 was 33 days, and median time to platelet recovery ≥50k was 35 days. 6 pts proceeded to allogeneic HCT after therapy. Conclusion: We conclude that lintuzumab Ac225 in combination with CLAG-M chemotherapy has a clinically acceptable safety profile. Dose escalation yielded highly encouraging efficacy results for RR-AML. With acceptable safety at 0.75uCi/kg, we have amended this protocol to study a 4th dose level at 1.0uCi/kg. Overall, this regimen represents a safe and potentially effective therapy for medically fit RR-AML pts, particularly as a bridge to allogeneic HCT. Disclosures Abedin: Helsinn Healthcare: Honoraria; Actinium Pharmaceuticals: Research Funding; Helsinn Healthcare: Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Honoraria; Agios: Honoraria. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen R&amp;D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau. Michaelis:Jazz Pharmaceuticals: Research Funding. Atallah:Abbvie: Consultancy; Genentech: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Novartis Pharmaceutical Corporation: Consultancy.

S2273 A Drug Reaction to Ustekinumab in a Patient With Crohn’s Disease

INTRODUCTION: In 2016, ustekinumab became the newest biologic with FDA approval for treatment of Crohn’s disease (CD). It is a human monoclonal antibody that binds to the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23). It is overall very well tolerated. Dermatologic complications are relatively uncommon. During post-marketing approval, there have been reports of pustular psoriasis, erythrodermic psoriasis, pseudolymphomatous drug eruption, and eczematous drug eruption in psoriasis patients. CASE DESCRIPTION/METHODS: A 42 year old man with a complicated 25 year history of ileocolonic CD, prior ileocolic resection for a colonic stricture, and partial left hemicolectomy for a colo-cutaneous fistula and abdominal abscess while on adalimumab presented with abdominal pain after 4 years without follow up. Imaging and colonoscopy showed ileitis and an enterocolonic fistula. Ustekinumab was started. 2 days later, he developed a pruritic erythematous blistering skin rash on his neck, arms, and trunk without mucous membrane involvement or fever. Skin biopsy revealed a hypersensitivity skin reaction, which resolved in 10 days. He received 4 days of premedication with acetaminophen, famotidine, prednisone, and diphenhydramine before his maintenance dose of 90 mg subcutaneously without any reaction. He continues to be on the drug with good effect. DISCUSSION: Only a few case reports of drug eruptions to ustekinumab exist in the literature, and all are in patients treated for psoriasis. One patient had urticaria 3 weeks after their 4th dose of ustekinumab and subsequent doses. They likely formed drug antibodies and had a change in therapy. Another patient had multiple painless indurated pink papules and plaques on their trunk 9 days after the 1st dose. Biopsy showed a lymphomatoid drug reaction, which resolved spontaneously after 2 months. Another patient had a psoriasiform eczematous drug eruption on their trunk and limbs 3 days after the 2nd injection; it resolved in 2 weeks with topical steroids. This is the first case report of a drug eruption in a patient with ustekinumab for CD. Management varies. Antibody formation requires discontinuation of therapy. If we extrapolate from anti-TNF literature, non-antibody reactions may be able to be managed with short term topical or systemic therapy and without necessarily discontinuing the drug. Treatment should occur on a case-by-case basis because reported dermatologic reactions are so few in number.

First-in-human (FIH) phase I study of GST-HG161, a potent and highly selective c-met inhibitor, in patients with advanced solid tumor.

e16126 Background: GST-HG161 is an orally bioavailable novel potent and highly selective c-Met inhibitor, which displayed significant antitumor activity in preclinical models as well as very desirable pharmaceutical properties for oral dosing. Preclinical studies demonstrated that GST-HG161 has the potential to be effective in HCC patients with active c-Met signaling. Methods: This is an open label, first-in-human, single center, dose-escalation study (NCT04228406) utilizing an accelerated dose escalation design using single patient cohorts for the first two dose levels (60 and 150 mg) followed by a conventional 3+3 design at the 3rd dose cohort (300 mg). Dose escalation is expected to continue to the proposed 7th dose cohort (900 mg). The objective of the study is to determine the maximum tolerated dose and/or recommended Phase II dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of GST-HG161 in patients with advanced solid tumors. Eligible patients are adults with advanced solid tumors refractory to standard therapies with confirmed c-Met positive. The definition of c-Met positive is a) IHC expression of c-Met (positive criteria: 1+ and above) and/or b) FISH amplification of c-Met and/or c) MET exon 14 (METex14) skipping. GST-HG161 is administered orally once-a-day starting on day 1 of each 21 days cycle. Results: To date, 6 patients (CRC 2, Gastric 1, NSCLC 1, HCC 1, Cholangiocarcinoma 1) were enrolled to 3 dose levels (60, 150, and 300 mg). Of these 6 patients, 4 had discontinued GST-HG161 treatment at the data cut-off date of Feb 1, 2020, due to progressive disease (3) and adverse event (1). Two patients at the 300 mg cohort are still on treatment. Overall, 4/6 patients showed no drug-related AEs &gt; Grade 1. One patient reported a DLT: asymptomatic Grade 3 lipase elevation after a single dose of 60mg. To date, no other patients showed elevations of lipase and amylase. Bioanalysis of PK samples from study patients are currently ongoing. PK summary will be reported in the presentation. Conclusions: GST-HG161 has been well tolerated to date in study patients with a manageable safety profile. The dose escalation is expected to continue to the proposed 7th cohort at 900 mg. Clinical trial information: NCT04228406 .

ENGOT-cx11/KEYNOTE-A18: A phase III, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer.

TPS6096 Background: High-risk locally advanced cervical cancer has a poor prognosis, and more than half of patients recur in 2 y. External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer. The immunostimulatory activity of the PD-1 inhibitor pembrolizumab (pembro) may be enhanced by concurrent chemoradiotherapy (CRT). After the KEYNOTE-158 study, in which pembro showed durable antitumor activity, pembro monotherapy was approved for patients with PD-L1–positive recurrent or metastatic cervical cancer who progressed during or after chemotherapy. ENGOT-cx11/KEYNOTE-A18 (NCT04221945) is a phase III, randomized, placebo-controlled study evaluating pembro with concurrent CRT for the treatment of locally advanced cervical cancer. Methods: Approximately 980 patients with high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive either 5 cycles of pembro 200 mg every 3 wk (Q3W) + CRT followed by 15 cycles of pembro 400 mg Q6W or 5 cycles of placebo Q3W + CRT followed by 15 cycles of placebo Q6W. The CRT regimen includes 5 cycles (with optional 6th dose) of cisplatin 40 mg/m2 Q1W + EBRT followed by brachytherapy. Randomization is stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cancer stage at screening (stage IB2-IIB vs III-IVA), and planned total radiotherapy dose. Treatment will continue until the patient has received 20 cycles of pembro (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 y) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints are PFS at 2 y, OS at 3 y, complete response at 12 wk, ORR, PFS and OS in PD-L1–positive patients, EORTC QLQ-C30 and QLQ-CX24, and safety. Enrollment is ongoing. Clinical trial information: NCT04221945.

Recovery of Sense of Smell by Mepolizumab in a Patient with Chronic Rhinosinusitis and Nasal Polyposis – A Case Report

Introduction: To date, there is no permanent medical treatment for nasal polyposis and loss of sense of smell. Mepolizumab is an anti-IL-5 monoclonal antibody approved for the treatment of patients with eosinophilic asthma. It has been suggested that it is capable of improving olfactory dysfunction in patients with chronic rhinosinusitis and nasal polyposis. Case: We present a 35-year-old Emirati male with progressively worsening rhinosinusitis, recurring nasal polyps and total loss of sense of smell. He was treated with oral steroids, normal saline nasal sprays and all available topical steroids without significant or permanent symptom relief. He was commenced on Mepolizumab, and upon receiving the 4th dose, he reported full recovery of his sense of smell. Conclusion: Mepolizumab appears to be very effective in treating loss of sense of smell. Further studies should be conducted to assess the efficacy and effectiveness of Mepolizumab in patients with chronic rhinosinusitis, nasal polyposis and anosmia.

Dose-dependent effectiveness of acellular pertussis vaccine in infants: A population-based case-control study

BackgroundPertussis is a vaccine-preventable disease which is most severe in young infants. More than two decades after the introduction of acelluar pertussis vaccines (aPV) in national immunization programs in many countries worldwide, a resurgence of pertussis has been recognized. Suboptimal effectiveness of aPV has been blamed as one major reason but only few studies have evaluated dose-dependent vaccine effectiveness (VE) provided by aPV in current practice. MethodsWe performed a population-based retrospective case-control study by comparing pertussis immunization data of children 2.5 months to 2 years of age hospitalized for pertussis and residing in Switzerland with immunization data of a random control sample of children aged 2 years and residing in Switzerland. VE was defined as the percentage of hospitalizations avoided by number of aPV doses. It was calculated as 1-infection rate ratio (IRR)*100. IRR was calculated by dividing infection rates of vaccinated children and infection rates of unvaccinated children. To get dose specific VE,infection rates were stratified by number doses received. ResultsVE against hospitalization due to pertussis increased significantly with each consecutive aPV dose in a “3 + 1” primary course in infants: 42.1% (95% CI: 11.3–62.6), 83.9% (70.2–92.1), 98.2% (96.1–99.3), and 100% (97.9–100) after the 1st, 2nd, 3rd, and 4th dose, respectively. ConclusionAcellular pertussis vaccines continue to demonstrate protection against hospitalization due to pertussis in infants and young children. Therefore, together with advancing immunization of pregnant women and household contacts, better control of severe pertussis in young infants can be achieved by timely initiation of immunization.

ANTI-PD-1 Treatment in a Family with Constitutional Mismatch Repair Deficiency Syndrome with Multiple Cancers from Turkey. Is Cancer Immunoprevention with Checkpoint Inhibitors HAS a Role in CASES with Homozygous Mutationis

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations of MMR genes and it is poorly recognised by clinicians so far. Here we present affected children of 1st degree consanguinous parents diagnosed with CMMRD syndrome due to germline bi-allelic MSH 6 mutations with multiple cancers and mimicking NF 1 in a family from Turkey A 8-yr-old female,referred with brain tumor with follow up Neurofibromatosis 1 and Familial Mediterranean Fever. One of the female siblings had died of aggressive brain tumor at 4yrs of age, one male sibling due to medulloblastoma, followed by diagnosis of a metachronous metastatic colon adenocarcinoma at 15yrs of age. No additional cancers have been reported in the extended family, with the exception of colorectal cancer in the maternal and paternal great uncle diagnosed at age 45 years, paternal grandfather with brain tumor at 70 age of years and maternal aunt with papillary thyroid cancer at age 50 years. Her physical examination was unremarkable other than 8 to 10 cafe-au- lait spots and hipodense macules with irregular borders on her body. Laboratory tests were normal with low IG G2 levels. Cranial MRI revealed a mass in the left cerebellar region, subcortical hyperdens lesions in fronto-parietal area. She underwent near-total resection,histopathology revealed classic desmoplastic medulloblastoma.Postoperative craniospinal MRI showed no residue or metastasis.Craniospinal RT and CT of CCNU, cisplatin,VCR were given. At initial, due to colon adenocarcinoma history in her family, the colonoscopy was performed which did not reveal any polypoid lesions. In addition, because of the family history, the genetic analysis was carried out and disclosed a novel homozygous single base insertion mutation in exon 5 of the MSH 6 gene ( c.3261dupC/ p.Phe1088Leu ).Five cycles of previously mentioned chemotherapy combination and Nivolumab, obtained by pediatric extended use, was commenced at 3 mg/kg/dose in every 2 weeks as new polyps were detected in the following colonoscopy. After 10th dose,9 polyps were removed of tubular adenoma histopathology .She is still on antiPD1 treatment (18.th dose and in remission. Last colonoscopy revealed only one polyp mm in size. The genetic test results of the family: Blood samples were obtained from parents and siblings. One of the siblings was also found to be homozygous. She is 24- months- old age and has multiple cafe-au-lait spots on her body. She is still under follow up with screening tests for development of possible neoplasms. The parents and the other two siblings ( 11 and 6 years old boys) were heterozygous for the mutation. The male sibling who died from medulloblastoma and metastatic colorectal carcinoma genetic test had revealed same homozygous mutation. Conclusions: As the use of immune modulation for cancer prevention rather than therapy has gained considerable attention, we wonder if 24-months-old female sibling with homozygous mutation will be a candidate for cancer immunoprevention with AntiPD1drugs. We think that an international collaboration is required to evaluate guidelines for screening and treatment of malignancies and to explore prevention strategies patients with CMMRD syndrome. Disclosures Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau.

Mass balance and metabolite profiling of 14C-guadecitabine in patients with advanced cancer

SummaryPurpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14C-guadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.

Novel mRNA-Based Therapy Reduces Toxic Galactose Metabolites and Overcomes Galactose Sensitivity in a Mouse Model of Classic Galactosemia.

Classic galactosemia (CG) is a potentially lethal inborn error of galactose metabolism that results from deleterious mutations in the human galactose-1 phosphate uridylyltransferase (GALT) gene. Previously, we constructed a GalT-/- (GalT-deficient) mouse model that exhibits galactose sensitivity in the newborn mutant pups, reduced fertility in adult females, impaired motor functions, and growth restriction in both sexes. In this study, we tested whether restoration of hepatic GALT activity alone could decrease galactose-1 phosphate (gal-1P) and plasma galactose in the mouse model. The administration of different doses of mouse GalT (mGalT) mRNA resulted in a dose-dependent increase in mGalT protein expression and enzyme activity in the liver of GalT-deficient mice. Single intravenous (i.v.) dose of human GALT (hGALT) mRNA decreased gal-1P in mutant mouse liver and red blood cells (RBCs) within 24h with low levels maintained for over a week. Repeated i.v. injections increased hepatic GalT expression, nearly normalized gal-1P levels in liver, and decreased gal-1P levels in RBCs and peripheral tissues throughout all doses. Moreover, repeated dosing reduced plasma galactose by 60% or more throughout all four doses. Additionally, a single intraperitoneal dose of hGALT mRNA overcame the galactose sensitivity and promoted the growth in a GalT-/- newborn pup.

PSII-20 Effect of mixing of extended boar semen using a bulk semen delivery system after 2 and 5 days in storage

Abstract With the increase in utilization of bulk semen delivery systems, the objective of this study was to determine whether differences in semen quality exist from mixing stored bulk semen. Semen with motility and normal morphology &gt;75% were used to create 4, 70-dose and 4, 35-dose bulk semen bags. Semen was cooled and transported 235 miles. On d2 or d5, a bag was mixed and hung for 15 min. Doses were removed every 2 minutes. One 70-dose (70M) and one 35-dose bag (35M) were mixed every 5th dose, while the remaining 70-dose (70NM) and 35-dose (35NM) bags were not mixed. Doses were weighed and analyzed for concentration using CASA and agglutination assessed. Every 5th dose was warmed and evaluated for motility. One milliliter of semen from the 5th dose was preserved and evaluated for sperm cell morphology. Doses averaged 0.04 ± 0.0001 x 109/mL cells in 31.5 ± 0.077 mL resulting in 1.26 billion sperm/dose. All bags averaged &gt;80% motility on d2 and 69% on d5 with &gt;90% normal morphology on both days. There were minor differences in concentration and normal morphology from variation in preparing bags, not associated with mixing. On d2, mixing had no significant effects on agglutination or motility (P &gt; 0.05). Concentration differed between 35M and 35NM (0.0385 ± 0.0004 vs 0.0417 ± 0.0002 x 109/mL; P &lt; 0.001), with no identifiable trend. On d5, mixing had no effects on concentration, normal morphology or agglutination (P &gt; 0.05). Bag 70M had more distal droplets compared with 70NM (3.78 ± 0.31 vs 2.36 ± 0.34%; P = 0.023). There was a non-significant linear decrease in concentration in the 70NM and 35NM bags, where concentration decreased by 0.124 x109 cells. Mixing alleviated this reduction in the 35-dose bags and partially alleviated it in the 70-dose bags. These data demonstrate that mixing had minimal impact on semen quality and was able to mitigate the decrease in concentration in the 35-dose bag.