Phase I clinical pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A)

Citation
Jp. Stevenson et al., Phase I clinical pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A), J CL ONCOL, 17(7), 1999, pp. 2227-2236
Citations number
34
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
JOURNAL OF CLINICAL ONCOLOGY
ISSN journal
0732183X → ACNP
Volume
17
Issue
7
Year of publication
1999
Pages
2227 - 2236
Database
ISI
SICI code
0732-183X(199907)17:7<2227:PICPAP>2.0.ZU;2-T
Abstract
Purpose: Raf-1 is a protein kinase that plays a broad role in oncogenic sig naling and acts as a downstream effector of Pas in the mitogen-activated pr otein kinase pathway. The present study war designed to determine the maxim um-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846 A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-ra f-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treate d patients was studied using a reverse transcriptase polymerase chain react ion assay. Patients and Methods: Patients with refractory malignancies received ISIS 5 132 as a 2-hour intravenous infusion three times weekly for 3 consecutive w eeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-l 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 no t reached. The harmonic mean half-life of ISIS 5132 war 59.8 minutes (range , 35.5 to 107.3 minutes). The area under the concentration-time curve incre ased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (rang e, 121 to 2.41 mL/kg/min). Two patients experienced prolonged stable diseas e lasting more than 7 months, which was associated with persistent reductio n in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expressi on were identified at time points after the baseline value (P < .05) at dos es greater than or equal to 2.5 mg/kg. Conclusion: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when admin istered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pha rmacokinetic behavior of the drug is reproducible, and suppression of targe t gene expression is observed in circulating PBMCs. (C) 1999 by American So ciety of Clinical Oncology.