3-AP and Gemcitabine in Treating Patients With Refractory Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
Phase II trial to study the effectiveness of combining 3-AP with gemcitabine in treating patients who have refractory metastatic breast cancer. Drugs used in chemotherapy, such as 3-AP and gemcitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining 3-AP with gemcitabine may kill more tumor cells

Detailed Description
-----------------
OBJECTIVES: Primary I. Determine antitumor activity of 3-AP (Triapine®) and gemcitabine by measuring tumor size in patients with refractory metastatic breast cancer. Secondary I. Determine the safety and tolerability of this regimen in these patients. II. Determine the time to disease progression in patients treated with this regimen. III. Determine the effect of multidrug resistance polymorphisms on pharmacokinetics and toxicity of this regimen in these patients. OUTLINE: This is a multicenter study. Patients receive 3-AP (Triapine®) IV over 2 hours followed by gemcitabine IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 3 years after registration. PROJECTED ACCRUAL: A total of 30-75 patients will be accrued for this study within 24 months.

Official Title
-----------------
A Phase II Trial Of Gemcitabine And Triapine In Refractory Metastatic Breast Cancer

Conditions
-----------------
Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
-----------------
* Drug: triapine
* Drug: gemcitabine hydrochloride
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed breast cancer Refractory metastatic disease Measurable disease At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan Must have received 1, and only 1, prior chemotherapy regimen for metastatic disease Patients overexpressing HER2/neu antigen must have received a prior trastuzumab (Herceptin®)-containing regimen No known brain metastases Hormone receptor status: Not specified Male or female Performance status - ECOG 0-2 At least 12 weeks WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal Creatinine normal Creatinine clearance ≥ 60 mL/min No uncontrolled congestive heart failure No unstable angina pectoris No cardiac arrhythmia No severe pulmonary disease requiring oxygen Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No glucose-6-phosphate dehydrogenase (G6PD) deficiency No other uncontrolled illness No active or ongoing infection No history of allergic reaction attributed to compounds of similar chemical or biological composition to 3-AP (Triapine®) or other study agents No psychiatric illness or social situation that would preclude study compliance No other malignancy within the past 5 years See Disease Characteristics No concurrent immunotherapy No concurrent routine colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) See Disease Characteristics More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) No prior gemcitabine for metastatic disease No other concurrent chemotherapy More than 4 weeks since prior hormonal therapy More than 4 weeks since prior radiotherapy No concurrent radiotherapy Recovered from prior therapy No concurrent antiretroviral therapy for HIV-positive patients No other concurrent investigational therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (triapine, gemcitabine hydrochloride)<br>Patients receive 3-AP (Triapine®) IV over 2 hours followed by gemcitabine IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: triapine<br>* Given IV<br>* Other names: OCX-191;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed response (complete or partial response) | Ninety five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 3.0 |  | Up to 3 years | 
| Time to progression | The distribution of time to progression will be estimated using the method of Kaplan-Meier. | Time from registration to the time of progression, assessed up to 3 years | 
| Overall survival | The distribution of overall survival will be estimated using the method of Kaplan-Meier. | Time from registration to death due to any cause, assessed up to 3 years | 
| Changes in tyrosyl radical and cell-cycle arrest on buccal mucosa |  | Pre-infusion, 2 and 4.5 hours post-infusion | 
| Changes in R2 messenger ribonucleic acid (mRNA) on protein levels before and after treatment with triapine |  | Pre-infusion, 2 and 4.5 hours post-infusion | 
| MDR polymorphism on tumor tissue |  | Baseline |