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

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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


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.


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.

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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose limiting toxicities

Outcome Time Frame:

Up to 3 years

Safety Issue:


Principal Investigator

John Murren

Investigator Role:

Principal Investigator

Investigator Affiliation:

Yale University


United States: Food and Drug Administration

Study ID:




Start Date:

July 2003

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



Yale University New Haven, Connecticut  06520