Days Of First Dose Research Articles

Risk of abducens nerve palsy following COVID-19 vaccination

To investigate the prevalence and risk of new-onset abducens nerve palsy and acute-onset diplopia following mRNA COVID-19 vaccination. In this retrospective, population-based study, patient data from the COVID-19 Research Network of TriNetX was searched via the TriNetX Analytics platform for patients who received specific vaccinations based on Common Procedural Technology codes. We recorded instances of newly diagnosed abducens nerve palsy and diplopia within 21 days following each vaccination event. Of the 3,545,224 patients (mean age at vaccination, 46.2 ± 21.3 years) who received the mRNA COVID-19 vaccine, 12 (<0.0001%) patients had a new diagnosis of abducens nerve palsy and 453 (0.013%) had acute-onset diplopia within 21 days of first dose of COVID-19 vaccination. After propensity score matching, the relative risk for new abducens nerve palsy diagnosis after the first dose of COVID-19 vaccination was not significantly different from that after influenza (RR, 0.77), Tdap (RR, 1.0), or the second dose of the COVID-19 vaccinations (RR, 1.00). Furthermore, there was a lower risk of abducens nerve palsy diagnosis after the first dose of the COVID-19 vaccination compared with the risk after COVID-19 infection (RR, 0.15). The risk of a new abducens nerve palsy diagnosis following the first dose of the COVID-19 vaccine is lower than the risk associated with COVID-19 infection itself. There is no evidence to suggest a causal relationship between COVID-19 vaccination and the development of abducens nerve palsy.

In-Vivo And Histological Toxicity Profiling Of A Natural Phenol: Phloretin

Phloretin is a flavonoid, which is having strong antioxidant potentials and used in the treatment of numerous disorders. The aim of this study to evaluate the possible toxicological effect of Phloretin in Swiss albino mice. Methods: Single dose of Phloretin was administered stepwise in two groups by oral route and general behaviour, adverse effects and mortality were determined up to 14 days and compared to normal group. In sub-acute study, Phloretin was administered orally for 28 days to the four experimental groups and their body weight was measured each alternate day from the first day of dosing. The final body weight was recorded on 29th day and animals were euthanized by using thiopentone sodium, blood was collected and later haematological, lipid profile, biochemical parameter was evaluated and compared to normal group. Result: In acute toxicity study, no abnormal general behaviour, adverse effects were reported. The body weight, haematological, lipid profile and biochemical parameter also not recorded with any significant changes in sub-acute toxicity study. No significant mortality was reported in both the study. Histopathological examination revealed no alterations in clinical signs or organ weight at any dose. Conclusion: The result concludes that the oral administration of Phloretin did not produce any significant toxic effect in swiss albino mice. Hence, the test drug Phloretin is safe for therapeutic uses.

ADVERSE EVENTS FOLLOWED BY COVID-19 VACCINATION AMONGST HEALTHCARE PROVIDERS

Background:&#x0D; Effective mass vaccination appears to be the only way out of COVID-19 Pandemic. Unlike every other vaccine, adverse events with COVID-19 vaccine are common. Sinopharm made two vaccines which got approval by a prestigious medical journal. The Journal for American Medical Association (JAMA) recently published the clinical trial results for two Sinopharm inoculates-code named WIVO04 and HB02. After two month of peer review the jabs were considered potent, safe and effective to curb the mortality related to COVID-19(1).WHO Strategic Advisory Group Experts (SAGE) re-evaluated the quality, safety and efficacy of both vaccines and recommended its use for people aged 18 and above. &#x0D; Methods:&#x0D; We designed a single page online Performa containing most common adverse events as expected from a viral vaccine. For adverse events not mentioned in the Performa the participant could select an option ‘Other’, to document their experienced adverse event.&#x0D; Results:&#x0D; Out of 101 participants 54 (52.4%) experienced adverse events. Most of the adverse events were mild except one participant who had anaphylactic reaction. Six participants had COVID-19 infection within fourteen days of first dose, confirmed either through PCR or HRCT. One participant had COVID-19 infection after thirty-seven days of 2nd dose of vaccine confirmed through PCR.&#x0D; Conclusion:&#x0D; Our data show that people vaccinated with Sinopharm Vaccine will have high odds to experience mild adverse events. Minor proportion of the population is at risk to develop anaphylactic reaction. The frequency to develop clinically significant COVID-19 disease decreases after second dose of vaccine.

CAMRESBRT: Randomized Phase II Trial of Camrelizumab with Stereotactic Body Radiotherapy vs. Camrelizumab Alone in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitor (ICI) therapy has significantly expanded the therapeutic armamentarium for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Radiation stimulation of abscopal responses, combined with ICI, has been examined in single-arm trials with various tumor types, but randomized evaluation of nivolumab with stereotactic body radiotherapy (SBRT) in R/M HNSCC was frustrated. We aimed to test whether anti–PD-1 therapy, Camrelizumab, may act synergistically with SBRT to improve response through the abscopal effect. <h3>Materials/Methods</h3> We conducted a single-center, randomized, phase II trial. Patients older than 18 years of age with R/M HNSCC who have not been treated with ICIs, regardless of PD-L1 status, are eligible for this study. This trial planned to enroll approximately 70 patients. Patients were randomly assigned (1:1), stratified by human papillomavirus status and PD-L1 status, to camrelizumab versus camrelizumab plus SBRT. Patients have at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Drug: camrelizumab (200mg intravenously every 2 weeks). Radiation: SBRT (27 Gy over 3 fractions given every other day) to single lesion to start by study day (study day 1 is day of first dose of camrelizumab). The primary end point was objective response rate (ORR) in nonirradiated lesions, which was assessed by RECIST 1.1. The secondary objectives were safety and tolerability (adverse events of grade 3-4 or higher, rate of long-term adverse events), 6-month and 1-year disease control rate (DCR), 6-month and 1-year progression free survival (PFS), overall survival (OS). <h3>Results</h3> As of January 2022, 31.4% of the planned 70 subjects have been enrolled. Median age was 54.5 years; 17 patients were male. 14 patients received camrelizumab alone and 8 patients received camrelizumab plus SBRT. The PD-L1 status was known in 14 of 18 patients, including 1 patient with PD-L1 CPS (combined positive score) less than 1, 3 patients more than 20, and 10 patients between 1-20. ClinicalTrials.gov Identifier: NCT04830267. <h3>Conclusion</h3> Clinical trial in progress.

P563: A RANDOMIZED, DOUBLE-BLIND, 2-ARM, MULTICENTER, PH3 STUDY OF VENETOCLAX &amp; ORAL AZACITIDINE VS. ORAL AZACITIDINE AS MAINTENANCE THERAPY FOR PTS WITH AML IN FIRST REMISSION AFTER INTENSIVE CHEMOTHERAPHY

Background: Acute myeloid leukemia (AML) is an aggressive, heterogenous hematologic malignancy with poor prognosis. For eligible patients, standard treatment includes intensive chemotherapy during induction, followed by consolidative chemotherapy or stem cell transplantation. Despite current therapies, the prevention of relapse is still a major therapeutic challenge and an unmet need for patients in remission. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. Ven in combination with Azacitidine (Aza) leads to prolonged overall survival (OS) and rapid, durable remissions in treatment-naïve AML patients ineligible for intensive chemotherapy. The QUAZAR AML-001 (NCT01757535) trial showed that the median OS in patients receiving maintenance oral Aza was superior to patients receiving placebo following upfront induction and consolidation; this benefit was also observed for patients who achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi). VIALE-M is a randomized, double-blind, two-part study (NCT04102020) to determine the recommended Phase 3 dose (RPTD) of Ven in combination with oral Aza (CC-486) that can be safely administered as maintenance therapy, and to evaluate the safety and efficacy of Ven in combination with oral Aza + BSC compared to placebo and oral Aza + BSC in patients with AML who have achieved CR or CRi after intensive induction and consolidation. Aims: N/A Methods: The study is enrolling patients aged ≥18 years with newly diagnosed AML per WHO 2016 classification, with confirmed CR or CRi following intensive induction and consolidation therapies, from > 200 sites worldwide. Patients must have achieved first CR or CRi (after induction) ≤120 days of first dose of study drug or ≤75 days past last dose of last consolidation cycle, have intermediate or poor risk cytogenetics per NCCN 2016 categorization, ECOG ≤2, and no history of acute promyelocytic leukemia or active central nervous system involvement with AML. For the dose finding part of the study, patients will receive Ven QD for up to 24 cycles and oral Aza QD on D1-14 of each 28-day cycle for up to 24 cycles to determine the RPTD. For safety expansion, patients will receive Ven QD for up to 24 cycles and oral Aza QD on D1-14 of each cycle for up to 24 cycles at the RPTD. For the randomization part, patients will be randomized 1:1 to receive placebo or Ven QD at the RTPD and oral Aza QD on D1-14 of each cycle for 24 cycles. In all parts, treatment may discontinue due to relapse/unacceptable toxicity, or continue beyond 24 cycles under investigator’s discretion. For the randomization portion, the primary endpoint is relapse-free survival; secondary outcomes include OS, minimal residual disease conversion, and improvement in quality of life. Results: N/A Summary/Conclusion: N/A

Abstract CT536: Tepotinib efficacy and safety in patients with MET exon 14 (METex14) skipping NSCLC

Abstract Introduction: In the primary analysis of VISION, tepotinib — a highly selective, potent MET inhibitor — demonstrated durable efficacy, and a tolerable safety profile in patients (pts) with METex14 skipping NSCLC. We report updated outcomes, with interim analyses from a confirmatory cohort. Methods: In the Phase II VISION study, pts with advanced/metastatic METex14 skipping NSCLC, identified by liquid (L+) and/or tissue (T+) biopsy, received 500 mg (450 mg active moiety) tepotinib once daily. All pts were assessed for safety; pts with ≥3 months’ follow-up were assessed for efficacy. Primary endpoint was objective response by independent review (RECIST v1.1). Secondary endpoints were disease control (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of Feb 1, 2021, 7,882 pts were pre-screened, and 275 pts were analyzed for efficacy. Patients analyzed for efficacy had a median age of 72.4 years (range, 41-94]), 50.9% were female, 46.5% had smoking history, and median tumor load [target lesions by IRC] was 57.4 mm [range, 10.2-227.8]). Tumor load in L+ pts was 68.0 mm (11.6-227.8) and 52.9 mm (10.2-227.8) in T+ pts. In treatment-naïve pts (n=137), ORR was 54.0% (95% CI: 45.3, 62.6), DCR was 74.5% (66.3, 81.5), and &amp;gt;90% of pts had tumor shrinkage. Median (m) DOR was 32.7 months (9.0, not estimable), mPFS was 10.4 months (8.4, 15.3), and mOS was 17.6 months (13.4, 29.7). In previously treated pts (n=138), ORR was 44.2% (35.8, 52.9), DCR was 75.4% (67.3, 82.3), and &amp;gt;90% of pts had tumor shrinkage. mDOR was 11.1 months (8.4, 18.5), mPFS was 11.0 months (8.2, 12.4), and mOS was 19.9 months (15.8, 22.3). Meaningful clinical activity was observed in L+ and T+ pts (Table). Overall, 14.1% of pts discontinued due to TRAEs; tepotinib was well-tolerated across treatment lines (Table). Conclusions: Tepotinib demonstrated robust and durable clinical activity across treatment lines in pts with METex14 skipping NSCLC, with particularly durable efficacy in first line. TRAEs were manageable with few discontinuations. Table 1. Tepotinib efficacy and safety in patients with METex14 skipping NSCLC (VISION) Tepotinib efficacy (pts with ≥3 months’ follow-up in Cohorts A+C) Overall Treatment-naϊve (n=137) Previously treated (n=138) Combined (N=275) Liquid biopsy* (n=81) Tissue biopsy* (n=86) Liquid biopsy* (n=78) Tissue biopsy* (n=88) Objective response rate, % (95% CI) 49.1 (43.0, 55.2) 54.3 (42.9, 65.4) 54.7 (43.5, 65.4) 43.6 (32.4, 55.3) 47.7 (37.0, 58.6) Disease control rate, % (95% CI) 74.9 (69.4, 79.9) 71.6 (60.5, 81.1) 80.2 (70.2, 88.0) 69.2 (57.8, 79.2) 79.5 (69.6, 87.4) Median duration of response, months (95% CI) 13.8 (9.9, 19.4) 13.8 (7.2, ne) 32.7 (10.8, 32.7) 11.1 (8.4, 19.4) 10.1 (8.3, 15.7) Median progression-free survival, months (95% CI) 10.8 (8.5, 12.4) 8.5 (6.9, 11.3) 15.3 (9.6, ne) 8.3 (5.7, 11.0) 11.1 (8.2, 16.8) Median overall survival, months (95% CI) 19.7 (15.6, 22.1) 15.1 (9.5, 22.1) 29.7 (15.3, ne) 19.9 (12.8, 22.3) 22.3 (17.0, 27.2) Tepotinib safety (all pts who received tepotinib in Cohorts A+C) Overall (N=291) Treatment-naϊve (n=148) Previously treated (n=143) Treatment-related AEs†, n (%) Any grade 264 (90.7) 137 (92.6) 127 (88.8) Grade ≥3 86 (29.6) 49 (33.1) 37 (25.9) Leading to death 2 (0.7) 1 (0.7) 1 (0.7) Leading to a dose reduction 90 (30.9) 51 (34.5) 39 (27.3) Leading to temporary discontinuation 114 (39.2) 63 (42.6) 51 (35.7) Leading to permanent discontinuation 41 (14.1) 24 (16.2) 17 (11.9) All-cause AEs† in ≥20% of patients, n (%) Peripheral edema 191 (65.6) 98 (66.2) 93 (65.0) Nausea 88 (30.2) 51 (34.5) 37 (25.9) Diarrhea 81 (27.8) 42 (28.4) 39 (27.3) Hypoalbuminemia 81 (27.8) 41 (27.7) 40 (28.0) Blood creatinine increase 76 (26.1) 34 (23.0) 42 (29.4) Dyspnea 60 (20.6) 40 (27.0) 20 (14.0) Data cut-off: Feb 1, 2021. *Patients with METex14 skipping detected by both liquid and tissue biopsy are included in both analysis sets (overall, n=59; treatment-naïve, n=30; previously treated, n=29); testing by both methods was not required for enrollment. †AEs were defined as events that started within the day of first dose of trial treatment until 30 days after last dose of treatment or started prior to first dose but worsened during the treatment period. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. AE, adverse event; CI, confidence interval; MET, mesenchymal-epithelial transition factor; METex14; MET exon 14; ne, not estimable. Citation Format: Marina C. Garassino, Xiuning Le, Wade T. Iam, Enriqueta Felip, Hiroshi Sakai, Remi Veillon, Egbert F. Smit, Julien Mazieres, Jo Raskin, Alexis B. Cortot, Karin Berghoff, Rolf Bruns, Gordon Otto, Paul K. Paik. Tepotinib efficacy and safety in patients with MET exon 14 (METex14) skipping NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT536.

Antibody response after two doses of homologous or heterologous SARS-CoV-2 vaccines in healthcare workers at health promotion centers: A prospective observational study.

Assaying of anti‐spike‐protein receptor‐binding domain (S‐RBD) antibodies are used to aid evaluations of the immune statuses of individuals. The aim of this study was to determine the antibody response after two doses of homologous or heterologous severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines and to identify the factors affecting this response among healthcare workers (HCWs) at health promotion centers. In this prospective observational study, 1095 consenting HCWs were recruited from 16 health checkup centers and were tested at T0 (day of first dose), T1‐1 (1 month after first dose), T2‐0 (day of second dose), T2‐1 (1 month after second dose), and T2‐3 (3 months after second dose). SARS‐CoV‐2 antibodies were measured using a chemiluminescence microparticle immunoassay with SARS‐CoV‐2 IgG II Quant in the ARCHITECT system (Abbott Diagnostics). At T1‐1, anti‐SARS‐CoV‐2 S‐RBD IgG levels were significantly higher in participants who received messenger RNA (mRNA) vaccines than in those who received viral vector vaccines (p < 0.001). At T2‐1, anti‐SARS‐CoV‐2 S‐RBD IgG levels were about 10 times higher than at T1‐1 in participants who received homologous mRNA vaccines, which decreased to a third of those at T2‐3. Anti‐SARS‐CoV‐2 S‐RBD IgG levels were highest among those who received homologous mRNA vaccines, followed by heterologous mRNA viral vector vaccines and homologous viral vector vaccines at T2‐3 (p < 0.001). In a multivariable linear regression analysis, being female, taking at least one mRNA vaccine, and having a history of recovery from coronavirus disease 2019 (COVID‐19) were significantly associated with anti‐S‐RBD levels. Anti‐SARS‐CoV‐2 S‐RBD IgG levels were decreased at 3 months after two‐dose vaccinations and were associated with sex, vaccine type, and COVID‐19 history.

Serosurveillance among healthcare workers vaccinated with ChAdOx1 nCoV-19 Corona vaccine in a tertiary hospital of Kerala, India: prospective cohort studу

Aim. To evaluate antibody responses following two doses of ChAdOx1 nCoV-19 Corona vaccination in a tertiary care setting and the association of host factors like age, body mass index and comorbidities in determining this antibody response.Materials and methods. This prospective serosurveillance study was done among healthcare workers of Jubilee Mission Medical College, vaccinated during January- April 2021. Blood samples were drawn from 170 participants after their first dose and from 156 participants after their second dose of CovishieldTM to measure the specific Ig G antibodies against the recombinant S1 subunit of the S protein of SARS-CoV-2.Results. The median level of anti-SARS-CoV-2 Ig G antibody 28–56 days after the first dose vaccination was 3.64 S/C (1.33, 7.24) and 11.6 S/C (8.61, 14.27) after 14 days of second dose vaccination. Protective levels of anti-SARS CoV-2 Ig G antibodies (≥ 9.5 S/C) was developed by 25 participants (14.7%, 95% confidence interval: 9.8% to 20.9%) after 28–56 days of first dose of vaccination and by 109 participants (69.9%, 95% confidence interval: 62% to 77%) after 14 days of second dose. Health care workers in the age group below 60 years (p = 0.027) and without comorbidities (p = 0.079) showed higher protective Ig G levels. But on multiple logistic regression only age under 60 years was found to be statistically significant.Conclusion. After the first dose of the ChAdOx1 nCoV-19 vaccine, the formation of Ig G antibodies was observed, the level of which increased after the second dose. Among the various associated factors studied only the age of the participants below 60 years was found to be statistically significant for protective antibody levels. Follow up studies involving larger and different ethnic population is key to decoding the antibody response especially in the elderly and high-risk groups.

Abstract 51: Age Stratified Risk Of Cerebral Venous Sinus Thrombosis After Sars-Cov-2 Vaccination

Introduction: Cerebral Venous Sinus Thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of SARS-CoV-2 vaccination. The estimated background rate of CVST in adults is around 1 case per million per month, and CVST with thrombocytopenia accounts for 8% of all CVST. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination. Methods: We estimated the absolute risk of any CVST, CVST with thrombocytopenia, and CVST without thrombocytopenia, within 28 days of first dose SARS-CoV-2 vaccination, using data from the European Medicines Agency’s EudraVigilance database (until 13 June 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category. Results: The absolute risk of CVST within 28 days of first dose vaccination was 7.5 (95%CI 6.9-8.3), 0.7 (95%CI 0.2-2.4), 0.6 (95%CI 0.5-0.7) and 0.6 (95%CI 0.3-1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2 and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95%CI 3.9-4.9), 0.7 (95%CI 0.2-2.4), 0.0 (95%CI 0.0-0.1) and 0.0 (95%CI 0.0-0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2 and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the risk of CVST, both with and without thrombocytopenia, was the highest in the 18-24 years age group (7.3 per million, 95%CI 2.8-18.8 and 3.7, 95%CI 1.0-13.3, respectively). The risk of CVST with thrombocytopenia was the lowest in ChAdOx1 nCov-19 recipients ≥70 years (0.2, 95%CI 0.0-1.3). Age &lt;60 compared to ≥60 was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79; 95%CI 2.98-11.24, p&lt;0.001). Discussion: The risk of CVST with thrombocytopenia within 28 days of first dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S, comparing with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of mRNA vaccines for SARS-CoV-2.

524. Assessing the Safety of an Outpatient Remdesivir Infusion Program for Patients with Severe COVID-19 in the Setting of a Pandemic Surge

Background(i) Remdesivir (RDV) shortens recovery time among COVID-19 patients in an inpatient setting. (ii) Treatments for outpatients diagnosed with COVID-19 are limited. (iii) In early 2021, there was a national surge in COVID-19 hospitalizations, which resulted in hospital bed and staff shortages. (iv) In the face of this pandemic surge, we piloted a program to expand our RDV treatment capacity by establishing an off-label, outpatient infusion tent (OIT) for patients with severe COVID-19. (v) This is a retrospective, descriptive report examining the safety and efficacy of this program, with outcomes of interest being 30-day mortality and hospital admission within the subsequent 30 daysMethods(i) The OIT, consisting of 11 chairs capable of treating 35 patients per day, was operational from January 1 to February 19, 2021. (ii) Patients were referred to the outpatient RDV program primarily from urgent care (UC) and the emergency department (ED), and from the inpatient setting to complete therapy. Patients received at least one dose prior to referral. (iii) Eligibility criteria included a confirmed COVID-19 diagnosis, radiographic evidence of viral pneumonia, and an oxygen saturation less than or equal to 94 on room air. (iv) Exclusion criteria included pregnancy, sepsis, end-stage renal disease or GFR < 30, hepatitis with transaminases 10 times the limit of normal. Patients with BMI > 40, age > 75, chronic lung disease, dementia, were considered on a case by case basis. (v) Patients received dexamethasone and deep vein thrombosis prophylaxisResults(i) A total of 88 patients received 258 infusions. The average number of outpatient infusions per participant was 2.9. (ii) Four out of 88 patients died (4.5%) within 30 days of first dose in the infusion tent. No deaths occurred in the outpatient setting. (iii) Fourteen out of 88 patients were admitted to the hospital within the subsequent 30 days (15.9%). (iv) 11/14 admissions (78.6%) were due to progression of COVID-19. There were no admissions due to adverse drug reactionsTable 1. Patient Characteristics Table 2. Admissions Within Subsequent 30 Days ConclusionMortality rate in outpatients with severe COVID-19 treated with RDV was similar to that reported in inpatients. In this cohort of patients with severe COVID, a majority (84.1%) avoided hospitalization while still receiving appropriate treatment. Results suggest RDV can be safely delivered to outpatients with severe COVID-19.Disclosures All Authors: No reported disclosures

Antibody response induced by the BNT162b2 mRNA COVID-19 vaccine in a cohort of health-care workers, with or without prior SARS-CoV-2 infection: a prospective study

ObjectivesTo assess the antibody response to BNT162b2 mRNA COVID-19 vaccine in a cohort of health-care workers (HCW), comparing individuals with previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and SARS-CoV-2-naive individuals. MethodsHCW were tested at T0 (day of first dose), T1 (day of second dose) and T2 (2–3 weeks after second dose) for IgG anti-nucleocapsid protein, IgM anti-spike protein and IgG anti-receptor binding domain (IgG-RBD-S). The antibody response was compared between four main groups: group A, individuals with previous infection and positive antibodies at baseline; group B, individuals with the same history but negative antibodies; group C, individuals with no infection history but positive antibodies; group D, naive individuals. Repeated measures analysis was used to compare results over time-points. ResultsA total of 1935 HCW were included. Median IgG-RBD-S titre was significantly higher for group A (232 individuals) than for group B (56 individuals) both at T1 (A: 22 763 AU/mL, interquartile range (IQR) 14 222–37 204 AU/mL; B: 1373 AU/mL, IQR 783–3078 AU/mL, p 0.0003) and T2 (A: 30 765 AU/mL, IQR 19 841–42 813 AU/mL; B: 13 171 AU/mL, IQR 2324–22 688 AU/mL, p 0.0038) and for group D (1563 individuals; 796 AU/mL, IQR 379–1510 AU/mL at T1; 15 494 AU/mL, IQR 9122–23 916 AU/mL at T2, p < 0.0001 for both time-points). T1 values of group A were also significantly higher than T2 values of group D (p < 0.0001). Presence of symptoms, younger age and being female were associated with stronger antibody response. HCW infected in March showed a significantly stronger response (T1: 35 324 AU/mL, IQR 22 003–44 531 AU/mL; T2: 37 648 AU/mL, IQR 27 088–50 451 AU/mL) than those infected in November (T1: 18 499 AU/mL, IQR 11 492–27 283 AU/mL; T2: 23 210 AU/mL, IQR 18 074–36 086 AU/mL, p < 0.0001 for both time-points. ConclusionsIndividuals with past SARS-CoV-2 infection had a strong antibody response after one single vaccine shot. A single dose might be sufficient for this group, regardless of the time elapsed since infection; however, the clinical correlation with antibody response needs to be studied.

Abstract CT216: A Phase 1/2 Study of INCB000928 as Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

Abstract Background: Anemia represents a therapeutic challenge in patients with myelofibrosis (MF). ALK2 activation is associated with elevated hepcidin, which may contribute to anemia of chronic disease and anemia due to hematologic malignancies, and is associated with increased transfusion rate and reduced overall survival. This phase 1/2, open-label, multicenter, dose-escalation/dose-expansion study will evaluate the safety and tolerability of INCB000928, a potent, highly selective, ALK2 inhibitor, as monotherapy or combined with ruxolitinib in patients with anemia due to MF (INCB 00928-104; NCT04455841). Methods: Patients with histologically confirmed primary/secondary MF presenting with transfusion-dependent or symptomatic anemia will receive oral INCB000928 either alone (treatment group [TG] A) or combined with ruxolitinib (TGB). In TGA, patients must have intermediate (INT)-2 or high-risk (per Dynamic International Prognostic Scoring System [DIPSS]) disease that is intolerant, resistant, refractory, or has lost response to prior JAK inhibitor therapy (≥12 weeks). In TGB, patients must have received stable ruxolitinib therapy for ≥12 consecutive weeks before first dose and have INT-1/INT-2, or high-risk disease. Eligibility also requires age ≥18 y, ECOG PS 0-1 (dose-escalation) or 0-2 (dose-expansion), life expectancy &amp;gt;6 months, no other hematologic malignancy, no prior stem cell transplantation, no major surgery within 28 days, and no prior disease-directed therapy within 5 half-lives or 28 days of first dose. In Part 1 (dose escalation), TGA will receive INCB000928 monotherapy starting at 50 mg/day (28-day cycles). Dose-escalation will follow a Bayesian optimal-interval design to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE). Dose increases not exceeding 2-fold will continue until Grade ≥2 treatment-related toxicity occurs. TGB will receive INCB000928 plus ruxolitinib; INCB000928 dose escalation will start 2 dose levels below the highest dose determined to be safe and tolerable in TGA. In Part 2 (dose expansion), the RDE in TGB will be evaluated in combination with ruxolitinib in ~25 patients; treatment will continue for ≤12 months, and may continue if clinically beneficial and no progression occurs. Primary objective is to determine the safety and tolerability of INCB000928 as monotherapy or combined with ruxolitinib. Secondary objectives are to determine the efficacy of INCB000928 as monotherapy or combined with ruxolitinib (anemia response, duration of anemia response, mean change from baseline in hemoglobin, and RBC transfusion rate through weeks 24 and 48); evaluate INCB000928 pharmacokinetics; and evaluate effects of INCB000928 as monotherapy or combined with ruxolitinib on hepcidin levels and other measures of iron homeostasis and erythropoiesis. Citation Format: Stephen T. Oh, Jean-Jacques Kiladjian, Francesca Palandri, Jason R. Gotlib, Sanjay Mohan, Haris Ali, Ekatherine Asatiani, Francis Seguy, Feng Zhou, Srdan Verstovsek. A Phase 1/2 Study of INCB000928 as Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT216.

IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate (ADC) Demonstrates Initial Antileukemia Activity in Patients with Relapsed or Refractory Acute Myeloid Leukemia

IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate (ADC) Demonstrates Initial Antileukemia Activity in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial

Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. Astellas Pharma Global Development and Seagen.

Abstract OT-03-08: A Phase 2, open-label study to evaluate the safety and efficacy of the probody therapeutic (Pb-Tx) CX-2009 in metastatic HR-Positive/HER2-negative breast cancer (mHR+/HER2− BC) and of CX-2009 as monotherapy and in combination therapy with CX-072 in metastatic triple-negative breast cancer (TNBC)

Abstract Background: Probody® therapeutics (Pb-Tx) are masked antibodies designed to be selectively activated in the tumor microenvironment by tumor-associated proteases, while remaining largely inactive in normal tissue and in circulation. This allows Pb-Tx to address previously undruggable targets that are highly expressed in both tumor and normal tissue, such as the activated leukocyte cell adhesion molecule (ALCAM) CD166. CX-2009 is an investigational Probody drug conjugate consisting of an anti-CD166 monoclonal antibody conjugated to the microtubule inhibitor DM4. A Phase 1 study demonstrated safety and durable clinical activity in patients with mHR+/HER2− BC and in mTNBC patients who had received a median of 7 prior regimens. In the efficacy evaluable subgroup receiving doses of at least 4 mg/kg Q3W, the overall response rate (ORR; includes confirmed and unconfirmed responses) was 11% (HR+/HER2−; n=18) and 38% (TNBC; n=8), with a clinical benefit rate at 24 weeks (CBR24) of 35% in all breast cancer patients. Gr ≥3 DM4-associated ocular toxicities related to CX-2009 ≤7mg/kg were reported in 2%. In this Phase 2 study, CX-2009 monotherapy will be evaluated in patients with mHR+/HER2− BC and mTNBC. In addition, CX-2009 will be combined with CX-072, a Probody therapeutic directed against PD-L1, to evaluate the safety of the combination and whether the cytotoxic activity of the DM4 payload is additive with PD-L1 blockade via CX-072 in patients with mTNBC. CD166 expression in patients with HR+/HER2− BC was high (&amp;gt;90%) in the Phase 1 study; this cohort will enroll without screening for CD166. CD166 expression in patients with TNBC was variable and, as such, patients will undergo screening for CD166 positivity. Methods: This Phase 2, open-label noncomparative study with 3 parallel arms (n≈40/arm) is investigating the safety and activity of CX-2009 monotherapy (7 mg/kg Q3W) and the combination of CX-2009 (7 mg/kg Q3W) + CX-072 (1200 mg Q3W) in patients with previously treated locally advanced or metastatic HER2− BC. All patients will be adults with an ECOG status of 0-1, acceptable end-organ function, measurable disease, and willingness to receive ocular prophylaxis for DM4 related toxicities. Tumor tissue is required for CD166 expression analysis. Key eligibility criteria for the mHR+/HER2− BC cohort include 2-4 prior regimens (not including single-agent hormonal therapy). Patients with mTNBC must be CD166 positive by IHC and have received 1-3 regimens. For mTNBC patients who receive the doublet, key exclusion criteria include known PD-L1-negative tumor status, history of or active autoimmune disease, and progression within 120 days of first dose of an IO agent. Patients with active or chronic corneal disorders will be excluded from the study. All treatments will be given until disease progression or unacceptable toxicity. Radiology assessments will be done Q6W. The primary endpoint will be ORR assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints will include ORR, DoR, CBR16 and CBR24, and PFS by investigator, OS will also be assessed. This study will also evaluate tolerability, pharmacokinetics, and antidrug antibodies with CX-2009 as monotherapy and in combination with CX-072. Exploratory endpoints will include potential predictive markers of response or toxicity. This trial is actively enrolling. Email address for questions or comments: gpaton@cytomx.com Citation Format: Kathy D. Miller, Leisha A. Emens, Sara Tolaney, Sara A. Hurvitz, Erika Hamilton, Virginia Paton, Alison Hannah, Valentina Boni. A Phase 2, open-label study to evaluate the safety and efficacy of the probody therapeutic (Pb-Tx) CX-2009 in metastatic HR-Positive/HER2-negative breast cancer (mHR+/HER2− BC) and of CX-2009 as monotherapy and in combination therapy with CX-072 in metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-08.

An exploratory analysis on the toxicity & safety profile of Polyherbal combination of curcumin, quercetin and rutin

BackgroundCurcumin, quercetin and rutin are flavonoids having strong antioxidant potential, individually used in treatment of numerous ailments. The safety assessment of each of them is already established but no toxicological assessment has been done that would guarantee the safe use of these three flavonoids when used as a polyherbal combination (PHC). The aim of this study to evaluate the possible toxicological effect of polyherbal combination of these three flavonoids in female Swiss albino mice.MethodsIn acute toxicity study, the oral dose of poly herbal combination was administered to four groups stepwise in single dose and general behaviour, adverse effects and mortality were determined up to 14 days and compared to normal group. In sub-acute study, the tested poly herbal combination was administered orally for 28 days to the four experimental groups and their body weight was measured each alternate day from the first day of dosing. On 29th day the final body weight was recorded and euthanized by using thiopentone sodium, blood was collected and later haematological, lipid profile, biochemical parameter was evaluated and compared to normal group.ResultIn acute toxicity study, no abnormal general behaviour, adverse effects were reported. No significant changes were reported in body weight, haematological, lipid profile, biochemical parameter in sub-acute toxicity study. No mortality was reported in both the study. Histopathological examination revealed no alterations in clinical signs or organ weight at any dose.ConclusionThe result concludes that the oral administration of Polyherbal combination did not produce any significant toxic effect in swiss albino mice. Hence, the Polyherbal combination can be utilized safely for therapeutic use.

A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

Trials in Progress: A Phase I Study to Evaluate the Safety and Pharmacokinetic Profiles of CB-5339 in Participants with Relapsed/Refractory Acute Myeloid Leukemia or Relapsed/Refractory Intermediate or High-Risk Myelodysplastic Syndrome

Trials in Progress: A Phase I Study to Evaluate the Safety and Pharmacokinetic Profiles of CB-5339 in Participants with Relapsed/Refractory Acute Myeloid Leukemia or Relapsed/Refractory Intermediate or High-Risk Myelodysplastic Syndrome

Phase 2 Study of Tagraxofusp Therapy for BPDCN Patients Post-Autologous or Post-Allogeneic Hematopoietic Cell Transplantation

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with historical overall survival (OS) of 8-14 months from diagnosis. Tagraxofusp is a targeted therapy directed to CD123. The US FDA has approved tagraxofusp for the treatment of BPDCN in adult and pediatric patients 2 years and older. CD123 is ubiquitously expressed at high levels on plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, and targeting of CD123 with tagraxofusp resulted in high response rates, durable remissions, and a significant proportion of patients bridged to hematopoietic cell transplant (HCT) in first remission (45%). While HCT has the potential to prolong remission of patients with hematologic cancers, relapses after transplantation still occur in patients with certain risk factors including minimal residual disease (MRD). This study is designed to assess the safety and efficacy of tagraxofusp monotherapy as a maintenance treatment in patients with BPDCN post-HCT. The study is open for enrollment and expected to recruit approximately 20 patients. NCT04317781 Rationale: Available data suggest long-term remission can be expected in approximately 50% of patients with BPDCN that undergo allo-HCT. Accordingly, strategies are needed to further reduce the risk of relapse post-HCT. Methods: The study is a Phase 2, single-center, open-label, single-arm clinical trial of tagraxofusp in patients with BPDCN that have undergone HCT. Planned enrollment is 20 patients. Treatment with tagraxofusp will be initiated between day 45 and 120 post-HCT, and dosed days 1-3 in cycles 1-4, and days 1-2 in cycles 5 and beyond. Each treatment cycle is 28 days. Duration of therapy for patients in complete response (CR) or clinical CR (CRc) post-transplant is 24 cycles, with patients who are MRD-positive or remain at high risk of relapse, eligible for continued treatment for as long as they derive benefit. In patients whose post-HCT disease status is either CR with incomplete blood count recovery (CRi) or partial response (PR), treatment will continue until disease progression or unacceptable toxicity. Major Inclusion/Exclusion Criteria : Age ≥18; &amp;gt;30 days post-transplant without active or chronic infections; Karnofsky PS ≥60%; Lansky ≥60; adequate organ function including LVEF ≥ lower limit of normal (LLN); creatinine ≤1.5 mg/dL; albumin ≥3.2 g/dL; bilirubin ≤1.5 upper limit of normal (ULN); AST/ALT ≤2.5 times ULN; and ANC ≥1000. For allo-HCT, no ≥ grade 2 visceral (gut or liver) acute graft versus host disease (GVHD) and no ≥ grade 3 or any other acute GVHD (chronic GVHD allowed at investigator discretion). Key exclusions: Persistent clinically significant non-hematologic toxicities ≥ grade 2; CNS involvement; receiving chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days of first dose of study drug; uncontrolled infection; HIV/Hepatitis B and/or C; and clinically significant cardiopulmonary disease. Endpoints: Primary endpoints include safety and tolerability of tagraxofusp in patients with BPDCN post-HCT, with survival as secondary outcomes. Disclosures Bashir: Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Acrotech: Research Funding; StemLine: Research Funding; KITE: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Celgene: Research Funding. Shpall:Magenta: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Zelluna: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Popat:Bayer: Research Funding; Novartis: Research Funding. Pemmaraju:Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Plexxikon: Research Funding; Affymetrix: Other: Grant Support, Research Funding; AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; MustangBio: Honoraria; Cellectis: Research Funding; Incyte Corporation: Honoraria. Champlin:Takeda: Patents &amp; Royalties; Actinium: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy; Cytonus: Consultancy. Qazilbash:Bioline: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Janssen: Research Funding.

Evaluation of immunogenicity, safety and breakthrough following administration of live attenuated varicella vaccine in two doses three months apart regimen in Indian children.

Background:In India, where varicella outbreaks are reported at a younger age, a two-dose vaccine schedule administered at an early age could be highly efficacious in preventing varicella infection. The aim of this study was to evaluate the immunogenicity and safety of live attenuated varicella vaccine (VR 795 Oka strain) in a two-dose, 3 months apart regimen.Methodology:Healthy children (⩾ 12 months and ⩽12 years; mean age: 4.4 years) of either sex were included. Geometric mean titers (GMT) were measured at baseline and 28 days post first- and second-dose, and seroprotection rates were measured 28 days post first and second dose. The incidence of breakthrough (BT) infections post vaccination was determined from 42 days post first and second dose of vaccine up to 12 months. Adverse events (AEs) were monitored and recorded throughout the study period.Results:Of 305 subjects enrolled, 217 were seronegative. The seroconversion rate (a change from a seronegative to a seropositive condition) was 93.3% post first-dose and 100% post two-doses. High levels (9 times) of GMT were reported since post first-dose to post second-dose in children aged 12–18 months, 18–60 months (99.43%); and in and above 60 months (99.02%). The extent of rise of anti-VZV IgG antibody titer post 28 days of first-dose at two-fold, three-fold and four-fold rise was 93.39%, 90.56% and 80.66%, respectively and 100% 4-fold rise post second-dose. A single case, a day after the first-dose of vaccination of mild BT infection, was observed after close contact with a severe case. AEs were mild and none of the serious AEs were related to the study drug.Conclusion:The two-dose schedule of varicella vaccine was safe and immunogenic when given 3 months apart. However, further comparative studies and follow up for both dosing schedules are needed to validate the advantage of early dosing.