A Dose Finding Phase I Trial of the Combination of Topotecan and PS-341, a Novel Proteasome Inhibitor, in Advanced Malignancies

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00068484
First received: September 10, 2003
Last updated: January 31, 2013
Last verified: January 2013

September 10, 2003
January 31, 2013
July 2003
February 2006   (final data collection date for primary outcome measure)
  • Dose limiting toxicities [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  • Maximum tolerated dose (MTD) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
Not Provided
Complete list of historical versions of study NCT00068484 on ClinicalTrials.gov Archive Site
  • Pharmacokinetics of topotecan hydrochloride [ Time Frame: 5 minutes immediately after sample collection ] [ Designated as safety issue: No ]
  • Levels of topoisomerase I [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • DNA repair enzymes [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Objective response according to the RECIST criteria [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
Not Provided
 
A Dose Finding Phase I Trial of the Combination of Topotecan and PS-341, a Novel Proteasome Inhibitor, in Advanced Malignancies
A Dose Finding Phase I Trial of the Combination of Topotecan and PS-341, a Novel Proteasome Inhibitor, in Advanced Malignancies

Drugs used in chemotherapy such as topotecan use different ways to stop tumor cells from dividing so they stop growing or die. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Combining topotecan with bortezomib may kill more tumor cells. This phase I trial is studying the side effects and best dose of topotecan and bortezomib when given together in treating patients with metastatic or unresectable cancer

PRIMARY OBJECTIVES:

I. Determine the safety of the combination of PS-341 and topotecan. II. Determine the dose limiting toxicities and maximum tolerated dose as well as the recommended phase II doses of the combination.

III. Assess the pharmacokinetics of topotecan alone and in combination with PS-341.

SECONDARY OBJECTIVES:

I. Estimate the objective response rate of a combination of PS-341 and topotecan delivered on days 1-5 every three weeks as defined by the RECIST criteria.

II. Assess the pharmacodynamics of topo I levels. III. Determine the expression of the DNA repair enzyme XRCC1 in tumor biopsies.

OUTLINE: This is a dose-escalation study.

Patients receive topotecan IV over 30 minutes on days 1-5. Beginning with course 2, patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of topotecan and bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 1 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A total of 20-25 patients will be accrued for this study.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Unspecified Adult Solid Tumor, Protocol Specific
  • Drug: topotecan hydrochloride
    Given IV
    Other Names:
    • hycamptamine
    • Hycamtin
    • SKF S-104864-A
    • TOPO
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (topotecan hydrochloride, bortezomib)
Patients receive topotecan IV over 30 minutes on days 1-5. Beginning with course 2, patients also receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: topotecan hydrochloride
  • Drug: bortezomib
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
25
Not Provided
February 2006   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • Tumor accessible to core needle biopsy and willingness to undergo this procedure prior to the start of treatment
  • Evaluable disease as defined in the RECIST criteria
  • ECOG performance status =< 2
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count > 1,500/ul
  • Platelets > 100,000/ul
  • Total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal
  • Creatinine < 2.0 mg/ml
  • Ability to understand and the willingness to sign a written informed consent document
  • Metastatic brain or meningeal tumors are allowed if the patient is > 1 month from surgery and/or radiation and is clinically stable with respect to the tumor at the time of the study entry and currently off corticosteroids
  • Pregnancy test for pre-menopausal women
  • The effects of PS-341 and topotecan on the developing human fetus are unknown; for this reason women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Exclusion Criteria:

  • Creatinine clearance < 40 mL/min
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
  • Those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to topotecan, PS-341 or other agents used in this study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because topotecan is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with topotecan and PS-341, breastfeeding should be discontinued; these potential risks may also apply to other agents used in this study
  • Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with topotecan and PS-341 or other agents administered during the study.; appropriate studies will be undertaken for patients receiving combination anti-retroviral therapy when indicated
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00068484
NCI-2013-00044, HIC #12760, R21CA097750, CDR0000322889
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: John Murren Yale University
National Cancer Institute (NCI)
January 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP