Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116).
OBJECTIVE
ISIS 5132 is a 20-base phosphorothioate DNA oligonucleotide against human c-raf kinase, a downstream effector of ras oncogene function. C-raf kinase is a molecule in the MAP kinase signaling cascade which is essential for cellular proliferation, the overexpression of which leads to malignant expression. Activity of this compound was documented in a woman with ovarian cancer in a Phase I study.


METHODS
We evaluated ISIS 5132 at a dose of 4 mg/kg/day by continuous venous infusion, administered for 21 days q 4 weeks in 22 patients with recurrent ovarian cancer in a standard two-stage Phase II design. Three patients were ineligible; 19 patients are evaluable for toxicity and 16 for response. All patients had previously received systemic therapy for ovarian cancer (6 had one and 13 had two prior regimens). Patients were treated with a median of two cycles and 79% of the patients received >90% planned dose intensity.


RESULTS
ISIS 5132 was well tolerated with no episodes of Grade 3 or 4 hematologic or biochemical (creatinine, AST, bilirubin) toxicity. There were six episodes of grade 3 nonhematologic toxicity in 4 patients thought to be treatment related (lethargy 2; anorexia 1; abdominal pain 2; shortness of breath 1). No responses were seen in the 16 patients who are evaluable for response; 4 had stable disease for a median of 3.8 months and 12 patients had documented progressive disease.


CONCLUSIONS
ISIS 5132 at 4 mg/kg/day as a single agent did not show activity in recurrent ovarian cancer.
Oza
A M
AM
Princess Margaret Hospital, Toronto, M5G 2M9 Ontario, Canada. amit.oza@uhn.on.ca
Elit
L
L
Swenerton
K
K
Faught
W
W
Ghatage
P
P
Carey
M
M
McIntosh
L
L
Dorr
A
A
Holmlund
J T
JT
Eisenhauer
E
E
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013873:Thionucleotides / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; C099587:ISIS 5132