A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer.
OBJECTIVE
A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to protein kinase C-alpha, in patients with refractory solid tumors.


METHODS
Fourteen patients were treated in sequential cohorts of aprinocarsen by 24-hour continuous infusion (CIV), weekly, at doses of 6, 12, 18 and 24 mg/kg.


RESULTS
One grade 4 toxicity was observed, transient grade 4 neutropenia at 18 mg/kg. Grade 3 toxicities included neutropenia at 12 mg/kg, fever and hemorrhage at 18 mg/kg, and neutropenia, nausea, and chills at 24 mg/kg. Grade 2 toxicities included thrombocytopenia myalgias, chills, headache, fatigue, fever and nausea/vomiting. Mean prothrombin times and activated partial thromboplastin times (aPTT) increased by 10% and 29% from baseline (p = 0.006 and 0.005). Mean complement split products (Bb and C3a) increased 1.6-fold and 3.6-fold (from p = 0.014 and 0.004, respectively). These changes correlated with dose and were transient with recovery to baseline by day 7. Steady state plasma concentrations (Css) of aprinocarsen were achieved within four hours. Css better described changes in aPTT than dose. Clinical evidence of complement activation was not observed.


CONCLUSIONS
In contrast to 21-day protracted infusion schedules, delivery of aprinocarsen over a 24-hour infusion schedule showed concentration-dependent effects on coagulation and complement, which are consistent with nonclinical toxicology studies performed in the phosphorothioate DNA antisense drug class. These coagulation and complement changes resulted in a maximum tolerated dose 24 mg/kg.
Advani
Ranjana
R
Oncology Division, Stanford University School of Medicine, Stanford, CA 94305-5151, USA. radvani@stanford.edu
Lum
Bert L
BL
Fisher
George A
GA
Halsey
Joanne
J
Geary
Richard S
RS
Holmlund
Jon T
JT
Kwoh
T Jesse
TJ
Dorr
F Andrew
FA
Sikic
Branimir I
BI
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects*; D003167:Complement Activation / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D054735:Phosphorothioate Oligonucleotides; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D016207:Cytokines; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D051571:Protein Kinase C-alpha; C488084:aprinocarsen