Temperature-Sensitive Liposomal Doxorubicin and Hyperthermia in Treating Women With Locally Recurrent 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. Hyperthermia therapy kills tumor cells by heating them to several degrees above normal body temperature. Giving temperature-sensitive liposomal doxorubicin together with hyperthermia may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of temperature-sensitive liposomal doxorubicin when given together with hyperthermia in treating women with locally recurrent breast cancer.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of temperature-sensitive liposomal doxorubicin (ThermoDox™) when used in combination with local-regional hyperthermia in women with locally recurrent breast cancer. Determine the pharmacokinetic profile of ThermoDox™ when used in multiple-course dosing. OUTLINE: This is a dose-escalation study of temperature-sensitive liposomal doxorubicin (ThermoDox™). Patients receive ThermoDox™ IV over 30 minutes immediately followed by hyperthermia to the chest wall/axilla over 1-2 hours on day 1. Treatment repeats every 21-35 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of ThermoDox™ (with or without standard-dose granulocyte colony-stimulating factor [G-CSF] support) until the maximum tolerated dose (MTD) is determined. The MTD without G-CSF support is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT). At least 6 patients are treated at the MTD. If the only DLT is neutropenia in > 1 of 6 patients treated at any dose level, then additional cohorts of 3-6 patients receive escalating doses of ThermoDox™ with G-CSF support (standard-dose G-CSF or standard-dose pegfilgrastim) until the MTD is determined. The MTD with G-CSF support is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT after the addition of G-CSF support. Quality of life and pain are assessed at baseline, prior to courses 3 and 5, and at 21-42 days after completion of therapy. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Official Title
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A Phase I, Dose Escalation and Pharmacokinetics Study of Temperature Sensitive Liposome Encapsulated Doxorubicin (ThermoDox™) and Hyperthermia in Patients With Local-Regionally Recurrent Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: filgrastim
* Biological: pegfilgrastim
* Drug: lyso-thermosensitive liposomal doxorubicin(Thermodox)
* Procedure: hyperthermia treatment


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast Locally recurrent disease involving the chest wall and/or its overlying skin Clinically and biopsy proven disease on the chest wall area measuring ≥ 1 cm Overall surface extent of tumor ≤ two 16 x 16 cm fields Tumor thickness ≤ 3 cm by clinical exam and CT scan or MRI Disease extent on the chest wall that exceeds the above criteria allowed provided no other local therapies are available Patients with axillary disease involvement only must meet the above criteria in order to be eligible Prior skin changes consistent with inflammatory breast cancer are allowed Distant metastasis (excluding known brain metastases) allowed No resectable chest wall recurrence as the only site of metastatic disease No refractory pain secondary to metastatic disease Must have undergone prior local radiotherapy to the chest wall or breast in the adjuvant or metastatic setting Must have progressed on ≥ 1 course of hormonal therapy for metastatic disease (if tumor is estrogen receptor positive or progesterone receptor positive) AND ≥ 1 course of chemotherapy Prior contralateral breast malignancy allowed provided not previously treated with chemotherapy Hormone receptor status not specified PATIENT CHARACTERISTICS: Female Menopausal status not specified Zubrod performance status 0-1 OR Karnofsky performance status 90-100% Not pregnant Negative pregnancy test Fertile patients must use effective contraception Granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL Bilirubin normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) Creatinine ≤ 1.5 times ULN left ventricular ejection fraction (LVEF) ≥ 50% by multiple gated acquisition scan (MUGA) or echocardiogram No nonhealing wounds or active infection in the area of the chest wall No clinically significant findings on baseline evaluations, including laboratory and physical examinations, vital signs, and ECG No prior sensitivity (e.g., rash, dyspnea, wheezing, urticaria, or other symptoms) attributed to anthracyclines or other liposomally encapsulated drugs No other prior or concurrent primary malignancy except for melanoma in situ, nonmelanoma skin cancer, squamous cell carcinoma, or noninvasive cervical carcinoma No history of any of the following: Cardiac ischemia or acute coronary artery syndrome, myocardial infarction (MI), cerebral vascular accident, or abnormal cardiac stress testing within the last 6 months Coronary artery disease (including non-Q wave MI) Uncontrolled hypertension or cardiomyopathy Cardiac valvular surgery or open heart surgery Known structural heart disease No other serious medical illness including, but not limited to, the following: Congestive heart failure Life-threatening cardiac arrhythmias Acute or chronic liver disease No major psychiatric illness that required inpatient treatment within the past 3 months or that would preclude obtaining informed consent No concurrent devices or conditions that might interfere with the hyperthermia portion of the trial, including any of the following: Functioning cardiac pacemaker Metal plates, rods, or prosthesis of the chest wall Severe numbness and/or tingling of the chest wall or breast Skin grafts and/or flaps on the breast or chest wall Unstable cardiovascular or pulmonary status No known allergy to eggs or egg products PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 3 months since prior major surgery No prior therapy with anthracyclines exceeding the following doses: Doxorubicin hydrochloride > 450 mg/m^2 Epirubicin hydrochloride > 900 mg/m^2 More than 42 days since prior trastuzumab (Herceptin®) More than 90 days since prior radiotherapy to the involved chest wall area No other concurrent systemic anticancer therapy, including hormonal therapy, chemotherapy, or investigational anticancer therapy No concurrent radiotherapy, including radiotherapy for pain control No concurrent administration of any of the following drugs: Amphotericin B by injection Antithyroid agents Azathioprine Chloramphenicol Colchicine Flucytosine Ganciclovir Interferon Plicamycin Zidovudine Sulfinpyrazone Probenecid Cyclosporine Phenobarbital Phenytoin Streptozocin Live vaccines Concurrent bisphosphonates for palliation of bony metastasis 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thermodox<br>ThermoDox20-40mg/m2 every 21-35 days followed by Chest Wall Hyperthermia | Biological: filgrastim<br> <br> Biological: pegfilgrastim<br> <br> Drug: lyso-thermosensitive liposomal doxorubicin(Thermodox)<br> <br> Procedure: hyperthermia treatment<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of temperature-sensitive liposomal doxorubicin (ThermoDox™) in combination with hyperthermia |  | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics |  | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III B breast cancer, stage III C breast cancer, stage IV breast cancer, inflammatory breast cancer, recurrent breast cancer