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


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.


CONCLUSIONS
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.
Stevenson
J P
JP
Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA, USA.
Yao
K S
KS
Gallagher
M
M
Friedland
D
D
Mitchell
E P
EP
Cassella
A
A
Monia
B
B
Kwoh
T J
TJ
Yu
R
R
Holmlund
J
J
Dorr
F A
FA
O'Dwyer
P J
PJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013873:Thionucleotides / Q000009:adverse effects / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides; C099587:ISIS 5132; D019908:Proto-Oncogene Proteins c-raf