Phase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks.
OBJECTIVE
To identify a recommended phase II dose for the second generation glycinamide ribonucleotide transformylase (GARFT) inhibitor, AG2034, administered by intravenous bolus every 3 weeks without folate supplementation and to describe AG2034 pharmacokinetics.


METHODS
Adults with advanced malignancies were enrolled in cohorts of three per dose level with expansion to six upon observation of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was defined as the dose at which two of up to six patients experienced DLT. Upon identification of an MTD and evidence of cumulative toxicity, a lower intermediate dose was explored as a candidate phase II dose. AG2034 plasma concentrations were measured using an ELISA assay.


CONCLUSIONS
The recommended phase II dose is 5.0 mg/m2. DLTs were anemia, thrombocytopenia, mucositis, diarrhea, hyperbilirubinemia, fatigue, and insomnia. Toxicities were modestly cumulative over three courses. Pharmacokinetic analysis showed a dose-AUC0-24 relationship and a progressive increase in AG2034 AUC0-24 over three courses. Both pharmacokinetic and pharmacodynamic factors may contribute to the modest cumulative toxicity observed with AG2034.
Roberts
J D
JD
Massey Cancer Center, Richmond, VA 23298-0037, USA. roberts@mcc1.mcc.vcu.edu
Shibata
S
S
Spicer
D V
DV
McLeod
H L
HL
Tombes
M B
MB
Kyle
B
B
Carroll
M
M
Sheedy
B
B
Collier
M A
MA
Pithavala
Y K
YK
Paradiso
L J
LJ
Clendeninn
N J
NJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005971:Glutamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D051026:Phosphoribosylglycinamide Formyltransferase; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005971:Glutamates; D011743:Pyrimidines; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; C105066:AG 2034