A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers

Purpose: GEM®231 is a second-generation antisense oligonucleotide targeting the mRNA of the R1α regulatory subunit of cAMP dependent protein kinase A. Preclinical studies have demonstrated synergistic antitumor activity when GEM®231 is combined with docetaxel. This trial assesses the safety of this combination. Experimental Design: Docetaxel was administered once every three weeks (one-cycle) at doses between 50 - 75 mg/m². GEM®231 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 GEM®231 is 75 mg/m ² and 220 mg/m², respectively. It is important to administer GEM®231 twice weekly for 2 consecutive weeks followed by a one-week break.