Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer.
BACKGROUND
PKC412 (N-benzoyl-staurosporine), an oral inhibitor of protein kinase C, is capable of cell cycle inhibition and is endowed with anti-angiogenic properties. This dose-finding phase I study was designed to establish the maximum tolerated dose (MTD) of PKC412 when combined with cisplatin-gemcitabine.


METHODS
Escalating doses of PKC412 were given every day of a 4 week cycle with cisplatin 100 mg/m2 on day 2 and gemcitabine 1000 mg/m2 on days 1, 8 and 15 in patients with non-small-cell lung cancer. Dose escalation was based on a modified continuous reassessment method.


RESULTS
Twenty-three patients, assigned to four cohorts receiving PKC412 at a dose ranging from 25 to 150 mg/day were evaluable. Grade 3 diarrhea occurring in 3/4 patients at cycle 1 led us to define 150 mg/day as the MTD. The MTD based on multiple cycles was redefined as 100 mg/day, since prolonged grade 2-3 nausea/vomiting leading to treatment discontinuation occurred in 3/7 patients after repeated cycles. The next lower dose tested of 50 mg/day was therefore considered as the recommended dose for phase II trials. Among 33 cycles in eight patients, toxicity consisted of grade 1-2 diarrhea (12.5%) and asthenia (50%) with only one patient experiencing grade 3 headache at this dose level. A partial response was observed in three patients.


CONCLUSIONS
The results of the present study indicate that PKC412 at a dose of 50 mg/day can be safely added to cisplatin and gemcitabine in patients with advanced non-small-cell lung cancer.
Monnerat
C
C
Department of Medicine, Institut Gustave-Roussy, Villejuif, France.
Henriksson
R
R
Le Chevalier
T
T
Novello
S
S
Berthaud
P
P
Faivre
S
S
Raymond
E
E
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001247:Asthenia / Q000209:etiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003967:Diarrhea / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin; D002945:Cisplatin; D000093542:Gemcitabine