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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

NCT01202370 · Status: COMPLETED · Phase: PHASE1 · Type: INTERVENTIONAL · Enrollment: 3

Last updated 2013-08-14

No results posted yet for this study

Summary

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.

Conditions

  • Solid Malignancies

Interventions

DRUG

7-t-butyldimethylsilyl-10-hydroxycamptothecin

IV Over 1 hour Days 1, 4, 8, 12 \& 15 of a 21 day cycle (7.5 mg/m\^2).

Sponsors & Collaborators

  • Arno Therapeutics

    collaborator INDUSTRY

  • University of Kentucky

    lead OTHER

Principal Investigators

  • Susanne M Arnold, MD · Lucille P. Markey Cancer Center at University of Kentucky

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2010-09-30
Primary Completion
2011-07-31
Completion
2011-07-31

Countries

  • United States

Study Locations

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Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT01202370 on ClinicalTrials.gov