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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: PF03512676
* Other: Correlative Studies


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: Treatment (PF03512676 in combination with Trastuzumab)<br>12 weekly treatments. Week 1-12 patients will receive Trastuzumab 2mg/kg IV(intervenous infusion). Patients who have not been treated wih Trastuzumab within 4 weeks will receive a loading dose of 4 mg/kg on week 1 and PF-03512676-0.16 mg/kg subcutaneous injection.Correlative studies will be drawn on week 1, 2, 6, 12 and 18. | Drug: Trastuzumab<br>* IV at 2 mg/kg over 30 minutes on day 1 of each weekly cycle. Patients who have not received trastuzumab for 4 weeks or more will receive a loading dose of 4 mg/kg over 90 minutes day 1 of the first cycle. The dose of trastuzumab will be based on the patient's actual weight at the start of each 4 week treatment cycle.<br>* Other names: Herceptin;Drug: PF03512676<br>* Patients also receive PF03512676 subcutaneously on days 15 and 22 of course 1 and on days 1, 8, 15, and 22 of all subsequent courses.<br>* Other names: agatolimod sodium;Other: Correlative Studies<br>* Blood for performing the correlative studies will be drawn on week 1, 2, 6, 12 and 18.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PF-03512676 Augments Antibody Mediated Cytoxicity (ADCC)Against Trastuzumab-coated Target Cells in Metastatic HER2 Overexpressing Breast Cancer. |  | up to 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival for Patients With Metastatic Breast Cancer That Are Receiving Trastuzumab Plus PF-03512676 | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | up to 18 weeks | 
| Combination of PF-03512676 and Trastuzumab Induces MIP-1 (Macrophage Inflammatory Protein 1), MCP-1 (Monocyte Chemoattract Protein 1) and RANTES. |  | up to 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage IV breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, HER2-positive breast cancer, male breast cancer