Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis.
OBJECTIVE
In this phase I trial in humans the safety and pharmacology of LY309887 on a weekly schedule combined with daily oral 5-mg doses of folic acid were evaluated.


BACKGROUND
LY309887 is an inhibitor of folate-dependent enzymes involved in de novo purine biosynthesis and has a broad preclinical antitumor activity. In murine systems, combining this agent with exogenous folic acid results in an enhanced therapeutic index.


METHODS
This study was a single-institution, open-label, clinical trial of dose escalation with toxicity and pharmacokinetic parameters determined. The dose range studied was 0.5-4 mg/m2 per week x6 and then a modified schedule weekly x3 every 6 weeks.


RESULTS
Dose-limiting toxicities were of delayed onset and associated with hematologic, neurologic, and mucosal effects. Pharmacokinetic parameters revealed dose linearity for AUC and Cmax. Low circulating levels of drug persisted for over 200 h. Urinary excretion accounted for approximately 50% of the parent drug but was highly variable. The urinary excretion was near maximal within 24 h of dosing.


CONCLUSIONS
The modified dosing schedule allowed repetitive dosing in patients. Further evaluation of the 2 mg/m2 per week x3 every 6 weeks with daily oral folate supplement as a potential phase II dose may be warranted.
Budman
D R
DR
Don Monti Division of Oncology, North Shore University Hospital, New York University School of Medicine, Manhasset 11030, USA. budman@nshs.edu
Johnson
R
R
Barile
B
B
Bowsher
R R
RR
Vinciguerra
V
V
Allen
S L
SL
Kolitz
J
J
Ernest
C S
CS
Kreis
W
W
Zervos
P
P
Walling
J
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013763:Tetrahydrofolates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
C105065:6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates