Phase 1/2 Study of ThermoDox With Approved Hyperthermia in Treatment of Breast Cancer Recurrence at the Chest Wall

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 LRR 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 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.

Diathermy refers to the therapeutic generation of local heat in body tissues by
high-frequency electromagnetic radiation, electric currents, or ultrasonic waves. In mild
hyperthermia local tissue temperatures are restricted to a range of 39-45°C. Two types of
external devices, microwave systems and ultrasound systems, have been approved by the FDA
for delivering mild hyperthermia to the chest wall.

Mild hyperthermia from either microwave or ultrasound devices has been used safely in breast
cancer treatment. In conjunction with external beam radiation, both types of devices have
been used to heat the chest wall and both devices have demonstrated enhanced effects when
compared to radiation therapy without additional hyperthermia.

Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic. The recommended
single-agent dose of doxorubicin HCl (Adriamycin®) for injection is 60 to 75 mg/m2
intravenously (IV) in three-week cycles. Acute myelosuppression and long term, cumulative,
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.

Lyso-thermosensitive liposomal doxorubicin (ThermoDox®) is a temperature sensitive liposomal
drug delivery system that selectively accumulates in tumors as a result of their leaky
vasculature. During ThermoDox/hyperthermia therapy, the tumor is heated locally while the
rest of the body remains at a normal temperature. When the liposomes encounter a temperature
of 39.5°C or above, they release doxorubicin locally into the heated area. Liposomal
doxorubicin is administered intravenously and, because it is particulate, will eventually be
removed from circulation by the reticuloendothelial system in the liver and spleen.
Pharmacokinetic data from liver cancer patients treated with radiofrequency ablation (RFA)
and ThermoDox show that the major portion of exposure to ThermoDox (about 95% of the
liposomal doxorubicin plasma AUC0-∞) occurs during the first six hours following the
infusion, establishing this time period as optimal for application of hyperthermia. Animal
studies have repeatedly shown higher tumor doxorubicin concentrations and enhanced tumor
cell killing when ThermoDox is combined with hyperthermia compared to doxorubicin without
hyperthermia.

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.

- Breast carcinoma for medical reasons not being resected

2. Tumor thickness must be clinically indicated for hyperthermia therapy, as measured by
clinical exam or imaging studies (CT or MRI). The target local tumor lesion(s) must
be able to be covered within two hyperthermia fields of treatment.

3. Disease that has progressed despite other available standard treatment options, based
on what is clinically indicated according to the investigator's clinical and medical
judgment, including:

- One or more radiation treatment(s) to the chest wall or breast up to a maximum
prior dose of 12,000 cGy in the hyperthermia field (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 metastases. Subjects with known
brain metastases are eligible if:

- They have received standard anti-tumor treatment for their brain metastases
without encephalopathy;

- Their neurological function is stable for at least 30 days and either off
steroid therapy or on a stable steroid regimen.

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 at baseline 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. Prior chemotherapy should not be
administered within 5 half-lives or 28 days whichever is shorter. Subjects on a
current stable dose of hormonal treatments may continue on a stable dose during the
study (i.e. arimidex, amarosin, herceptin).

2. Prior confirmed allergic reaction (including moderate rash, dyspnea, wheezing,
urticaria or other symptoms) attributed to the administration of either
anthracyclines or other liposomally encapsulated drugs that required discontinuation
of prior therapy.

3. Prior therapy with anthracyclines exceeding the following doses (subjects will be
discontinued at 600 mg/m2 lifetime dose irrespective of the number of ThermoDox®
cycles received):

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

4. Previous (required active treatment within 5 years) 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.

5. Baseline laboratories (repeat labs can be evaluated at baseline to establish
eligibility):

- ANC Granulocytes < 1,500/ microliter

- Platelets < 75,000/ microliter

- Hemoglobin < 9 gm/dL

- Total Bilirubin > 2 mg/dL

- ALT and AST > 2.5 X upper limit of normal

- Creatinine > 1.5 X upper limit of normal.

6. ECOG/Zubrod Performance Status > 2.

7. MUGA/Echocardiogram Left Ventricular Ejection Fraction < 50%.

8. 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.

9. History of:

- Acute coronary syndrome

- Cerebral vascular accident

- Abnormal cardiac stress testing within last 6 months

- Symptomatic coronary artery disease

- Uncontrolled hypertension or cardiomyopathy

- Cardiac valvular surgery or open heart surgery

- Known structural heart disease.

10. 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, breast reconstruction with implants, severe numbness and/or tingling of the
chest wall or breast, skin grafts and/or flaps on the breast or chest wall.

11. Active infection requiring antibiotic treatment

12. Has received any external radiation therapy within 28 days prior to enrollment.