Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha.


METHODS
Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites.


RESULTS
Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life.


CONCLUSIONS
No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.
Nemunaitis
J
J
PRN Research, Inc, and Sammons Cancer Center at Baylor, Dallas, TX, USA.
Holmlund
J T
JT
Kraynak
M
M
Richards
D
D
Bruce
J
J
Ognoskie
N
N
Kwoh
T J
TJ
Geary
R
R
Dorr
A
A
Von Hoff
D
D
Eckhardt
S G
SG
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D019075:Electrophoresis, Capillary; D005260:Female; D006207:Half-Life; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011493:Protein Kinase C / Q000187:drug effects*; D051571:Protein Kinase C-alpha; D013873:Thionucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed
D000970:Antineoplastic Agents; D007527:Isoenzymes; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; C108494:ISIS 3521; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha