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A Phase I Study of Triapine® in Combination With Doxorubicin in Refractory Tumors

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

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Trial Information

A Phase I Study of Triapine® in Combination With Doxorubicin in Refractory Tumors


I. To find the maximal tolerated dose for the combination of doxorubicin and Triapine® in
patients with refractory solid tumors.


I. To find the severity and frequency of toxicity associated with this combination and to
observe for and record any antitumor activity.


I. To evaluate the effect of Triapine®/doxorubicin on the ribonucleotide reductase tyrosyl
radical in vivo by EPR spectroscopy in buccal mucosal cells, peripheral blood lymphocytes
and in tumor biopsies. Formation of low molecular weight iron-Triapine® chelates will also
be assessed by EPR.

II. To evaluate the effect of Triapine®/doxorubicin on cell cycle in vivo by measuring
S-phase arrest in buccal mucosal cells.

III. To evaluate the effect of Triapine®/doxorubicin on MDR gene expression and
polymorphisms in blood.

IV. To evaluate the effect of Triapine®/doxorubicin on ribonucleotide reductase R2 mRNA and

V. To evaluate the pharmacokinetic profile of the combination. VI. To measure the
formulation of circulating isoprostanes as an indicator of oxidative stress with this

OUTLINE: This is a dose-escalation study of 3-AP (Triapine^®).

Patients receive doxorubicin IV over 15 minutes on day 1 and 3-AP (Triapine®) IV over 2
hours on days 1-4. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 3-AP (Triapine®) until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an
additional 6 patients are treated at that dose level.

Patients are followed until disease progression.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative or palliative chemotherapy measures do
not exist or are no longer effective

- Patients must not have previously received anthracyclines

- Patients must not have received radiation to > 25% of bone marrow

- ECOG performance status =< 2

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/μl

- Absolute neutrophil count >= 1,500/μl

- Platelets >= 100,000/μl

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal

- Creatinine =< 1.5 mg/dl OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Patients must have LVEF > 45%

- Patients must have baseline screening for G6PD (glucose-6-phosphate dehydrogenase)
deficiency; G6PD must be no lower than the lower limit of normal prior to starting
study treatment; patients who are above the upper limit of normal may enroll in the

- Patients must have measurable or evaluable disease

- The effects of Triapine® on the developing human fetus are unknown; for this reason
and because heterocyclic carboxaldehyde thiosemicarbazones as well as other
therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) 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

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study

- Patients who have not recovered from adverse events due to agents administered more
than 4 weeks earlier; patients with grade =< 1 adverse events from prior therapies
are eligible at the investigator's discretion

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Triapine® or other agents used in 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 Triapine® is a heterocyclic
carboxaldehyde thiosemicarbazone 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 Triapine®, breastfeeding should be
discontinued if the mother is treated with Triapine®; these potential risks may also
apply to other agents used in this study

- Patients with immune deficiency are at increased risk of lethal infections when
treated with marrow-suppressive therapy; therefore, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with Triapine® or other agents administered during the
study; appropriate studies will be undertaken in patients receiving combination
anti-retroviral therapy when indicated

- Patients with known G6PD deficiency are excluded

- Patients with severe pulmonary disease requiring oxygen and patients with baseline
hypoxia (< 95% oxygen saturations) are excluded

Type of Study:


Study Design:

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

Outcome Measure:

Number and severity of toxicity incidents categorized via Common Toxicity Criteria (CTC) standard toxicity grading

Outcome Description:

Hematologic toxicity measures of thrombocytopenia, neutropenia and leukopenia will be assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values). Nonhematologic toxicities such as diarrhea and stomatitis will be evaluated via the ordinal CTC standard toxicity grading only. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.

Outcome Time Frame:

Up to 4 years

Safety Issue:


Principal Investigator

George Wilding

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics


United States: Food and Drug Administration

Study ID:




Start Date:

January 2004

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001