Fresolimumab and Radiotherapy in Metastatic Breast Cancer

Inclusion criteria

• Biopsy-proven breast cancer, metastatic (persistent or recurrent).
• Failed ≥1 line of therapy (endocrine or chemotherapy) for metastatic disease.
• Min. 3 distinct metastatic sites, at least one measurable lesion which is at least 1 cm or larger in largest diameter.
• Must be ≥4 weeks since all of the following treatments (recovered from toxicity of prior treatment to ≤Grade 1, excluding alopecia):

• major surgery;
• radiotherapy;
• chemotherapy (≥6 weeks since therapy if a nitrosourea, mitomycin, or monoclonal antibodies such as bevacizumab);
• immunotherapy;
• biotherapy/targeted therapies.
• >18 years of age.
• Life expectancy >6 months.
• Eastern Cooperative Oncology Group (ECOG) status 0 or 1.
• Adequate organ function including:

• Hemoglobin ≥10.0g/dL, absolute neutrophil count (ANC) ≥1,500/mm3, and platelets ≥100,000/mm3.
• Hepatic: Serum total bilirubin ≤1.5x upper limit of normal (ULN) (Patients with Gilbert's Disease may be included if total bilirubin is ≤3.0mg/dL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5xULN. If patient has known liver metastases, ALT and/or AST ≤5xULN are allowed.
• Renal: creatinine clearance ≥60mL/min.
• Prothrombin (PT) and partial thromboplastin times (PTT) <ULN.
• Negative for hepatitis viruses B and C unless consistent with prior vaccination or prior infection with full recovery.
• Patients of childbearing potential must agree to use effective contraception while on study, and for ≥3 months after last treatment.
• Understand and sign written informed consent document. No consent by durable power of attorney.

Exclusion criteria

• Second malignancy - unless following curative intent therapy, has been disease free for ≥2 years with probability of recurrence <5%. Curatively treated early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are allowed.
• Concurrent cancer therapy.
• Uncontrolled central nervous system (CNS) metastases, meningeal carcinomatosis, malignant seizures, or disease that causes or threatens neurologic compromise (e.g. unstable vertebral metastases).
• History of ascites or pleural effusions, unless successfully treated.
• Organ transplant, including allogeneic bone marrow transplant.
• Immunosuppressive therapy including:

• Systemic corticosteroid therapy, including replacement therapy for hypoadrenalism. Inhaled or topical corticosteroids are allowed (if therapy is <5 days and is limited to systemic steroids as antiemetics);
• Cyclosporine A, tacrolimus, or sirolimus.
• Investigational agents within 4 weeks prior to study enrollment (≥6 weeks if treatment was long-acting agent such as monoclonal antibody).
• Significant or uncontrolled medical illness, e.g. congestive heart failure (CHF), myocardial infarction, symptomatic coronary artery disease, significant ventricular arrhythmias within the last 6 months, or significant pulmonary dysfunction. Patients with remote history of asthma or active mild asthma may participate.
• Active infection, including unexplained fever (>38.5°C).
• Systemic autoimmune disease (e.g. systemic lupus erythematosus, active rheumatoid arthritis).
• Known allergy to any component of GC1008.
• Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding, or anti-coagulation therapy (including anti platelet agents i.e. aspirin, clopidogrel, ticlopidine, dipyridamole, other agents inducing long-acting platelet dysfunction). Patients with history of deep venous thrombosis are allowed if treated, completely resolved, and no treatment for >4months.
• Calcium >11.0mg/dL (2.75mmol/L) unresponsive or uncontrolled in response to standard therapy (e.g. bisphosphonates).
• Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems, including, but not limited to:

• Other serious non-malignancy-associated conditions that may be expected to limit life expectancy or significantly increase the risk of SAEs;
• Conditions, psychiatric, substance abuse, or other, that, in the opinion of the Investigator, would preclude informed consent, consistent follow-up, or compliance with any aspect of the study;
• Pregnant or nursing women.