Phase I/II Trial of Amrubicin as Second- or Third-Line Treatment for Patients With HER2-Negative Metastatic Breast Cancer

Inclusion Criteria:

1. Females >=18 years of age.

2. Histologic diagnosis of HER2-negative breast cancer. HER-2 negativity must be
confirmed by one of the following:

- FISH-negative (FISH ratio <2.2), or

- IHC 0-1+, or

- IHC 2-3+ AND FISH-negative (FISH ratio <2.2)

3. Evidence of metastatic or locally advanced, inoperable breast cancer.

4. Minimum of 1 and maximum of 2 prior metastatic breast cancer chemotherapy regimens.

5. Patients with prior anthracycline therapy are eligible, provided their previous
anthracycline was ≥6 months prior to study entry.

6. Measurable disease per RECIST criteria version 1.1

7. Left ventricular ejection fraction (LVEF) ³50% by echocardiogram (ECHO) or multiple
gated acquisition scan (MUGA).

8. Patients must have QTc interval of <=450 msec.

9. No intercurrent significant medical conditions or cardiac illness.

10. Patients must be >=3 weeks since last chemotherapy, and recovered from all acute
toxicities, with the exception of alopecia.

11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.

12. Adequate organ function including the following:

- ANC >=1500 cells/mL

- Platelet count >=100,000 cells/mL

- Hemoglobin >=9 g/dL

- Total bilirubin <=1.5 x ULN; AST/ALT <=2.5 x ULN, (except if due to hepatic
metastases, then <=5 x ULN)

- Serum creatinine <1.5 x ULN

13. Women of childbearing potential must have a negative serum or urine pregnancy test
performed <=7 days prior to start of treatment. If a woman becomes pregnant or
suspects she is pregnant while participating in this study, she must agree to inform
her treating physician immediately.

14. Patients must be accessible for treatment and follow-up.

15. Patients must be able to understand the investigational nature of this study and give
written informed consent prior to study entry.

16. Patients who are on anticoagulation are acceptable if the therapeutic anticoagulation
is stable. Additionally, the patient's INR must be adequate if the patient is
receiving treatment with coumadin.

17. Prior hormonal therapy for metastatic breast cancer is permitted; however, the
therapy must be discontinued prior to the patient's enrollment in this study.

Exclusion Criteria:

1. Any concurrent therapy with other investigational, chemotherapeutic, or hormonal
therapy.

2. Prior treatment with >=3 regimens of cytotoxic therapy in the advanced disease
setting. (Any number of previous hormonal therapies are acceptable, as long as the
therapy is discontinued prior to the patient's enrollment into this study).

3. Major surgery or systemic therapy <=3 weeks of study treatment.

4. Prior high-dose chemotherapy requiring hematopoietic stem cell support.

5. Prior radiation therapy to >25% of the bone marrow.

6. Uncontrolled brain metastases. Patients with treated brain metastases (resection or
radiotherapy) are eligible if brain metastases have responded to treatment as
documented by CT or MRI scan obtained at >=2 weeks after completion of radiation
therapy, neurologic symptoms are absent, and steroids have been discontinued.

7. Suspected, diffuse idiopathic interstitial lung disease or pulmonary fibrosis.

8. Diagnosis of second malignancy within the last 3 years (with the exception of
carcinoma in situ of the cervix, squamous or basal cell skin cancer, thyroid cancer,
ductal carcinoma in situ [DCIS], or lobular carcinoma in situ [LCIS]).

9. Any of the following <=12 months prior to starting study treatment:

- myocardial infarction;

- severe unstable angina;

- congestive heart failure;

- ongoing cardiac dysrhythmia.

10. Family history of idiopathic cardiomyopathy or uncontrolled heart arrhythmia.

11. Patients with previous allergy or hypersensitivity to anthracyclines.

12. Patients who have had a ≥10% drop in LVEF on previous anthracycline therapy.

13. Palliative radiotherapy to areas of metastatic breast cancer must have been completed
>7 days prior to the first dose of study treatment. The exception is radiotherapy for
brain metastases, which must be completed >=21 days prior to study treatment. (Note:
Any measurable lesion that has been previously irradiated will not be considered as a
target lesion).

14. Concurrent severe, intercurrent illness including, but not limited to, ongoing or
active infection, or psychiatric illness/social situations that would limit
compliance with study requirements.

15. History of seropositive HIV, or patients who are receiving immunosuppressive
medications that increase the risk of neutropenic complications.

16. Mental condition that would prevent patient comprehension of the nature of, and risk
associated with, the study.

17. Use of any non-approved or investigational agent <=30 days of administration of the
first dose of study drug. Patients may not receive any other investigational or
anti-cancer treatments while participating in this study.