Methotrexate-
albumin conjugate (
MTX-HSA) is a novel
human albumin-based
prodrug conjugate of
methotrexate (MTX). A low MTX loading rate provided optimal
tumor targeting and therapeutic efficacy during preclinical testing. The objectives of this first Phase I study of
MTX-HSA were to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in a weekly regimen. Seventeen
cancer patients who were no longer amenable to standard treatment were enrolled and were evaluable for DLT. Up to eight
injections were performed in weekly intervals. Dose escalation was as follows: 20, 40, 50, and then 60 mg/m2
MTX-HSA (based on the amount of MTX bound to
albumin). Additional
MTX-HSA courses were feasible in case of
tumor response. DLT (mainly
stomatitis, Common Toxicity Criteria grade 3) occurred, beginning at the 50 mg/m2 dose level after repeated administrations; in one case,
thrombocytopenia was dose-limiting. Two events of DLT occurred at the 60 mg/m2 dose level within the first two administrations. Mild
anemia, transaminitis, and one case of skin toxicity were found. No significant
leukopenia,
nausea, renal toxicity, or other toxicities were observed.
MTX-HSA was well tolerated.
Drug accumulation occurred on the weekly schedule. The half-life of the
drug was estimated to be up to 3 weeks.
Tumor responses were seen in three patients: (a) a partial response was seen in one patient with
renal cell carcinoma (response duration, 30 months, ongoing); (b) a minor response was seen in one patient with pleural
mesothelioma (response duration, 31 months, ongoing); and (c) a minor response was seen in one patient with
renal cell carcinoma (response duration, 14 months until progression). Poststudy treatment was administered at 2-4-week intervals. No signs of toxicity or
drug accumulation were seen. Altered pharmacological properties of
MTX-HSA such as plasma half-life,
tumor targeting, or intracellular metabolism might have contributed to these responses. The MTD for weekly administration was 4
x 50 mg/m2
MTX-HSA during short-term treatment. A regimen with
MTX-HSA injections of 50 mg/m2 every 2 weeks was recommended for a further clinical Phase I study.