Journal: Regulatory Toxicology and Pharmacology

Article Title: Development of COVID-19 therapies: Nonclinical testing considerations

doi: 10.1016/j.yrtph.2022.105189

Figure Lengend Snippet: Nonclinical testing package for vaccines used against COVID-19.

Article Snippet: COVID-19 Vaccine AstraZeneca (ChAdOx1-S [recombinant]) or Vaxzevria in UK) is a recombinant replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein and containing ≥2.5 × 108 infectious units in a formulation of established excipients given as a 0.5 mL IM dose , • In vitro functional activity and examination of immunogenicity in mice and pigs as well as efficacy/immunogenicity testing ferrets and in rhesus monkeys (challenged with SARS-CoV-2) occurred; no evidence for concern for VAERD was seen • Safety pharmacology testing involved a cardiovascular and respiratory IM study in mice, while examination of CNS function was included in the repeat-dose toxicity study in mice; no effects were seen • Various biodistribution studies (including examination for viral shedding) in mice with the same or similar vector platform (and/or another viral insert) and a single dose IM biodistribution study in mice with COVID-19 Vaccine AstraZeneca (ongoing at time of initial authorization) • Toxicity testing comprised 3 GLP studies in mice with 2 IM doses, 14 days apart with a 13-day recovery period using the same or similar vector platform (and/or another viral insert) which showed low toxicity, with no other relevant effects than those related to a normal immune response and a GLP study in mice using 3 IM doses (control and one dose level of COVID-19 Vaccine AstraZeneca), 2 weeks apart with a 28-day recovery period. Findings were non-adverse and related to inflammatory reaction to the vaccine (slightly higher body temperature as well as changes in a few hematology and plasma chemistry parameters; raised spleen weights and dose site inflammation were seen); antibodies against the spike-glycoprotein were raised • Preliminary and main development and reproduction toxicity studies in mice with IM doses given 13 days prior to pairing and again on GD 6 or on GD 6 and again on GD 15 with one dose level and controls showed no adverse findings (the main study in mice was ongoing at time of initial authorization); an immune response was demonstrated in dams and seropositivity was measured in fetuses and pups , ; .

Techniques: Vaccines, Recombinant, Plasmid Preparation, Formulation, In Vitro, Functional Assay, Activity Assay, Immunopeptidomics, Control, Clinical Proteomics, Histopathology, Injection, Expressing, Luciferase, Virus, Construct, Mutagenesis, Adjuvant, Infection

Journal: Cancer

Article Title: Leptomeningeal metastasis from systemic cancer: review and update on management.

doi: 10.1002/cncr.30911

Figure Lengend Snippet: Active Therapeutic Clinical Trials for Patients with Leptomeningeal Metastases

Article Snippet: {"type":"clinical-trial","attrs":{"text":"NCT02616393","term_id":"NCT02616393"}} NCT02616393 , II , EGFR-mutant NSCLC , Multiple US sites, Kadmon Corp. LLC , Tesevatinib , Clinical activity using RECIST 1.1 (Cohorts A, C), symptom resolution (Cohort B) , QoL Median PFS CNS TTP Median OS PK , Dosing the same among all arms: 300 mg orally once daily A: NSCLC who have progressed with BM B: NSCLC who have progressed with LM C: NSCLC with BM at initial presentation , • Adults only • EGFR mutation that has clinical response to erlotinib, afatinib, or gefitinib • BM occurrence or progression while receiving erlotinib, afatinib, or gefitinib • Measurable BM (≥10 mm) • ECOG ≤2 • No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy , • First day of dosing with tesevatinib • <2 wks from the last treatment of cytotoxic chemotherapy, biological therapy, or immunotherapy, • <6 wks for nitrosoureas and mitomycin C • <2 wks since surgical procedure • <4 wks since last CNS-direct RT • <3 d since discontinuing erlotinib, afatinib, or TKI • Any concurrent BM (Cohorts A and C), LM (Cohort B) therapy other than study treatment , Yes.

Techniques: Clinical Proteomics, Biomarker Discovery, Injection, Fluorescence In Situ Hybridization, Magnetic Resonance Imaging, Infection, Activity Assay, Mutagenesis