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
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.