A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors.
OBJECTIVE
To define the maximum-tolerated dose (MTD) for weekly paclitaxel administered in combination with daily vatalanib (PTK787/ZK 222584, PTK/ZK) and assess for a drug-drug interaction.


METHODS
Patients were treated with escalating doses of weekly paclitaxel (75-85 mg/m(2)), and daily PTK/ZK (250-1,000 mg). During the first cycle only, paclitaxel was given on days 1 and 15, and PTK/ZK on days 3-28. Pharmacokinetic studies were conducted on cycle 1 days 1 and 15 for paclitaxel, and on cycle 1 day 15 for PTK/ZK. Therapy was given until disease progression.


RESULTS
Twenty-seven patients were accrued to four dose levels. Two of five patients treated with paclitaxel 85 mg/m(2) and PTK/ZK 1,000 mg had Grade 3 transaminase elevation as dose-limiting toxicity. Paired PK analyses demonstrated a significant increase in paclitaxel clearance on day 15 (p = 0.006). Activity included one partial response and 11 patients with stable disease > or =4 months, including patients previously treated with paclitaxel.


CONCLUSIONS
The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m(2) and 750 mg. PK analysis revealed a significant drug-drug interaction, with an increase in paclitaxel clearance. This combination was well tolerated with evidence of anti-cancer activity and provides guidance for phase 2 planning.
Chiorean
E Gabriela
EG
Department of Medicine, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
Malireddy
Srikar
S
Younger
Anne E
AE
Jones
David R
DR
Waddell
Mary-Jane
MJ
Sloop
Melissa I
MI
Yu
Menggang
M
Hall
Stephen D
SD
Schneider
Bryan
B
Sweeney
Christopher J
CJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D010793:Phthalazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D000637:Transaminases / Q000378:metabolism*; D016896:Treatment Outcome
D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D000637:Transaminases; D017239:Paclitaxel