PURPOSE: To assess the maximum-tolerated dose, toxicity, and
pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase
I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors.
EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once
every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0
mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life
exceeding the 2 weeks administration interval, the protocol was amended to
a 6-week interval between administrations also based on available
information from a parallel trial using an every 4 weeks schedule.
Conjugated DX-8951 (the carrier-linked molecule), and the metabolites
DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days
post first and second dose. RESULTS: Twenty-seven patients were enrolled
into the study and received a total of 86 administrations. Neutropenia and
grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive
disease, were dose-limiting toxicities. Other hematologic and
nonhematologic toxicities were mild to moderate and reversible. The
apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was
13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951
was 600. No drug concentration was detectable in erythrocytes, skin, and
saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable
in tumor biopsies. One patient with metastatic adenocarcinoma of unknown
primary achieved a histologically proven complete remission. One confirmed
partial remission was observed in a patient with metastatic pancreatic
cancer and disease stabilization was noted in 14 additional patients.
CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given
once every 6 weeks. The active moiety DX-8951 is released slowly from
DE-310 and over an extended period, achieving the desired prolonged
exposure to this topoisomerase I inhibitor