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Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP
J P Stevenson1, K S Yao, M Gallagher
1Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA, USA.
Purpose:
Raf-1 is a protein kinase that plays a broad role in oncogenic signaling and acts as a downstream effector of Ras in the mitogen-activated protein kinase pathway. The present study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-raf-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treated patients was studied using a reverse transcriptase polymerase chain reaction assay.
Patients And Methods:
Patients with refractory malignancies received ISIS 5132 as a 2-hour intravenous infusion three times weekly for 3 consecutive weeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-1 mRNA analysis were collected at baseline and on days 3, 5, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter.
Results:
Thirty-one patients received ISIS 5132 at one of nine dose levels ranging from 0.5 mg/kg to 6.0 mg/kg. Clinical toxicities included fever and fatigue, but these were not dose limiting. A clinically defined MTD was not reached. The harmonic mean half-life of ISIS 5132 was 59.8 minutes (range, 35.5 to 107.3 minutes). The area under the concentration-time curve increased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (range, 1.21 to 2.41 mL/kg/min). Two patients experienced prolonged stable disease lasting more than 7 months, which was associated with persistent reduction in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expression were identified at time points after the baseline value (P <.05) at doses >/= 2.5 mg/kg.
Conclusion:
ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.
Insights
ISIS 5132, a c-raf-1 antisense oligodeoxynucleotide, demonstrated good tolerability up to 6.0 mg/kg in patients with refractory malignancies. The drug showed reproducible pharmacokinetics and suppressed target gene expression in peripheral-blood mononuclear cells (PBMCs).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Raf-1 protein kinase is crucial in oncogenic signaling and Ras-mediated mitogen-activated protein kinase pathway.
- ISIS 5132 is an antisense oligodeoxynucleotide targeting c-raf-1, investigated for its therapeutic potential.
Purpose of the Study:
- Determine the maximum-tolerated dose (MTD), toxicity, pharmacokinetics, and antitumor activity of ISIS 5132.
- Evaluate the effect of ISIS 5132 on c-raf-1 gene expression in patient PBMCs.
Main Methods:
- Patients with refractory malignancies received ISIS 5132 intravenously three times weekly for 3 weeks.
- Pharmacokinetic sampling and analysis of c-raf-1 mRNA in PBMCs were conducted at various time points.
Main Results:
- ISIS 5132 was well tolerated up to 6.0 mg/kg; MTD was not reached. Clinical toxicities were mild and not dose-limiting.
- Pharmacokinetics were reproducible, with a harmonic mean half-life of 59.8 minutes. Dose-dependent increases in area under the curve and stable plasma clearance were observed.
- Two patients achieved prolonged stable disease (>7 months) associated with reduced c-raf-1 expression in PBMCs. Significant c-raf-1 mRNA suppression was noted at doses ≥2.5 mg/kg.
Conclusions:
- ISIS 5132 is well-tolerated at doses up to 6.0 mg/kg with reproducible pharmacokinetics.
- The drug effectively suppresses target gene (c-raf-1) expression in circulating PBMCs.
- ISIS 5132 shows potential for treating refractory malignancies by targeting oncogenic signaling pathways.