The data points correlate closely with 212Pb physical decay (Pharmacokinetics and imaging after 0.2?mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, 6% urinary excretion, and good tolerance. and animal model testing of 212Pb-TCMC-trastuzumab prior to this human trial. contact over the abdomen averaged 7.67?mR/h and dropped to 0.67?mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (Pharmacokinetics and imaging after 0.2?mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, 6% urinary excretion, and good tolerance. and animal model testing of 212Pb-TCMC-trastuzumab prior to this human trial. IP administration of 212Pb-TCMC-trastuzumab in a preclinical setting has demonstrated therapeutic activity against a variety of human tumor xenografts, and has allowed assessment of redistribution from the peritoneal cavity.13C17 Those studies provided the information required to progress to this initial clinical trial of IP 212Pb-TCMC-trastuzumab. Materials and Methods Patient population Three patients with ovarian cancer who had progressed after multiple therapies were treated in the initial imaging/pharmacokinetics cohort of a Phase I trial. At the time of trial entry they had no evidence of significant compromise of normal organ function or other major illnesses. All had ascites but none had required paracentesis. Trial design The trial design included delivery of the investigational agent, 212Pb-TCMC-trastuzumab, as a single IP injection in patients with HER-2-expressing malignancies IPI-549 mainly confined to the peritoneal cavity who had failed standard therapy. The study was approved by the Western Institutional Review Board and was authorized by the food and drug administration (FDA). HER-2 expression of at least 1+ by immunohistochemistry in 10% of the cells was acceptable for gastric cancer; 30% was required for other diseases. Alternatively, HER-2 serum levels 15?ng/mL by enzyme-linked immunosorbent assay (ELISA) were allowed. Patients had to have free flow of fluid in the peritoneal cavity and were excluded for serious cardiac dysfunction, left ventricular ejection fraction 50%, poor organ function (defined as any of the following: elevated creatinine, total bilirubin 1.5 normal, aspartate transaminase (AST) and alanine aminotransferase (ALT) 2.5 normal, absolute neutrophil counts 1.5103/L, or platelets 100103/L), or other conditions that might compromise safety. Other exclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status 2, pregnancy or breast feeding, evidence of bowel obstruction or transmural involvement, prior IPI-549 radiation to the whole abdomen, prior IP radionuclide therapy, stem cell transplant, history of human immunodeficiency virus (HIV) or Hepatitis A antibody positivity, or detectable antibody to trastuzumab. Eligible, consenting, adult patients were housed in a Clinical Research Unit where they received a single IP injection of 0.2?mCi/m2 (7.4?MBq/m2) 212Pb-TCMC-trastuzumab in 50?mL 4 hours following 4?mg/kg IV trastuzumab. Additional saline was instilled into the peritoneal cavity before and after 212Pb-TCMC-trastuzumab, for a total volume of 1000?mL. Post-treatment blood pharmacokinetics, urinary excretion, and biodistribution studies were performed. Blood samples were obtained immediately post-infusion and at 2, 8, 12, 18, 24, and 63 hours; urine was collected for 24 hours. Each void Ephb3 was collected, the volume was determined, and then 1?mL was counted. Blood samples were allowed to clot and spun, and a 1?mL aliquot of serum was counted. The well counter was operated with the window open to include 238.6?keV detection. Counts were corrected for decay between the time of collection and measurement. Simultaneous whole-body anterior and posterior images were obtained post-treatment and were repeated at 18C24 hours using a dual-headed Phillips Skylight Camera. These used a peak-energy window of 238.6?keV, which corresponds to a 212Pb emission. Images were obtained with a medium-energy general-purpose collimator at 12?cm/min, and high-resolution matrix settings. Dosimetry IPI-549 data were obtained with radiation detector counts immediately post-treatment and at 3 additional times over 24 hours. Probe measurements were taken at the axilla, the mid femur, the umbilicus, and over the sternum IPI-549 using the Inspector 1000 portable radiation detector (Canberra). The patients were followed for toxicity as defined in the Common Terminology Criteria for Adverse Events (NCI CTCAE v.4.03). As a precautionary measure (based on prior studies of other -emitter conjugates) adjuvant medications were used. A saturated solution of potassium iodide (SSKI) was initiated the evening before treatment and it was continued for 3 days. Furosemide (40?mg) was also started the day before 212Pb-TCMC-trastuzumab and it was used for 10 days, and then followed by 100? mg spironolactone daily for 6 months as renal protective agents. Investigational agent 212Pb-TCMC-trastuzumab Trastuzumab is an FDA-approved humanized monoclonal IPI-549 antibody (Genentech) which has therapeutic effectiveness by immunologic mechanisms in tumors that overexpress the HER-2 receptor.18 TCMC-trastuzumab was provided in a form for further manufacturing.
The data points correlate closely with 212Pb physical decay (Pharmacokinetics and imaging after 0
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a 67 kDa type I transmembrane glycoprotein present on myeloid progenitors
and differentiation. The protein kinase family is one of the largest families of proteins in eukaryotes
Apoptosis
bladder
brain
breast
cell cycle progression
cervix
CSP-B
Cyproterone acetate
EGFR) is the prototype member of the type 1 receptor tyrosine kinases. EGFR overexpression in tumors indicates poor prognosis and is observed in tumors of the head and neck
EM9
endometrium
erythrocytes
F3
Goat polyclonal to IgG H+L)
Goat polyclonal to IgG H+L)Biotin)
GRK4
GSK1904529A
Igf1
Mapkap1
monocytes andgranulocytes. CD33 is absent on lymphocytes
Mouse monoclonal to CD33.CT65 reacts with CD33 andtigen
Palomid 529
platelets
PTK) or serine/threonine
Rabbit Polyclonal to ARNT.
Rabbit polyclonal to BMPR2
Rabbit Polyclonal to CCBP2.
Rabbit Polyclonal to EDG4
Rabbit polyclonal to EIF4E.
Rabbit polyclonal to IL11RA
Rabbit polyclonal to LRRIQ3
Rabbit Polyclonal to MCM3 phospho-Thr722)
Rabbit Polyclonal to RBM34
SB 216763
SKI-606
SNX-5422
STK) kinase catalytic domains. Epidermal Growth factor receptor
stomach
stomach and in squamous cell carcinoma.
TNFSF8
TSHR
VEGFA
vulva