GTI-2040 and Capecitabine in Treating Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving GTI-2040 together with capecitabine works in treating patients with metastatic breast cancer. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. GTI-2040 may help capecitabine kill more tumor cells by making them more sensitive to the drug

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the response rate and response duration to combination therapy with GTI-2040 and capecitabine in the treatment of metastatic breast cancer. II. To safely evaluate the toxicity of this drug combination and schedule in this patient population by first using a lower dose followed by escalation. III. To determine pharmacokinetic data on plasma levels of GTI-2040 in this patient population. IV. To investigate potential molecular markers of ribonucleotide reductase inhibition and fluoropyrimidine metabolism in this patient population treated with the combination of GTI-2040 and capecitabine. OUTLINE: This is a multicenter study. Patients receive GTI-2040 IV continuously on days 1-15 of the first course and days 1-14 of all subsequent courses. Patients also receive oral capecitabine twice daily on days 2-15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Official Title
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A Phase 2 Study of GTI-2040 (NSC 722929) in Combination With Capecitabine in Metastatic Breast Cancer

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

Intervention / Treatment
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* Biological: GTI-2040
* Drug: capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed metastatic adenocarcinoma of the breast Patients must have measurable disease, defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan Patients must have progressed on at least one but no more than two prior chemotherapy regimens for metastatic disease; patients must not have received prior capecitabine or 5-fluorouracil; patients with hormone-sensitive tumors should have received hormone treatment and any prior number of hormonal agents will be allowed; patients with tumors that overexpress HER-2/neu (3+ by immunohistochemistry or amplified by fluorescent in situ hybridization) should have received herceptin, either in the adjuvant or metastatic setting, unless there is a contraindication to herceptin therapy; all prior therapies must have been completed 4 weeks before treatment Life expectancy of greater than 3 months ECOG performance status =< 2 (Karnofsky >= 50%) 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 within normal institutional limits OR creatinine clearance >= 60 mL/min Patients must have completed radiation treatment > 4 weeks prior to study entry; previously radiated area(s) must not be the only site of disease All major surgical procedures must be completed > 4 weeks prior to study entry; placement of vascular access device or tissue biopsy will not be considered major surgery 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 agree to the placement of a central venous catheter in order to receive the continuous infusion treatment Exclusion Criteria: Patients with only non-measurable disease, defined as all other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions, which include the following: bone lesions leptomeningeal disease ascites pleural/pericardial effusion inflammatory breast disease lymphangitis cutis/pulmonis abdominal masses that are not confirmed and followed by imaging techniques cystic lesions Patients who have had chemotherapy, hormone therapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or 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; patients may not have received prior GTI-2040 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 GTI-2040 or to capecitabine or 5-fluorouracil Patients requiring anticoagulant therapy; low-dose anticoagulant (warfarin 1 mg per day) for the primary prophylaxis of venous catheter-associated thrombosis is permitted 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 GTI-2040 and capecitabine have 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 GTI-2040 and capecitabine, breastfeeding should be discontinued if the mother is treated 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 GTI-2040 or other agents administered during the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (GTI-2040, capecitabine)<br>Patients receive GTI-2040 IV continuously on days 1-15 of the first course and days 1-14 of all subsequent courses. Patients also receive oral capecitabine twice daily on days 2-15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Biological: GTI-2040<br>* Given IV<br>Drug: capecitabine<br>* Given orally<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose Determined by Dose-limiting Toxicities | 1st 3 pts will be treated on arm 2. If 0/3 DLTs observed, the dose will be escalated to arm 3. If 1/3 DLTs onserved on arm 2, 3 more pts will be treated on arm 2. If no additional DLTs are observed on arm 2, the dose will be escalated to arm 3. If at most 1/6 DLTs observed on arm 3, arm 3 will be considered the MTD. If more than 1/6 DLTs observed on arm 3, the dose will be de-escalated to arm 2. If at most 1/6 DLTs observed on arm 2, arm 2 will be considered the MTD. If more than 1/6 pts on arm 2 experience a DLT, the dose will be de-escalated to arm 1. The remaining pts will be treated on arm 1 as the MTD, unless more than 1/6 DLTs, in which case the study will stop. DLT is defined as any grade III or IV non-hematologic toxicity (incl. diarrhea w\ adequate antidiarrheal treatment & hydration & nausea/vomiting w\ maximal antiemetic prophylaxis, as per protocol) or grade IV hematologic toxicity. DLT will be based on the 1st course of treatment according to the revised NCI CTC v 2.0 | 21 days | 
| Response Rate of a Combination of GTI-2040 and Capecitabine | Following the dose escalation step, additional patients will be accrued at the MTD and evaluated for disease response using RECIST v1.0 criteria. Patients with confirmed complete or partial response are considered to have responded favorably to treatment.The sample size and early stopping for futility was governed by a two stage Optimum design suggested by Simon. It was assumed that a true response rate less than 25% would not warrant further study of this agent. It was also assumed that a response rate of 45% would be considered promising. In the first stage (following the dose escalation step), 15 evaluable patients were treated. Four or fewer observed responses, would stop accrual, while 5 or more observed would continue accrual for an additional 12 patients during the second stage of the study. Ten or more responses out of 27 patients will be considered evidence warranting further study of the regimen providing toxicity and survival also appear favorable. | Up to 6 years |