Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.
OBJECTIVE
N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days.


METHODS
Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles.


RESULTS
The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L.


CONCLUSIONS
PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.
Propper
D J
DJ
Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Glasgow, UK.
McDonald
A C
AC
Man
A
A
Thavasu
P
P
Balkwill
F
F
Braybrooke
J P
JP
Caponigro
F
F
Graf
P
P
Dutreix
C
C
Blackie
R
R
Kaye
S B
SB
Ganesan
T S
TS
Talbot
D C
DC
Harris
A L
AL
Twelves
C
C
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D019311:Staurosporine; C059539:midostaurin