Irinotecan and 3-AP in Treating Patients With Metastatic or Unresectable Solid Tumors

Phase 1

Completed

• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Interventions: Drug: triapine; Drug: irinotecan hydrochloride; Other: laboratory biomarker analysis; Other: pharmacological study

• Registration Number: NCT00084877
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase I trial is studying the side effects and best dose of irinotecan and 3-AP in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy such as irinotecan work in different ways to stop tumor cells from dividing so they stop growing or die. 3-AP may stop the growth of tumor cells by blocking the enzymes necessary for their growth and may help irinotecan kill more tumor cells by making them more sensitive to the drug.

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

TERTIARY OBJECTIVES:

I. To evaluate the effect of Triapine®/irinotecan on the ribonucleotide reductase tyrosyl radical in vivo by Electron Paramagnetic Spectroscopy (EPR) 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® /irinotecan on cell cycle in vivo by measuring S-phase arrest in buccal mucosal cells.

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

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

V. To evaluate the pharmacokinetic profile of the combination.

OUTLINE: This is a dose-escalation study.

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

Cohorts of 3-6 patients receive escalating doses of irinotecan and 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, 6 additional patients are treated at that dose.

Patients are followed until disease progression.

Study Timeline

• Study Start: 2004-03
• Study First Submitted: 2004-06-10
• Study First Submitted QC: 2004-06-10
• Study First Posted: 2004-06-11
• Primary Completion: 2008-07
• Status Verified: 2013-05
• Last Update Submitted: 2013-05-15
• Last Update Posted: 2013-05-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

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 irinotecan
• 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 >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Patients must have measurable or evaluable disease
• 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 trial
• 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 immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients must have a baseline screening test for UGT1A1; the UGT1A1 cannot be the 7/7 genotype; patients who have any other combinations (6/6, 6/7, 5/7, etc.) may enroll in the trial

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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
• 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 a history of myocardial infarction or severe pulmonary disease requiring oxygen are excluded
• Because of the potential for enzyme-inducing anticonvulsant agents (EIACAs) to alter the metabolism and pharmacokinetics of irinotecan, patients who are taking EIACAs are excluded
• Metastatic brain or meningeal tumors unless the subject is > 6 months from definitive therapy, had a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry; also the patient must not be undergoing acute steroid therapy or taper
• Patients with UGT1A1 7/7 genotype are excluded

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (triapine, irinotecan hydrochloride)	triapine	Patients receive irinotecan IV over 1 hour on day 1 and 3-AP (Triapine®) IV over 2 hours on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan and 3-AP (Triapine®) until the 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, 6 additional patients are treated at that dose.
Treatment (triapine, irinotecan hydrochloride)	laboratory biomarker analysis	Patients receive irinotecan IV over 1 hour on day 1 and 3-AP (Triapine®) IV over 2 hours on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan and 3-AP (Triapine®) until the 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, 6 additional patients are treated at that dose.
Treatment (triapine, irinotecan hydrochloride)	pharmacological study	Patients receive irinotecan IV over 1 hour on day 1 and 3-AP (Triapine®) IV over 2 hours on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan and 3-AP (Triapine®) until the 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, 6 additional patients are treated at that dose.
Treatment (triapine, irinotecan hydrochloride)	irinotecan hydrochloride	Patients receive irinotecan IV over 1 hour on day 1 and 3-AP (Triapine®) IV over 2 hours on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan and 3-AP (Triapine®) until the 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, 6 additional patients are treated at that dose.

Primary Outcome Measures

Name	Time	Method
Number and severity of toxicity incidents categorized via CTC standard toxicity grading	Up to 4 years	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.

Secondary Outcome Measures

Name	Time	Method
Number of responses	Up to 4 years	Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease.

Trial Locations

Locations (1)

University of Wisconsin Hospital and Clinics; 🇺🇸 Madison, Wisconsin, United States