Agatolimod and Trastuzumab in Treating Patients With Locally Advanced or Metastatic Breast Cancer

A Phase II Open-label Study of Subcutaneous CPG ODN (PF03512676) in Combination With Trastuzumab in Patients With Metastatic Breast Cancer

RATIONALE: Biological therapies, such as agatolimod, may stimulate the immune system in different ways and stop tumor cells from growing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving agatolimod together with trastuzumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving agatolimod together with trastuzumab works in treating patients with locally advanced or metastatic breast cancer.

OBJECTIVES:

Primary

• To evaluate the progression-free survival of patients with HER2-overexpressing locally advanced or metastatic breast cancer treated with trastuzumab (Herceptin®) and agatolimod sodium.

Secondary

• To determine if agatolimod sodium augments antibody-mediated cytoxicity (ADCC) against trastuzumab-coated target cells by evaluating the ability of patient immune-effector cells to conduct ADCC and produce interferon gamma.

OUTLINE: This is a multicenter study.

Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes on day 1. Patients also receive agatolimod sodium subcutaneously on days 15 and 22 of course 1 and on days 1, 8, 15, and 22 of all subsequent courses. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for correlative laboratory studies. Samples are analyzed for antibody-mediated cytotoxicity (ADCC) by chromium-release assay; IFN-γ production and quantification by flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR); and levels of cytokines (IFN-γ and TNF-α) by ELISA.

After completion of study therapy, patients are followed periodically.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

  • Locally advanced or metastatic disease

• HER2-overexpressing tumor, defined as 3+ overexpression by IHC and/or HER2 amplified by FISH

• Non-measurable disease allowed

• Achieved partial response, complete response, or stable disease (i.e., no disease progression for ≥ 12 weeks) while on trastuzumab (Herceptin®) and chemotherapy, hormonal therapy alone, or trastuzumab alone

  • Last dose of trastuzumab must have been administered within the past 16 weeks

• No unstable brain metastases

  • Patients with brain metastases are eligible provided they have been stable for ≥ 1 month after surgery or radiotherapy/radiosurgery AND off corticosteroids and anticonvulsants for ≥ 4 weeks

• Hormone receptor status unspecified

PATIENT CHARACTERISTICS:

• ECOG(Eastern Cooperative Oncology Group)performance status (PS) 0-2 (Karnofsky PS 70-100%)
• Absolute neutrophil count ≥ 1,500/mm³
• Hemoglobin > 8 g/dL (transfusion/epoetin alfa allowed)
• Platelet count ≥ 100,000/mm³
• Total bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN if known liver metastases)
• Creatinine < 2 mg/mL
• Ejection fraction ≥ 50% by echocardiogram or MUGA
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception before, during, and for ≥ 3 months after completion of study treatment
• No ongoing or active infection requiring oral or IV antibiotics
• No known autoimmune disorders or antibody-mediated disorders
• No known HIV positivity
• No known history of hepatitis B or C (active and/or previously treated)
• No other malignancies within the past 5 years except nonmelanoma skin cancer or cervical cancer in situ
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 12 weeks since prior chloroquine
• More than 4 weeks since prior growth factors
• More than 4 weeks since prior systemic corticosteroids
• More than 4 weeks since prior chemotherapy, radiotherapy, or monoclonal antibody therapy (except trastuzumab)
• No prior agatolimod sodium
• No prior allogeneic stem cell transplantation
• No prior continuous treatment with single-agent trastuzumab for > 6 months
• No more than 3 prior chemotherapy regimens for metastatic breast cancer
• Any number of prior hormonal therapies allowed
• No other concurrent investigational agents or monoclonal antibodies
• No other concurrent anticancer agents or therapies
• Concurrent bisphosphonates for skeletal metastasis allowed