Phase I Trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer.
Raf-1 is a serine/threonine kinase that functions as a critical effector of Ras-mediated signal transduction via the mitogen-activated protein kinase pathway. Constitutive activation of this pathway directly contributes to malignant transformation in many human tumors. A 20-base phosphorothioate oligonucleotide complementary to c-raf-1 mRNA (ISIS 5132; CGP 69846A) has been shown to specifically suppress Raf-1 expression both in vitro and in vivo. This Phase I trial, involving 22 patients with advanced cancer, was designed to evaluate the safety, feasibility, and maximum tolerated dose of ISIS 5132 administration as a weekly 24-h i.v. infusion. Pharmacokinetic analysis was performed, and c-raf-1 mRNA levels in peripheral blood mononuclear cells were assessed using quantitative reverse transcription-PCR. This trial defined a maximum tolerated dose of 24 mg/kg/week on this schedule. Two of four patients treated at 30 mg/kg/week had serious adverse events after the first dose of ISIS 5132, including acute hemolytic anemia and acute renal failure and anasarca. There were no major responses documented. Dose-dependent complement activation was demonstrated on this schedule, but not on previously evaluated schedules, of ISIS 5132 administration. In contrast to other trials of ISIS 5132, there appeared to be no consistent suppression of peripheral blood mononuclear cell c-raf-1 mRNA level on this schedule at any of the dose levels analyzed. These data suggest that the efficacy and toxicity profiles of antisense oligonucleotides may be highly dependent on the schedule of administration and support the analysis of the putative molecular target in the evaluation of novel therapeutics.
Rudin
C M
CM
Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois 60637-1470, USA. crudin@meecine.bsd.uchicago.edu
Holmlund
J
J
Fleming
G F
GF
Mani
S
S
Stadler
W M
WM
Schumm
P
P
Monia
B P
BP
Johnston
J F
JF
Geary
R
R
Yu
R Z
RZ
Kwoh
T J
TJ
Dorr
F A
FA
Ratain
M J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D003165:Complement System Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000097:blood; D013873:Thionucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides; C099587:ISIS 5132; D003165:Complement System Proteins; D019908:Proto-Oncogene Proteins c-raf