Vaccine Therapy in Combination With Rintatolimod and/or Sargramostim in Treating Patients With Stage II-IV HER2-Positive Breast Cancer

Study Overview
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Brief Summary
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This randomized phase I/II trial studies the side effects and best dose of rintatolimod when given together with vaccine therapy and sargramostim (GM-CSF) to see how well it works in treating patients with stage II-IV human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Vaccines made from synthetic HER2/neu peptides may help the body build an effective immune response to kill tumor cells that express HER-2/neu. Adjuvant therapies, such as GM-CSF and rintatolimod, are additional cancer treatments given after the primary treatment to lower the risk that the cancer will come back and are one way to help vaccines produce stronger immune responses. Giving vaccine therapy together with rintatolimod and/or GM-CSF may be a safe and effective treatment for breast cancer.

Detailed Description
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OBJECTIVES: I. To choose the most promising (maximum biologic dose [MBD]) of five different doses (4, 20, 79, 495 and 2000 mcg) of Ampligen (rintatolimod) administered intradermally (i.d.) as an adjuvant with HER2 vaccination, with respect to toxicity and incidence and magnitude of immune response. II. To determine, using MBD of Ampligen (defined in first primary aim), whether Ampligen when given with GM-CSF as a combined adjuvant strategy with HER2 vaccination increases both the incidence and magnitude of HER2 Th1 immunity as compared to the standard GM-CSF adjuvant strategy. OUTLINE: This will be a phase I-II randomized two-stage HER2 vaccine study in breast cancer patients. STUDY STAGE I: There are five groups of patients randomized to 1 of 5 arms with each arm receiving the synthetic HER-2/neu peptide vaccine admixed with rintatolimod (different doses) given i.d. STUDY STAGE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive the synthetic HER-2/neu peptide vaccine admixed with rintatolimod given i.d. ARM II: 24 patients will receive the HER-2/neu peptide vaccine admixed with GM-CSF and the other 24 patients will receive the HER-2/neu peptide vaccine admixed with GM-CSF in addition to rintatolimod (dose set by Stage I group that had the most active response) given i.d. In both study stages, treatment repeats every month for up to 3 months in the absence of disease progression or unacceptable toxicity. After completion of last vaccine, patients are followed up at 1 and 12 months.

Official Title
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Phase I-II Study of HER2 Vaccination With Poly(I) • Poly(C12U) (Ampligen®) as an Adjuvant in Optimally Treated Breast Cancer Patients

Conditions
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Male Breast Cancer, HER2-positive Breast Cancer, Recurrent Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Biological: HER-2/neu peptide vaccine
* Biological: sargramostim
* Drug: rintatolimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with stage II, or III HER2+ breast cancer who have completed definitive standard treatment and are in complete remission - or - Patients with stage IV HER2+ breast cancer treated to: No evidence of disease, or Stable bone only disease after definitive therapy Patients must have demonstrated HER2 positive disease, by one of the following methods: Immunohistochemical (IHC) staining of 1+, 2+ or 3+ for the HER2 protein, or Amplification of the HER2 gene on fluorescence in situ hybridization (FISH) Patients must be at least 14 days post cytotoxic chemotherapy prior to enrollment Patients must be at least 14 days post systemic steroids prior to enrollment Patients on bisphosphonates or continued hormone therapy are eligible Men and women of reproductive ability must agree to contraceptive use during the entire study period Patients must have Zubrod Performance Status Score of =< 2 Patients must have recovered from major infections and/or surgical procedures, and in the opinion of the investigator, not have any significant active concurrent medical illnesses precluding protocol treatment White blood cell count (WBC) >= 3000/mm^3 Hemoglobin (Hgb) >= 10 mg/dl Serum creatinine =< 2.0 mg/dl or creatinine clearance > 60 ml/min Total bilirubin =< 1.5 mg/dl Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5 times the upper limit of normal Patients on trastuzumab monotherapy must have adequate cardiac function as demonstrated by normal ejection fractions (EF) on multi gated acquisition scan (MUGA) scan or echocardiogram performed within the last 3 months of eligibility sign off Exclusion Criteria: Restrictive cardiomyopathy Unstable angina within 6 months prior to enrollment New York Heart Association functional class III-IV heart failure Symptomatic pericardial effusion Patients with any contraindication to receiving rhuGM-CSF based products Patients with any clinically significant autoimmune disease requiring active treatment Patients receiving any concurrent immunomodulators within 30 days of eligibility sign-off Patients who are pregnant or breast-feeding Patients who are simultaneously enrolled in any other treatment study Patients who have received a previous HER2 breast cancer vaccine

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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage I, Arm 1 (HER-2/neu peptide vaccine and rintatolimod)<br>Arm 1: HER2 peptide vaccine + 4 mcg Ampligen® Five groups of randomized patients with each group receiving the synthetic HER-2/neu peptide vaccine admixed with rintatolimod (different doses). | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Drug: rintatolimod<br>* Given ID<br>* Other names: poly(I):poly(C12U) RNA;|
| Active Comparator: Stage II, Arm I (HER-2/neu peptide vaccine and sargramostim)<br>Patients receive synthetic HER-2/neu peptide vaccine admixed with GM-CSF ID. | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Biological: sargramostim<br>* Given ID<br>* Other names: Prokine;|
| Experimental: Stage II, Arm II (HER-2 vaccine, sargramostim, rintatolimod)<br>Patients receive synthetic HER-2/neu peptide vaccine admixed with GM-CSF and rintatolimod ID | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Biological: sargramostim<br>* Given ID<br>* Other names: Prokine;Drug: rintatolimod<br>* Given ID<br>* Other names: poly(I):poly(C12U) RNA;|
| Experimental: Stage I, Arm 2 (HER-2/neu peptide vaccine and rintatolimod)<br>Arm 2: HER2 peptide vaccine + 20 mcg Ampligen® Five groups of randomized patients with each group receiving the synthetic HER-2/neu peptide vaccine admixed with rintatolimod (different doses). | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Drug: rintatolimod<br>* Given ID<br>* Other names: poly(I):poly(C12U) RNA;|
| Experimental: Stage I, Arm 3 (HER-2/neu peptide vaccine and rintatolimod)<br>Arm 3: HER2 peptide vaccine + 79 mcg Ampligen® Five groups of randomized patients with each group receiving the synthetic HER-2/neu peptide vaccine admixed with rintatolimod (different doses). | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Drug: rintatolimod<br>* Given ID<br>* Other names: poly(I):poly(C12U) RNA;|
| Experimental: Stage I, Arm 4 (HER-2/neu peptide vaccine and rintatolimod)<br>Arm 4: HER2 peptide vaccine + 495 mcg Ampligen® Five groups of randomized patients with each group receiving the synthetic HER-2/neu peptide vaccine admixed with rintatolimod (different doses). | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Drug: rintatolimod<br>* Given ID<br>* Other names: poly(I):poly(C12U) RNA;|
| Experimental: Stage I; Arm 5 (HER-2/neu peptide vaccine and rintatolimod)<br>Arm 5: HER2 peptide vaccine + 2000 mcg Ampligen® Five groups of randomized patients with each group receiving the synthetic HER-2/neu peptide vaccine admixed with rintatolimod (different doses). | Biological: HER-2/neu peptide vaccine<br>* Given ID<br>* Other names: HER-2;Drug: rintatolimod<br>* Given ID<br>* Other names: poly(I):poly(C12U) RNA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of immune response among the different treatment arms in Stage I and II | Standard interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assay will be used to evaluate CD4+ 1 T cell responses to HER2 immunizing peptides. | Up to 12 months post-vaccination | 
| Evaluation of safety and systemic toxicity among the different treatment arms in Stage I and II | Toxicity grading will be evaluated per Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) 4.0 and monitoring of adverse events (AEs) will be done per Food and Drug Administration (FDA) and National Cancer Institute (NCI) guidelines. | Up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Though not statistically powered to this endpoint, large differences if observed between the vaccine treatment groups will be noted and described. | Time from study enrollment to time of first event, assessed up to 12 months post-vaccination | 
| Overall survival | Though not statistically powered to this endpoint, large differences if observed between the vaccine treatment groups will be noted and described. | Time from study enrollment to time of first event, assessed up to 12 months post-vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, HER2+, Vaccine, Stage II, Stage III, Stage IV