title: A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit alpha of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors.
abstract: OBJECTIVE
  The purpose of this study was to define the safety and pharmacodynamics of GEM231, a mixed backbone antisense oligonucleotide targeting the type I regulatory subunit alpha of protein kinase A, administered as a continuous i.v. infusion.
  
  
  METHODS
  Fourteen cancer patients received escalating doses of GEM231 as a 3-day (1 patient) or a 5-day continuous i.v. infusion (13 patients) at doses ranging from 80 to 180 mg/m(2)/day.
  
  
  RESULTS
  The maximum tolerated dose of GEM231 was 180 mg/m(2)/day, based on dose-limiting elevation of serum transaminases (STs). At the recommended Phase II dose, 120 mg/m(2)/day (n = 8), the median number of cycles delivered was 2 (range, 1-4 cycles). Toxicities were tolerable, with one patient experiencing grade 3 ST elevation after 8 weeks. Plasma activated partial thromboplastin time changes were transient, reached a peak at the end of each weekly infusion, and were not associated with spontaneous bleeding. There was a significant difference between the mean preinfusion and postinfusion activated partial thromboplastin time measurements (2.05 s; P = 0.029). The most significant nonhematological toxicity was elevation in ST, usually observed after >/==" BORDER="0">4 weeks of therapy. There was a positive correlation between weekly dose and change in aspartate and alanine aminotransferase from baseline [r(2) = 0.56 (P = 0.031) and r(2) = 0.64 (P = 0.019), respectively]. ST elevations were reversible to near baseline in all patients within 3-4 weeks of interruption of GEM231 dosing. Low-grade fatigue was common (57%), cumulative by weeks 4-6, and reversible after GEM231 discontinuation.
  
  
  CONCLUSIONS
  GEM231 administered as a continuous infusion is safe; however, continuous protracted dosing is limited by ST elevations. Alternative dosing schedules should include intermittent administration to minimize cumulative toxicity. Additional studies using intermittent continuous infusion schedules of GEM231 are warranted.
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D021122:Protein Subunits / Q000235:genetics
chemical_list: C425328:GEM231; D009841:Oligonucleotides; D021122:Protein Subunits; D017868:Cyclic AMP-Dependent Protein Kinases