Toll-like Receptor (TLR) 7 Agonist, Cyclophosphamide, and Radiotherapy for Breast Cancer With Skin Metastases

By harnessing the cytocidal and immunostimulatory properties of two local treatment
modalities, RT and IMQ, an effective, adaptive immune response can be generated, resulting in
systemic control of metastatic breast cancer after local treatment of cutaneous metastases.
Additionally, based on investigators' recent preclinical data, the investigators intend to
estimate in patients with metastatic breast cancer, if the addition of immunomodulatory
cyclophosphamide can increase anti-tumor responses.

This trial originally had one treatment arm IMQ/RT(patients were treated with IMQ and RT).
Recent evidence has emerged that the addition of immunomodulatory cyclophosphamide (CTX)
increased anti-tumor responses, therefore the IMQ/RT arm is closed and the trial will
continue with two additional cohorts (CTX/IMQ/RT and CTX/RT) which include cyclophosphamide.

Inclusion Criteria:

1. Patients with biopsy-confirmed breast cancer.

2. Patients with at least measurable skin metastases and distant, measurable metastases
(outside of skin) by Response Evaluation Criteria in Solid Tumors (RECIST). For
patients without distant measurable metastases, an area of the skin metastases
designated to not receive local therapy can be substituted. Patients with multiple (>=
2) metastatic sites (skin involvement not required), with at least one site measurable
by RECIST, will be eligible for the CTX/RT cohort.

3. Age >= 18 years.

4. Eastern Cooperative Oncology Group performance status 0-2.

5. Patients must agree to tumor fine-needle aspiration required by protocol.

6. Concurrent systemic cancer therapy (hormones, biologics or chemotherapy) can be
continued if distant metastases are non-responsive (i.e. no complete response or
partial response) on that regimen for >= 8 weeks as assessed by the investigator.

7. Patients must have adequate organ and bone marrow function as defined below:

- absolute neutrophil count >= 1,300/microliter

- hemoglobin >= 9.0 grams/deciliter

- platelets >= 75,000/microliter

- total bilirubin =< 1.5 X institutional upper limit of normal

- AST (aspartate aminotransferase) =< 2.5 X institutional upper limit of normal

- ALT (alanine aminotransferase) =< 2.5 X institutional upper limit of normal

- creatinine =< 2 X institutional upper limit of normal if patient has chronic
renal insufficiency and creatinine has been stable for > 4 months)

8. Informed consent.

Exclusion Criteria:

1. Brain metastases unless resected or irradiated and stable >= 4 weeks.

2. Concurrent treatment with other investigational agents.

3. Patients who have received any local therapy (radiotherapy, high-potency
corticosteroids, intralesional therapy, laser therapy or surgery) other than biopsy to
the target area within 4 weeks prior to first dosing of study agent.

4. Patients who have received hyperthermia to the target area within 10 weeks prior to
first dosing of study agent.

5. Patients with an uncontrolled bleeding disorder.

6. Patients (with skin metastases only) who will be therapeutically anticoagulated with
heparins or coumadin at the time of the biopsy (they are eligible if anticoagulation
can be held prior to biopsy as per investigator). Patients on aspirin and other
platelet agents are eligible.

7. Patients with known immunodeficiency or receiving immunosuppressive therapies.

8. History of allergic reactions to imiquimod or its excipients.

9. Uncontrolled intercurrent medical illness or psychiatric illness/social situations
that would limit compliance with study requirements.

10. Pregnancy or lactation.

11. Women of childbearing potential not using a medically acceptable means of
contraception.