Study of AR-67 (Formerly DB-67) in Adult Patients With Refractory or Metastatic Solid Malignancies

This study has been completed.
Sponsor:
Collaborators:
University of Kentucky
Arch Medical Services Inc., DBA The Center for Cancer Care and Research
Information provided by:
Arno Therapeutics
ClinicalTrials.gov Identifier:
NCT00389480
First received: October 17, 2006
Last updated: August 7, 2009
Last verified: August 2009
  Purpose

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.


Condition Intervention Phase
Tumors
Drug: AR-67 (formerly DB-67)
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Arno Therapeutics:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 26
Study Start Date: October 2006
Study Completion Date: May 2009
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: I
Dose escalating
Drug: AR-67 (formerly DB-67)
infusion daily x 5 days, every 21 days

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 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).

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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • >18 year old subjects with solid malignancies that have progressed after at least one prior chemotherapy regimen and have exhausted other therapies
  • Treated and clinically stable brain metastases
  • Measurable OR non-measurable disease
  • Greater than three weeks since surgery
  • Normal organ and marrow function
  • ECOG Performance Status of < 2
  • No other prior malignancy except for treated basal cell or squamous cell skin cancer, in situ cervical cancer, Stage I or II cancer (patient in complete remission) or other cancer from which the patient has been disease-free for 5 years.
  • Computed tomography (CT) scan of involved areas within 28 days of registration
  • Life expectancy of greater than 12 weeks.

Exclusion Criteria:

  • Pregnant or nursing females
  • Chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) of entering the study.
  • Patients may not be receiving any other investigational agent. Uncontrolled intercurrent illness including active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Allergic reactions to compounds of similar chemical or biologic composition to DB-67 (i.e. camptothecins such as irinotecan, topotecan, or others of this class of pharmaceuticals).
  • Subjects with prior anaphylactic injection reaction of > grade 3 to paclitaxel or any other product formulated with cremophor
  • Subjects with HIV
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00389480

Locations
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
Sponsors and Collaborators
Arno Therapeutics
University of Kentucky
Arch Medical Services Inc., DBA The Center for Cancer Care and Research
Investigators
Principal Investigator: Susanne Arnold, MD University of Kentucky
  More Information

No publications provided

Responsible Party: Arno Therapeutics
ClinicalTrials.gov Identifier: NCT00389480     History of Changes
Other Study ID Numbers: ARN-AR67-CT101
Study First Received: October 17, 2006
Last Updated: August 7, 2009
Health Authority: United States: Food and Drug Administration

Keywords provided by Arno Therapeutics:
Solid Tumors
Solid Malignancies
Phase I

Additional relevant MeSH terms:
Neoplasms
10-hydroxycamptothecin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 22, 2014