This is a research study to evaluate the effects of ThermoDox in combination with therapeutic heating of the chest wall in the treatment of recurrent regional breast cancer. The main purpose of this study is to find out if adding ThermoDox to therapeutic heat will increase how long the breast cancer stays away after treatment.

Breast cancer is the most common malignancy in women in both the United States and the world. Despite a variety of hormonal, cytotoxic and biologic approaches, a significant number of tumors will recur in the chest wall and axillary area following primary treatment. Any local recurrence of breast cancer after mastectomy is generally regarded as a poor prognostic indicator. However, it is also generally agreed that those who present without measurable metastatic disease at the time of loco-regional recurrence (LRR) have a more favorable disease and may experience long-term survival. Overall up to 35% of women with operable breast cancer will experience an isolated loco-regional recurrence following their primary treatment. Patients with LRR suffer from disfiguring tumors and other clinical signs and symptoms including pain, lymphedema limiting range of motion in the affected extremity, foul-smelling wounds, and a visual reminder of tumor progression. Up to 40% of patients undergoing a mastectomy as their primary treatment will experience a recurrence at the chest wall or overlying skin (RCW). For the purpose of this study, RCW is defined as a subset of LR patients that has recurrent disease at the chest wall or its overlying skin following a mastectomy.

For initial curative intent in LRR, available interventions include surgical resection in patients whose tumor and clinical status permits anesthesia and surgical removal, radiation therapy in patients whose tumor and clinical status permits additional radiation, systemic hormonal and/or cytotoxic chemotherapy in patients whose tumors are sensitive to such drugs, and combinations of the aforementioned. For unresectable LRR tumors, radiation and chemotherapy are used to manage the disease. In this setting some success has been achieved; however, a patient who reoccurs following these treatments is often treated with palliative intent.

In microwave hyperthermia (MH), two microwave-phased array wave guide applicators apply an oscillating electrical charge to target tissue; interaction with water molecules causes the electrical charge of these molecules to flip back and forth. Movement of the water molecules causes heat, resulting in thermal damage to cells. Breast cancer cells have higher water content than surrounding normal cells, composed of glandular and adipose tissue. So, the tumor is heated to a greater extent than normal breast tissue and is selectively destroyed. Tumor cell heating alone for 60 minutes at 43°C is tumoricidal. There is also a differential response between normal and tumor microcirculation, with microvascular thrombosis occurring within tumors at temperatures of 41°C. In general, cell death seems to be caused by apoptosis at temperatures up to 45°C-46°C and by necrosis at higher temperatures.

MH monotherapy has been used safely in breast cancer. In a phase I trial, 10 patients each received a single MH treatment intended to administer a thermal dose equivalent to 60 minutes at 42°C; they then underwent mastectomy 5-27 days later. These investigators reported that eight (80.0%) of the 10 had either a reduction in tumor size on ultrasound or substantial cell kill.

Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic. The recommended single-agent dose of doxorubicin HCl for injection is 60 to 75 mg/m2 intravenously (IV) in three-week cycles. Myelosuppression and cardiotoxicity (congestive heart failure) are dose-limiting. Doxorubicin is active against breast cancer as a single agent and is used with other drugs in multi-agent chemotherapy regimens. In LRR breast cancer, single agent doxorubicin achieves response rates comparable to combination chemotherapy. Single agent doxorubicin at high doses produced an overall response in 22 (84.6%) of 26 metastatic breast cancer patients and a complete response in 10 (38.5%) of 26.

Lyso-thermosensitive liposomal doxorubicin (ThermoDox®) is a temperature sensitive liposome that can selectively deliver drug to tumors and when exposed to hyperthermic conditions rapidly releases its payload of doxorubicin. Liposomal doxorubicin is administered intravenously and, because it is a liposome, is removed from circulation by the phagocytic reticuloendothelial system of the liver and spleen.

Since liposomal doxorubicin is a larger than free doxorubicin, it is over 1,000 times less permeable across normal blood vessels than free doxorubicin, offering less potential for systemic toxicity. However, tumors have much higher microvascular permeability than normal blood vessels, so liposomal doxorubicin is able to accumulate in tumors. In addition, hyperthermia has been shown to preferentially increase liposomal permeability within the microvasculature in tumor versus normal tissue.

During ThermoDox/MH therapy, cytocidal heat is directed to a tumor. When heat-sensitive liposomes encounter a certain temperature, their doxorubicin is released into the heated area. In vitro studies have repeatedly shown enhancement of cell killing when doxorubicin is combined with hyperthermia compared to doxorubicin without hyperthermia.

This phase I-II study will enroll patients with breast cancer recurrence at the chest wall to assess the optimal dosing, safety, and efficacy of ThermoDox/MH therapy. RCW breast cancer patients will receive six ThermoDox/MH treatments at 21-day intervals unless unacceptable toxicity or progressive disease is seen. ThermoDox dosing will start at 40 mg/m2 and, to avoid cumulative doxorubicin cardiotoxicity, will not exceed the 50 mg/m2 dose level (total dose 300 mg/m2). Once the MTD is established, 100 evaluable patients will be enrolled in the phase II portion of the study to assess its safety and efficacy. The primary objective in the phase II portion is to determine the durable complete local response (DCLR) rate.

Inclusion Criteria:

1. Histologically documented recurrent/metastatic adenocarcinoma of the breast with a recurrence on the chest wall (or its overlying skin):

   • Subjects with ulcerative chest wall disease defined as non-healing wounds consistent with cancer are eligible
   • Subjects with prior skin changes consistent with inflammatory breast carcinoma are eligible.
2. Tumor thickness, as measured by clinical exam or imaging studies (CT or MRI), must be less than 3 cm. The tumor surface must be able to be covered within two hyperthermia fields of treatment.

3. Subjects must have exhausted other available standard treatment options, including:

   • Mastectomy with standard adjuvant radiation, and/or adjuvant chemotherapy, and/or hormonal therapy
   • Chest wall radiation for non-resectable recurrent chest wall disease, (not administered less than 14 days prior to enrollment)
   • At least two conventional systemic chemotherapy regimens for recurrent disease such as capecitabine, taxane, or anthracycline (not administered less than 28 days prior to enrollment)
   • If HER2+, then treatment with trastuzumab and lapatinib (not administered less than 28 days prior to enrollment)
   • If ER+ (or PR+), then at least one course of hormonal therapy in the metastatic setting (not administered less than 28 days prior to enrollment).
4. Subjects who have previously received hyperthermia in conjunction with either radiation therapy or chemotherapy are eligible.

5. Subjects may have distant metastasis, including brain metastasis. Subjects with known brain metastases are eligible if:

   • They have received standard antitumor treatment for their brain metastases as defined by the site's institutional standards.
   • Their neurological function is stable for at least 2 weeks prior to enrollment.
   • They are off steroid therapy or on a stable steroid regimen for 30 days prior to enrollment.
6. Non-pregnant female at least 18 years of age. If the subject is of child-bearing age, must have a negative serum pregnancy test prior to enrollment and must agree to practice an acceptable form of birth control while on the study.
7. Provide written informed consent and willing to comply with protocol requirements.

Exclusion Criteria:

1. Requires any concomitant antineoplastic therapy.
2. Prior sensitivity (including rash, dyspnea, wheezing, urticaria or other symptoms) attributed to the administration of either anthracyclines or other liposomally encapsulated drugs.

3. Prior therapy with anthracyclines exceeding the following doses:

   Free (i.e., non-liposomal) doxorubicin > 450 mg/m2 Free epirubicin > 900 mg/m2.

4. Refractory pain secondary to metastatic disease.
5. Previous or concomitant malignancy except basal cell cancer, in situ carcinoma of the cervix, or contralateral breast cancer. Subjects with a prior contralateral breast malignancy can be included if they did not receive any chemotherapy.

6. Baseline laboratories:

   • Granulocytes < 1,500/ microliter
   • Platelets < 75,000/ microliter
   • Hemoglobin < 9 gm/dL
   • Total Bilirubin > upper limit of normal
   • ALT and AST > 2.5 X upper limit of normal
   • Creatinine > 1.5 X upper limit of normal.
7. ECOG/Zubrod Performance Status > 2.
8. MUGA/Echocardiogram Left Ventricular Ejection Fraction < 50%.
9. Has a medical or psychiatric condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or post-dose follow-up examinations.

10. History of:

    1. Acute coronary syndrome
    2. Cerebral vascular accident
    3. Abnormal cardiac stress testing within last 6 months
    4. Symptomatic coronary artery disease
    5. Uncontrolled hypertension or cardiomyopathy
    6. Cardiac valvular surgery or open heart surgery
    7. Known structural heart disease.
11. Has a condition which may interfere with the hyperthermia portion of the trial such as: 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.
12. Known allergy to egg/egg products.
13. Active infection requiring treatment with IV antibiotics.
14. Has received any of the following medications within 14 days prior to enrollment: amphotericin B, antithyroid agents, azathioprine, chloramphenicol, colchicine, flucytosine, ganciclovir, interferon, plicamycin, zidovudine, probenecid, sulfinpyrazone, cyclosporine, phenobarbital, phenytoin, streptozocin or the administration of live viruses in immunocompromised patients.
15. Has received any external radiation therapy within 14 days prior to enrollment.