Ignite Creation Date:
2024-05-05 @ 5:07 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00389480
Status:
COMPLETED
Last Update Posted:
2009-08-11
First Post:
2006-10-17
Brief Title:
Study of AR-67 Formerly DB-67 in Adult Patients With Refractory or Metastatic Solid Malignancies
Sponsor:
Arno Therapeutics
Organization:
Arno Therapeutics
Study Overview
Official Title:
A Phase I Study of DB-67 7-t-butyldimethylsilyl-10-hydroxycamptothecin in Adult Patients With Refractory or Metastatic Solid Malignancies
Status:
COMPLETED
Status Verified Date:
2009-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hypothesis
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
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
Detailed Description:
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 Cremophorethanol 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
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 Cremophorethanol 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None