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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit alpha of protein
Sanjay Goel1, Kavita Desai, Anca Bulgaru
1Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Purpose:
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.
Experimental Design:
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.
Insights
Continuous infusion of GEM231, an antisense oligonucleotide, is safe but limited by serum transaminase elevations. Intermittent dosing may reduce cumulative toxicity in cancer patients.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- GEM231 is an antisense oligonucleotide targeting the type I regulatory subunit alpha of protein kinase A.
- Antisense oligonucleotides represent a novel therapeutic approach in cancer treatment.
Purpose of the Study:
- To evaluate the safety and pharmacodynamics of GEM231.
- To determine the maximum tolerated dose (MTD) of GEM231.
- To assess the toxicity profile of GEM231 when administered via continuous intravenous infusion.
Main Methods:
- Fourteen cancer patients received escalating doses of GEM231.
- Dosing was administered as a 3-day or 5-day continuous intravenous infusion.
- Dose range was from 80 to 180 mg/m(2)/day.
Main Results:
- The MTD of GEM231 was determined to be 180 mg/m(2)/day, with dose-limiting elevation of serum transaminases (STs).
- At the recommended Phase II dose of 120 mg/m(2)/day, toxicities were tolerable, with reversible ST elevations and transient changes in activated partial thromboplastin time.
- Low-grade fatigue was common, cumulative over time, and reversible upon discontinuation.
Conclusions:
- Continuous intravenous infusion of GEM231 is safe but its protracted use is limited by ST elevations.
- Intermittent administration schedules are recommended to minimize cumulative toxicity.
- Further investigation into intermittent continuous infusion schedules for GEM231 is warranted.
