Liposomal Doxorubicin Before Mastectomy in Treating Women With Invasive Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as liposomal doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy in different ways, such as into the breast ducts, may kill more tumor cells. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase I trial is studying the side effects and best dose of liposomal doxorubicin when given before mastectomy in treating women with invasive breast cancer.

Detailed Description
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OBJECTIVES: Primary Evaluate the feasibility, safety, and maximum tolerated dose of intraductal pegylated doxorubicin HCl liposome in women with invasive breast cancer awaiting mastectomy. Secondary Determine the pharmacokinetics of intraductal pegylated doxorubicin HCl liposome, including serial plasma concentrations of doxorubicin and doxorubicinol and tissue concentrations in different portions of the breast at the time of surgery. OUTLINE: This is a dose-escalation study. Patients receive an intraductal injection of pegylated doxorubicin HCl liposome* on day 1. Patients undergo mastectomy 2-4 weeks later. Cohorts of 3-6 patients receive escalating doses of pegylated doxorubicin HCl liposome* 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. At least 6 patients are treated at the MTD. NOTE: *The first cohort of 3 patients receive intraductal dextrose only followed by surgery as a feasibility study. An additional 3 patients receiving intravenous PLD will be enrolled in a pharmacokinetic control portion of the study.

Official Title
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A Phase I Study Assessing the Feasibility and Safety of Intraductal Administration of Pegylated Liposomal Doxorubicin (Doxil) in Women With Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Intraductal arm
* Drug: Intravenous arm


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed infiltrating carcinoma of the breast meeting any of the following criteria: T1-3, any N disease Proven ductal carcinoma in situ Unresected disease Planned mastectomy as definitive surgical procedure Known or suspected metastatic disease allowed provided mastectomy is planned Nonpalpable tumor allowed (e.g., initial T2-3 tumor that responded to preoperative therapy) No inflammatory breast cancer or other T4 features Successful baseline ductogram Baseline nipple aspiration procedure must identify a duct productive of nipple aspirate fluid No severe nipple retraction Hormone receptor status not specified PATIENT CHARACTERISTICS: Female patients Menopausal status not specified ECOG performance status 0-2 Absolute neutrophil count ≥1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9.0 g/dL Creatinine ≤ 2 times upper limit of normal (ULN) Bilirubin ≤ 2 times ULN AST and ALT ≤ 2.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No significant history of severe allergy to iodinated contrast material or debilitating anxiety that may not allow for a ductogram PRIOR CONCURRENT THERAPY: See Disease Characteristics Prior preoperative chemotherapy, trastuzumab (Herceptin®), or hormonal therapy allowed provided it was completed 7-14 days prior to study treatment No prior radiation therapy, excisional biopsy, breast reduction, areolar surgery, or breast implant (present or past history of implant that was removed) No other prior procedure that may have altered the breast ductal system in the ipsilateral breast No other concurrent chemotherapy, radiotherapy, endocrine therapy, or biologic agents for breast cancer No other concurrent investigational drugs Concurrent bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraductal arm<br>Participants received intraductal administration of dextrose or dextrose with pegylated liposomal doxorubicin hydrochloride (or PLD) prior to conventional surgery for breast cancer. | Drug: Intraductal arm<br>* Patients will receive PLD intraductally according to the dose escalation schema (Dose Level -1=1 mg, Dose Level 1=2 mg, Dose Level 2= 5mg, Dose Level 3=10 mg). The PLD dose will be diluted in 5% dextrose in water and will be mixed for a total volume of 5 ml. The PLD will be administered via a breast duct (i.e., intraductally) using a microcatheter<br>* Other names: Doxorubicin HCl Liposome Injection, Dox-SL, Doxil TM;|
| Active Comparator: Intravenous arm<br>Participants receiving standard intravenous administration of pegylated liposomal doxorubicin prior to breast biopsy for drug concentrations. | Drug: Intravenous arm<br>* Blood samples and a breast tissue biopsy collected to look at levels of doxorubincol from patients receiving intravenous pegylated liposomal doxorubin to compare to the group receiving drug intraductally.<br>* Other names: Doxorubicin HCl Liposome Injection, Dox-SL, Doxil TM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Maximum tolerated dose (MTD) of administering pegylated liposomal doxorubicin (PLD) into one duct of women with breast cancer awaiting mastectomy. MTD reflects highest dose of drug that did not cause Dose Limiting Toxicity (DLT) in more than 30% of patients. | Until up to 30 days after PLD administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of Doxorubicin in Blood (Plasma) at Definitive Surgery | Due to the limited number of samples and detectable levels, the maximum concentration of doxorubicin in blood (plasma) across all the participants in each group is reported. | Baseline, 4 hrs, day2/24 hrs, day 8, day of surgery/biopsy | 
| Concentrations of Doxorubicin in Tissue at Definitive Surgery | Due to the limited number of samples and detectable levels, the maximum concentration of doxorubicin in tissue across all the participants in each group is reported. | Day of surgery/biopsy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIC breast cancer, stage IV breast cancer, breast cancer in situ, ductal breast carcinoma in situ