Ixabepilone and Ketoconazole in Treating Patients With Advanced Solid Tumors

The Effect of Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Ixabepilone In Patients With Advanced Cancer

RATIONALE: Drugs used in chemotherapy, such as ixabepilone and ketoconazole, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving ixabepilone with ketoconazole may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving ixabepilone together with ketoconazole and to see how well they work in treating patients with advanced solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: ketoconazole; Drug: ixabepilone

Detailed Description

OBJECTIVES:

Primary

• Determine the effect of ketoconazole on the pharmacokinetics of ixabepilone in patients with advanced solid tumors.

Secondary

• Determine the safety of ixabepilone when administered alone and in combination with ketoconazole in these patients.
• Determine, preliminarily, the antitumor activity of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of ixabepilone.

During course 1, patients receive oral ketoconazole on days 0-5 and ixabepilone IV over 3 hours on day 1. During course 2 and subsequent courses, patients receive only ixabepilone IV over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of at least 3 patients receive escalating doses of ixabepilone during course 1 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 patients experience dose-limiting toxicity. At least 12 patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 3-35 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed solid tumor
• Unresponsive to currently available therapy OR no known effective treatment exists
• Measurable or nonmeasurable disease

• Brain metastases allowed, provided the following criteria are met:

  • Completed cranial radiotherapy at least 4 weeks ago
  • Stable or reduced brain metastases by brain imaging*
  • Clinically stable disease AND no steroid therapy within the past 2 weeks (Baseline brain imaging is not required for patients with no signs or symptoms of brain metastasis)

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Eastern Cooperative Oncology Group (ECOG) 0-1

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No more than 3 prior chemotherapy regimens
• No other concurrent chemotherapy (standard or investigational)

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics
• At least 3 weeks since prior radiotherapy and recovered
• No prior radiotherapy to > 25% of major bone-marrow containing areas (e.g., pelvis or lumbar spine)

Surgery

• At least 1 week since prior minor surgery and recovered
• At least 3 weeks since prior major surgery and recovered

Other

• More than 2 weeks since prior drugs that would inhibit or stimulate drug metabolism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Effect of ketoconazole on the pharmacokinetics of ixabepilone

Secondary Outcome Measures

Outcome Measure
Antitumor activity
Safety of ixabepilone with and without ketoconazole

Collaborators and Investigators

• Sponsor: Montefiore Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Sridhar Mani, MD, Albert Einstein College of Medicine

Publications and helpful links

General Publications

• Goel S, Cohen M, Comezoglu SN, Perrin L, Andre F, Jayabalan D, Iacono L, Comprelli A, Ly VT, Zhang D, Xu C, Humphreys WG, McDaid H, Goldberg G, Horwitz SB, Mani S. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res. 2008 May 1;14(9):2701-9. doi: 10.1158/1078-0432.CCR-07-4151.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2003
• Primary Completion (Actual): December 5, 2005
• Study Completion (Actual): December 5, 2005

Study Registration Dates

• First Submitted: November 9, 2004
• First Submitted That Met QC Criteria: November 8, 2004
• First Posted (Estimate): November 9, 2004

Study Record Updates

• Last Update Posted (Actual): October 31, 2018
• Last Update Submitted That Met QC Criteria: October 29, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Ketoconazole
• Other Study ID Numbers: CDR0000393439; P30CA013330 (U.S. NIH Grant/Contract); AECM-03099; AECM-CA163402; AECM-NMC-03-10-277C

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes