Summary
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/m2 and 220 mg/m2, respectively. It is important to administer GEM®231 twice weekly for 2 consecutive weeks followed by a one-week break.
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Abbreviations
- aPTT:
-
activated partial thromboplastin time
- ALT:
-
alanine aminotransferase
- AST:
-
aspartate aminotransferase
- ASO:
-
antisense oligonucleotide
- cAMP:
-
cyclic adenosine monophosphate
- DLT:
-
dose limiting toxicity
- MTD:
-
maximum tolerated dose
- PKA RIα:
-
regulatory subunit α of PKA-I
- RPTD:
-
recommended phase two dose
- ST:
-
serum transaminases
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This study was supported by grants from Hybridon, Inc. and Aventis Pharmaceuticals.
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Goel, S., Desai, K., Macapinlac, M. et al. 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. Invest New Drugs 24, 125–134 (2006). https://doi.org/10.1007/s10637-006-2378-x
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DOI: https://doi.org/10.1007/s10637-006-2378-x