Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors.
OBJECTIVE
To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq.


METHODS
The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm.


RESULTS
The dose of 716 mg/m2 per day x 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m2 per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added.


CONCLUSIONS
Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done.
Creaven
P J
PJ
Department of Investigational Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263-0001, USA.
Pendyala
L
L
Meropol
N J
NJ
Clendeninn
N J
NJ
Wu
E Y
EY
Loewen
G M
GM
Proefrock
A
A
Johnston
A
A
Dixon
M
M
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; C099178:nolatrexed