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.
|Study Design:||Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- To evaluate the feasibility of obtaining two serial tumor biopsies and plasma pharmacokinetics for the determination of AR-67 half life in tumor and plasma during day 1 of AR-67 treatment given on days 1, 4, 8, 12 and 15 of an every 21-day cycle. [ Time Frame: Cycle 1 days 1 and 2 ] [ Designated as safety issue: No ]
- Toxicities [ Time Frame: Days 1, 4, 8, 12 and 15 of an every 21-day cycle ] [ Designated as safety issue: Yes ]To document all toxicities of AR-67 after intravenous (IV) administration on days 1, 4, 8, 12 and 15 of an every 21-day cycle to adults with recurrent or refractory solid tumors in which standard therapies are not effective.
- Feasibility for testing topoisomerase-I and γ-H2AX in tumor tissue [ Time Frame: Cycle 1 days 1 and 2 ] [ Designated as safety issue: No ]To determine the feasibility for testing the expression of topoisomerase-I and γ-H2AX in tumor tissue biopsies using immunohistochemical techniques and western blot assays.
- Efficacy [ Time Frame: Days 1, 4 , 8, 12 and 15 of a 21 day cycle ] [ Designated as safety issue: No ]To collect efficacy data for these subjects using radiographic assessment of tumor response by RECIST 1.1.
|Study Start Date:||September 2010|
|Study Completion Date:||July 2011|
|Primary Completion Date:||July 2011 (Final data collection date for primary outcome measure)|
Phase 1 study
IV Over 1 hour Days 1, 4, 8, 12 & 15 of a 21 day cycle (7.5 mg/m^2).
Other Name: AR-67
|United States, Kentucky|
|Markey Cancer Center, University of Kentucky|
|Lexington, Kentucky, United States, 40536|
|Principal Investigator:||Susanne M Arnold, MD||Lucille P. Markey Cancer Center at University of Kentucky|