The purpose of this study is to determine the efficacy (ability to provide a beneficial treatment of the disease) of pralatrexate for the treatment of female patients with advanced or metastatic breast cancer who have failed prior chemotherapy. Patients will receive vitamin B12 and folic acid supplementation.

This is an open label, multi-center, Phase 2 study of pralatrexate with vitamin B12 and folic acid supplementation in patients with advanced or metastatic breast cancer who have failed prior treatment(s).

The start of study treatment is defined as the initiation of pralatrexate administration.

Pralatrexate will be administered as an intravenous (IV) push over 3-5 minutes on days 1 and 15 (± 1 day at each time point) of a 4-week cycle (ie, every [q] 2 weeks). The initial dose of pralatrexate will be 190 mg/m2. Dose reduction to 150 mg/m2 with further reduction to 120 mg/m2 and 100 mg/m2 will be allowed for defined toxicity (see Section 7.3). If 100 mg/m2 is not tolerated, pralatrexate must be discontinued.

Patients will receive vitamin supplementation consisting of vitamin B12, 1 mg intramuscular (IM) q 8-10 weeks and folic acid 1-1.25 mg by mouth (PO) once a day (QD). Patients must have received 1 mg vitamin B12 within 10 weeks prior to the initiation of pralatrexate and have received 7 days of 1-1.25 mg folic acid PO QD prior to the initiation of pralatrexate.

Vitamin supplementation will continue throughout the study and for at least 30 days after the last administration of pralatrexate.

Inclusion Criteria:

• HER-2 negative advanced or metastatic breast cancer
• Disease has become worse after at least 1 prior chemotherapy regimen for advanced or metastatic disease
• Advanced or metastatic disease resistant to both a taxane and an anthracycline-containing chemotherapy regimen, or resistant to taxanes and for whom further anthracycline therapy is not indicated
• Patients with controlled brain metastases must have finished receiving radiation therapy and if on corticosteroids, be on a stable or tapering dose of ≤ 10 mg/day of prednisone or equivalent for at least 28 days prior to study entry
• Measurable disease
• Female 18 years of age or older
• Performance status less than or equal to 2
• Life expectancy of more than 3 months
• Blood, liver and kidney laboratory test results that meet protocol requirements
• Patients must have a negative serum pregnancy test within 14 days before enrollment and agree to use medically acceptable and effective birth control from enrollment until at least 30 days after the last dose of pralatrexate. Patients who are postmenopausal for at least 1 year (more than 12 months since last menses) or are surgically sterilized do not require this test.
• Willing to attend visits for repeat dosing and follow up
• Give written informed consent

Exclusion Criteria:

• Patients with only bone metastasis

• Patients with a single metastatic site without histological proof that the lesion is metastatic breast cancer

• Patients with inflammatory breast cancer

• Treatment with systemic chemotherapy, hormone therapy, radiation therapy, or other investigational therapy within 3 weeks (6 weeks for nitrosoureas, mitomycin C) prior to enrollment, except for the following:

  • Bisphosphonates, if ongoing
  • Prior treatment with methotrexate
  • Prior treatment with anti-angiogenics within 6 months prior to enrollment

• Have received more than 2 prior chemotherapy regimens (more than 3 if one of the treatments was neoadjuvant or adjuvant chemotherapy)

• Have previously received pralatrexate

• Have received more than the allowed maximum total dose of anthracycline

• Prior radiation therapy on more than 30% of bone marrow reserve or prior bone marrow/stem cell transplantation

• Congestive heart failure Class III/IV

• Uncontrolled hypertension (high blood pressure)

• Active infection or any serious medical condition, which would impair the ability of the patient to receive protocol treatment

• Females who are pregnant or breastfeeding

• Major surgery within 14 days of enrollment

• Another active cancer in addition to advanced or metastatic breast cancer, except well treated in situ cervical cancer and basal cell skin cancer

• Dementia or other altered mental status that would prevent the patient from understanding and giving informed consent or limit her ability to follow the study requirements

• Patients who are human immunodeficiency virus (HIV)-positive and have a CD4 count of less than 100 mm3 or detectable viral load within past 3 months and is receiving anti-retroviral therapy

• Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) who have a detectable viral load or immunological evidence of chronic active disease or receiving/requiring antiviral therapy