Fresolimumab and Radiotherapy in Metastatic Breast Cancer

The purpose of this study is to test safety of combining fresolimumab and local radiotherapy and to see if the combination can achieve tumor regression.

• Drug: fresolimumab (GC1008)
  Fresolimumab is administered intravenously (i.v.) at a dose of 1mg/kg on day 1 of weeks 0, 3, 6, 9 & 12 and radiation administered at 7.5 Gy/fraction in 3 fractions during weeks 1 (to lesion 1) and 7 to lesion 2).
• Drug: fresolimumab (GC1008)
  Fresolimumab is administered i.v. at a dose of 10mg/kg on day 1 of weeks 0, 3, 6, 9 & 12 and radiation administered at 7.5 Gy/fraction in 3 fractions during weeks 1 (to lesion 1) and 7 to lesion 2).
• Radiation: Radiation Therapy
  7.5 Gy/Fraction for 3 days week 1 and 7.5 Gy/Fraction for 3 days week 7

• Experimental: Arm 1
  1 mg/kg
  Interventions:

  • Drug: fresolimumab (GC1008)
  • Radiation: Radiation Therapy
• Experimental: Arm 2
  10 mg/kg
  Interventions:

  • Drug: fresolimumab (GC1008)
  • Radiation: Radiation Therapy

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.