Ar. Yuen et al., Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer, CLIN CANC R, 5(11), 1999, pp. 3357-3363
Protein kinase C (PKC) is an attractive target in cancer therapy. It is ove
rexpressed in a variety of cancers, and nonspecific inhibitors of PKC have
demonstrated antitumor activity, Antisense oligonucleotides targeted agains
t PKC-alpha, which have high specificity, can inhibit mRNA and protein expr
ession as well as the growth of tumors in vitro and in vivo. This Phase I s
tudy sought to characterize the safety profile and to determine the maximum
tolerated dose of antisense to PKC-alpha when administered by continuous i
nfusion in patients. Patients with incurable malignancies received ISIS 352
1, a 20-length phosphorothioate oligodeoxynucleotide specific for PKC-alpha
. Treatment was delivered over a period of 21 days by continuous i.v. infus
ion followed by a 7-day rest period. Doses were increased from 0.5 to 3.0 m
g/kg/day. Patients continued on the study until evidence of disease progres
sion or unacceptable toxicity was detected. Between August 1996 and Septemb
er 1997, 21 patients were treated in five patient cohorts. The maximum tole
rated dose was 2.0 mg/kg/day. The dose-limiting toxicities were thrombocyto
penia and fatigue at a dose of 3.0 mg/kg/day. Pharmacokinetic measurements
showed rapid plasma clearance and dose-dependent steady-state concentration
s of ISIS 3521. Evidence of tumor response lasting up to 11 months was obse
rved in three of four patients with ovarian cancer. The recommended dose of
ISIS 3521 for Phase II studies is 2.0 mg/kg/day when given over a period o
f 21 days, Side effects are modest and consist of thrombocytopenia and fati
gue. Evidence of antitumor activity provides the rationale for Phase II stu
dies in ovarian cancer and other malignancies.