A Phase I Safety And Dose Escalation Trial Of Docetaxel Combined With GEM®231, A Second Generation Antisense Oligonucleotide Targeting Protein Kinase A R1[alpha] 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...

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Bibliographic Details
Published in:Investigational new drugs 2006-03, Vol.24 (2), p.125
Main Authors: Goel, Sanjay, Desai, Kavita, Macapinlac, Manuel, Wadler, Scott, Goldberg, Gary, Fields, Abbie, Einstein, Mark, Volterra, Fabio, Wong, Benny, Russell, Martin, Mani, Sridhar
Format: Article
Language:English
Subjects:
Cancer therapies
Chemotherapy
Drug dosages
Glycoproteins
Kinases
Oncology
Patients
Proteins
Toxicity
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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
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-006-2378-x