title: A phase I safety and dose escalation trial of docetaxel combined with GEM231, a second generation antisense oligonucleotide targeting protein kinase A R1alpha in patients with advanced solid cancers.
abstract: OBJECTIVE
  GEM231 is a second-generation antisense oligonucleotide targeting the mRNA of the R1alpha regulatory subunit of cAMP dependent protein kinase A. Preclinical studies have demonstrated synergistic antitumor activity when GEM231 is combined with docetaxel. This trial assesses the safety of this combination.
  
  
  METHODS
  Docetaxel was administered once every three weeks (one-cycle) at doses between 50-75 mg/m2. GEM231 was administered twice weekly at 220 mg/m2 for 3 (schedule-A), or 2 (schedule-B) weeks.
  
  
  RESULTS
  Twenty patients with chemotherapy-refractory advanced cancer received a total of 39 cycles of therapy. Six patients in schedule-A received docetaxel 50 mg/m2, and 14 patients in schedule-B received docetaxel 50-75 mg/m2. In schedule-A, 2 of 6 patients developed cycle-1 dose limiting toxicity (DLT)-grade-3 fatigue or grade-3 serum transaminase elevation. In schedule-B, 1 of 4 patients developed cycle-1 DLT at the highest dose of docetaxel tested (75 mg/m2)--grade-3 febrile neutropenia. Subsequent dose escalations were not pursued since the overall incidence of grade-3 toxicities (including those that occurred after cycle 1) was 75%, and this dose was close to the single agent MTD of docetaxel. Grade-3 toxicities included fatigue (2 patients), transaminase elevation (4 patients), and altered mentation (1 patient). The mean post-infusion aPTT was significantly higher than the pre-infusion value [14.8 seconds; p<0.001]; however, there were no hemorrhagic episodes.
  
  
  CONCLUSIONS
  The recommended dose for further development of the combination of docetaxel and GEM231 is 75 mg/m2 and 220 mg/m2, respectively. It is important to administer GEM231 twice weekly for 2 consecutive weeks followed by a one-week break.
authors: Albert Einstein Cancer Center, Bronx, NY, USA. sgoel@montefiore.org
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