A Phase I Study of AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) Given on Days 1, 4 8, 12 & 15 of an Every 21-day Cycle in Adult Patients With Refractory or Metastatic Solid Malignancies

Camptothecins are a potent class of anticancer drugs that inhibit DNA Topoisomerase I.
While seen strictly as cytotoxic compounds, camptothecins are actually also targeted agents,
inhibiting DNA-Topoisomerase I (Topo I) cleavable complex. First and second generation
cogeners are hampered by a labile α-hydroxy-δ-lactone pharmacophore, which hydrolyzes to
yield the inactive carboxylate form of the drug. AR-67
(7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog engineered to
be stable in blood and highly potent. Its enhanced stability results from two factors: (1)
AR-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. In a recently completed phase I trial, AR-67 showed over 85%
lactone stability at all time points studied, and was well-tolerated with grade 4
thrombocytopenia, neutropenic fever and grade 3 fatigue as dose limiting toxicities. The
MTD was established at 7.5 mg/m2/day in a daily times five of a 21 day cycle. Preclinical
data indicates that AR-67 may concentrate in tumors for a prolonged period of time, compared
to plasma clearance of the drug, a phenomenon which has the potential to improve efficacy
and decrease toxicity of this compound. What is not known is the optimal dose and schedule
of AR-67 needed to produce high tumor penetration, and modest systemic exposure. This pilot
proposal seeks to study AR-67 in a novel dosing schedule and to evaluate the feasibility of
performing tumor biopsies to determine the tumor half-life of AR-67 in humans. By using
multiple tumor biopsies, as a means to document penetration of tumor tissue by AR-67, and
compare that to plasma clearance of the drug, the investigators will establish direct
pharmacokinetic evidence that AR-67 "hits the target". The investigators propose that a
rigorous evaluation of drug penetration into the tumor should be considered, in addition to
the MTD, when determining dose of new experimental compounds. Dose-tumor concentration
relationships should be established early in the course of clinical development to provide
data for rational selection of the phase-II dose. This pilot study will provide important
preliminary data to establish the feasibility of this approach for future study. If
successful, tumor half life will be used to develop an optimal biologic dose in a phase I
trial using this schedule of AR-67. Optimal biologic dosing could become a new standard for
dose escalation studies with this compound and other cytotoxic drugs that have specific
biologic targets in the future.