Food and Drug Administration

Food and Drug Administration. therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients. PROCEDURES Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014 and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard of care surgery were infused with doses between 0.06mg/kg to 2.83mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-days post-infusion for analysis. RESULTS 81 patients underwent infusion of the study drug at a range of doses. Six patients (7.4%) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged Rabbit Polyclonal to OR10H2 QTc interval which occurred in three patients (3.7%). Panitumumab-IRDye800CW had two OOS results Ciclesonide at 42 and 54 months, while meeting all other stability testing criteria. CONCLUSIONS Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4%) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies. Keywords: Antibody-dye complex, safety, stability, pharmacokinetics, oncology INTRODUCTION As the portfolio of antibody therapeutics grows, diagnostic application of antibodies as molecular targeting agents is recognized as an important diagnostic tool to detect disease in a range of settings such as tumor antigen-specific imaging to guide surgical resection [1], prevent iatrogenic nerve injury intraoperatively [2], and identify metastatic lymph nodes to improve tumor staging and prognosis [3]. However, the more important application will likely be to determine the delivery of these agents and predict potential clinical benefit. Although monoclonal antibody therapies have been successful in extensive preclinical studies, they have a low and unpredictable patient response in the clinic [4C6]. As a result, it is thought that antibodies can be bioconjugated to optical or radiolabels to evaluate the delivery of antibody and check point inhibitor therapies in human subjects and mice models [7C10]. While numerous therapeutic antibodies and optical dyes are well-characterized, the adoption of antibody-dye conjugates is limited due to lack of extensive pre-clinical and clinical testing. Panitumumab (Vectibix?; Amgen, Thousand Oaks, CA) is a fully-human, anti-EGFR monoclonal IgG2 antibody, initially approved by the FDA in September 2006 for EGFR-expressing metastatic colorectal cancer [11]. Panitumumab-IRDye800CW is a near-infrared fluorescently labelled antibody that binds to the epidermal growth factor receptor (EGFR), a protein of the ErbB family that is overexpressed in, amongst others, head and neck, glioma, pancreatic and lung cancers [12C15]. The attached IRDye800CW is a near-infrared fluorophore ideal for surgical visibility since it has higher tissue penetration depth than fluorophores in the visible range (400C700nm) and with minimal endogenous autofluorescence [16]. IRDye800CW has been demonstrated Ciclesonide to have low toxicity and a short half-life when unconjugated [17]. The N-hydroxysuccinimide (NHS) ester reaction binds randomly to lysines throughout the antibody during a standard labeling method that has been performed successfully for chimeric and fully human antibodies with a consistent dye to protein ratio and good imaging results [18C19]. In the current study, we reviewed the product stability of panitumumab-IRDye800CW over 4.5 years, as well as Ciclesonide the pharmacokinetics and safety in 81 patients across four cancer types. The purpose is to inform industry and regulatory agencies on the stability and safety of cGMP-produced antibody-dye conjugates for clinical applications. METHODS Study design We conducted four open-label phase I trials in head and neck squamous cell carcinoma (HNSCC; NCT02415881), pancreas (NCT03384238), brain (NCT03510208), and lung (NCT03582124) cancer, approved by the Stanford University Administrative Panel on Human Subjects Research and the FDA. Written informed consent was obtained from all patients. Adults with primary or recurrent HNSCC, pancreatic, brain or lung cancer scheduled for standard-of-care surgery were eligible. Qualifying patients had >12 weeks life expectancy, a Karnofsky performance status of 70%, or a level 1 ECOG/Zubrod. Exclusion criteria included abnormal magnesium or potassium levels, previous infusion reactions to monoclonal antibodies, QT interval prolongation (greater than 440ms in males and 450ms in females) on baseline electrocardiogram (ECG), substantial liver or cardiovascular disease. Patients taking Class IA or Class.