Trial Information

A Phase I Study of DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) in Adult Patients With Refractory or Metastatic Solid Malignancies

Overview of Study:

Camptothecins are a potent class of anticancer drugs that inhibit DNA topoisomerase I.
Topotecan and irinotecan are two FDA approved second generation congeners currently in
clinical use, and have a spectrum of activity which includes colorectal, ovarian, and lung
cancers. Unfortunately, these drugs are hampered by a labile α-hydroxy-δ-lactone
pharmacophore, which hydrolyzes to yield the inactive carboxylate form of the drug.

AR-67 (formerly DB-67) (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a third generation
analog engineered to be blood stable and highly potent. Its enhanced stability results from
two factors: (1) AR-67 (formerly DB-67) is highly lipophilic, partitioning into lipid
bilayers, thus protecting it from hydrolysis in the aqueous milieu of the bloodstream, and
(2) the 10-hydroxy functionality of the drug effectively ablates the high affinity
interactions of the carboxylate drug form with albumin, which has been previously shown to
diminish the levels of the active lactone species in the circulation.

On the basis of its stability and activity, AR-67 (formerly DB-67) was selected by the
National Cancer Institute (NCI) for development in the first cycle of the Rapid Access to
Intervention Development (RAID) program. Data from cycle I, as well as independent data from
collaborative efforts, revealed impressive in vitro and in vivo antitumor activity,
particularly in an intracranial glioma model system. Through the continued support of the
RAID program, the drug has been extensively studied in mice, rats and beagle dogs and the
pre-clinical MTD has been determined. After extensive investigation of various formulations,
a Cremophor:ethanol compound has been identified as the most appropriate for the phase I
study in humans and the GMP grade drug product has been refined and completed. This protocol
describes the initial phase I study in humans using AR-67 (formerly DB-67).

Primary Endpoint:

- To estimate the MTD and describe the DLT of intravenous AR-67 (formerly DB-67)
administered once daily for 5 days every 21 days to adults with recurrent or refractory
solid tumors in which standard therapies are not effective.

Secondary Endpoints:

- To characterize the plasma pharmacokinetics of AR-67 (formerly DB-67) and its
metabolites after intravenous administration.

- To explore the pharmacogenetic effects of polymorphisms in drug metabolism and
transport mediated by liver enzymes and by efflux or uptake proteins, respectively, and
relate these polymorphisms to AR-67 (formerly DB-67) pharmacokinetics and toxicity.