Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer

Citation
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
Citations number
20
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
5
Issue
11
Year of publication
1999
Pages
3357 - 3363
Database
ISI
SICI code
1078-0432(199911)5:11<3357:PISOAA>2.0.ZU;2-V
Abstract
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.