Study of AR-67 (Formerly DB-67) in Adult Patients With Refractory or Metastatic Solid Malignancies
AR-67 (formerly DB-67) represents a rationally engineered drug that possesses improved stability, toxicity, and efficacy compared to current Food and Drug Administration (FDA)-approved camptothecins, based on the extensive research of prior studies. Therefore, the investigators hypothesize that AR-67 (formerly DB-67) will be well-tolerated and efficacious in phase I clinical trials. This initial phase I trial will establish the maximum tolerated dose in humans, establish the toxicity profile, and define the appropriate dose of AR-67 (formerly DB-67) for future phase II and III clinical trials.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of DB-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) in Adult Patients With Refractory or Metastatic Solid Malignancies|
- Maximum tolerated dose (MTD) [ Time Frame: Any time during the four 21-day cycles ] [ Designated as safety issue: Yes ]
- Dose limiting toxicity (DLT) [ Time Frame: Any time during the four 21-day cycles ] [ Designated as safety issue: Yes ]
- Pharmacokinetics [ Time Frame: at each dose during week 1 ] [ Designated as safety issue: No ]
- Pharmacogenetic effects of polymorphisms [ Time Frame: at each dose during week 1 ] [ Designated as safety issue: No ]
|Study Start Date:||October 2006|
|Study Completion Date:||May 2009|
|Primary Completion Date:||February 2009 (Final data collection date for primary outcome measure)|
Drug: AR-67 (formerly DB-67)
infusion daily x 5 days, every 21 days
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).
- 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.
- 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.
|United States, Kentucky|
|University of Kentucky|
|Lexington, Kentucky, United States, 40536|
|United States, Missouri|
|Arch Medical Services Inc. DBA The Center for Cancer Care and Research|
|St Louis, Missouri, United States, 63141|
|Principal Investigator:||Susanne Arnold, MD||University of Kentucky|