Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study.
BACKGROUND
Because treatment of metastatic colon cancer is noncurative, new treatments are needed. This trial evaluated the antitumor effects of two targeted anticancer agents: (a) ISIS 3521, an antisense inhibitor of the protein kinase C alpha; and (b) ISIS 5132, an antisense inhibitor of c-raf kinase in patients untreated previously with recurrent or metastatic colorectal carcinoma.


METHODS
All patients had colorectal adenocarcinoma with measurable disease and no prior chemotherapy for metastatic disease. Patients were randomized to receive either ISIS 3521 or ISIS 5132 at a dose of 2 mg/kg/day as a continuous i.v. infusion 21 of 28 days. Cycles were repeated as long as progression was not seen, and doses of both agents were modified according to toxic effects. A two-arm study design was used with each study arm considered independently. Steady-state blood levels of both antisense molecules were measured on days 8, 15, and 22 of the first cycle of therapy.


RESULTS
Thirty-seven eligible patients were enrolled, and 32 were evaluable for response (17 receiving ISIS 3521 and 15 receiving ISIS 5132). No responses were noted. Four of the patients receiving ISIS 3521 had stable disease, and 5 patients receiving ISIS 5132 were stable.


CONCLUSIONS
Neither ISIS 5132 nor ISIS 3521given in the dose and schedule studied induced objective responses in untreated colorectal cancer patients.
Cripps
M Christine
MC
Ottawa Regional Cancer Centre, Ottawa, Ontario, K1H 8L6 Canada. Christine.Cripps@orcc.on.ca
Figueredo
Alvaro T
AT
Oza
Amit M
AM
Taylor
Marianne J
MJ
Fields
Anthony L
AL
Holmlund
John T
JT
McIntosh
Lynn W
LW
Geary
Richard S
RS
Eisenhauer
Elizabeth A
EA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics; D051571:Protein Kinase C-alpha; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D013873:Thionucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; C108494:ISIS 3521; C099587:ISIS 5132; D019908:Proto-Oncogene Proteins c-raf; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha