Ensayos clínicos

Pre-Registration Inclusion Criteria for All Patients (include Safety Lead-In) :

• Female age ≥ 18 years.
• Histologically confirmed adenocarcinoma of the breast stage ≥ T2 OR ≥ N1 based on the 7th edition of TNM staging system from the American Joint Committee on Cancer.
• Any ER or PR but HER2 positive defined as 3+ staining intensity (on a scale of 0 to 3) by means of IHC analysis OR gene amplification on fluorescence in situ hybridization (FISH) ratio ≥ 2.0.
• Patients must have adequate pretreatment biopsy sample available.
  • NOTE: Adequate tissue samples defined as core needle biopsy or incisional biopsy or excisional samples that can provide ≥ 3 core needle biopsies with at least 14G needle with 12 unstained sections of 5 micron thickness. Fine needle aspiration (FNA) sample alone is not sufficient.
  • NOTE: Patients without adequate pretreatment biopsy samples must be agreeable to have an additional research biopsy prior to neoadjuvant therapy.
• ECOG Performance Status (PS) 0, 1, 2.
• Willing to employ adequate contraception from the time of pre-registration through 6 months after the final vaccine cycle.
• Willing to receive a tetanus vaccination if subject has not had one <1 year prior to pre-registration.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to provide mandatory tissue and blood samples for correlative research purposes.
• Negative pregnancy test done ≤ 7 days prior to pre-registration, for persons of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Pre-Registration – Exclusion Criteria for all patients (include Safety Lead-In):

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant person;
  • Nursing person unwilling to stop breast feeding;
  • Person of child bearing potential who are unwilling to employ adequate contraception from the time of registration through 6 months after the final vaccine cycle.
• Clinical evidence of local recurrence or distant metastases.
  • NOTE: All patients must have either a PET/CT or CT chest, abdomen, and pelvis with bone scan to rule out distant metastases ≤ 90 days prior to pre-registration. If any of these is concerning, follow-up imaging or biopsy should be performed if indicated rule out distant metastases.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients including patients known to be HIV positive or those on chronic steroids.
  • NOTE: Must be off systemic steroids at least 14 days prior to pre-registration; however, topical steroids, inhalants or steroid eye drops are permitted.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Uncontrolled acute or chronic medical conditions including, but not limited to the following:
  • Active infection requiring antibiotics;
  • Congestive heart failure with New York Heart Association class III or IV; moderate to severe objective evidence of cardiovascular disease;
  • Myocardial infarction or stroke < 6 months prior to pre-registration;
  • Significant cardiac arrhythmia or unstable angina.
• Receiving any other investigational agent.
• Other active malignancy at time of pre-registration or < 3 years prior to pre-registration.
  • EXCEPTIONS: Non-melanoma skin cancer or carcinoma-in-situ (e.g., of cervix, prostate).
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (cytotoxics, monoclonal antibodies, small molecule inhibitors) for their cancer.
• Known history of autoimmune disease, including Type I diabetes.
• Any prior hypersensitivity or adverse reaction to GM-CSF.
• History of trastuzumab-related cardiac toxicity requiring interruption or discontinuation of therapy, even if LVEF fully recovered.
• Baseline LVEF <50%.
• Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment.
• History of myocardial infarction ≤ 168 days (6 months) prior to pre-registration, or congestive heart failure requiring use of ongoing maintenance therapy for life threatening ventricular arrhythmias.
• Patients who received tamoxifen or raloxifene or another agent for prevention of breast cancer ≤ 2 months prior to pre- registration.

Registration – Inclusion Criteria (Safety Lead-In):

• The following laboratory values obtained ≤ 28 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 75,000/mm^3;
  • Hemoglobin ≥ 9.0 g/dL;
  • Direct bilirubin < 1.5 x upper limit of normal (ULN);
  • Aspartate transaminase (AST) ≤ 3 x ULN;
  • Creatinine ≤ 2 X ULN;
  • • PT/INR/PTT ≤ 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulant.
• Completed planned curative breast surgeries (not including any future breast reconstructive surgery) and any radiation therapy ≥ 30 days prior toregistration.
• Completed last cycle of chemotherapy ≥ 90 days prior toregistration.
  • NOTE: Prior to randomization, patients must not receive ≥ 6 cycles of T-DM1 maintenance therapy after surgery.
• Have residual disease with ≥ 1 cm residual tumor in the breast (≥ ypT1c) and/or persistent lymph node positivity after trastuzumab ± pertuzumab based neoadjuvant chemotherapy.
• Adequate tissue specimens from both pre-treatment biopsy and surgery must be submitted. Adequate tissue samples defined as core needle biopsy or incisional biopsy or excisional samples that can provide ≥ 3 core needle biopsies with at least 14G needle with 12 unstained sections of 5 micron thickness.
  • NOTE: Fine needle aspiration (FNA) sample alone is not sufficient.
• Negative pregnancy test done ≤7 days prior toregistration, for persons of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• ECOG Performance Status (PS) 0, 1, 2.
• Willing to employ adequate contraception from the time of registration through 6 months after the final vaccine cycle.

Registration – Exclusion Criteria (Safety Lead In):

• *No exclusion criteria for registration.

Registration – Inclusion Criteria for Patients with No Residual Disease (pCR)- (PHASE II):

• ECOG Performance Status (PS) 0, 1, 2.
• The following laboratory values obtained ≤ 28 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 75,000/mm^3;
  • Hemoglobin ≥ 9.0 g/dL;
  • Direct bilirubin < 1.5 x upper limit of normal (ULN);
  • Aspartate transaminase (AST) ≤ 3 x ULN;
  • Calculated serum creatinine clearance of ≥ 50 mL/min.
  • PT/INR/PTT ≤ 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulants.
• Negative pregnancy test done ≤ 7 days prior to registration, for person of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Registration – Exclusion Criteria for Patients with no residual disease (pCR)- (PHASE II)

• *No exclusion criteria for registration.

Randomization – Inclusion Criteria for Patients with Residual Disease Post Neoadjuvant Tratuzumab ± Pertuzumab-based Chemotherapy (no PCR)- (PHASE II):

• The following laboratory values obtained ≤ 28 days prior to randomization.
  • Absolute neutrophil count (ANC) ≥ 1500/mm3;
  • Platelet count ≥ 75,000/mm3;
  • Hemoglobin ≥ 9.0 g/dL;
  • Direct bilirubin < 1.5 x upper limit of normal (ULN);
  • Aspartate transaminase (AST) ≤ 3 x ULN;
  • Creatinine ≤ 2 X ULN;
  • PT/INR/PTT ≤ 1.5 X ULN OR if patient is receiving anticoagulant therapy and PT or PTT is within therapeutic range of intended use of coagulant.
• Completed planned curative breast surgeries (not including any future breast reconstructive surgery) and any radiation therapy ≥ 30 days prior to randomization.
• Completed last cycle of chemotherapy ≥ 90 days prior to randomization.
  • NOTE: Prior to randomization, patients must not receive ≥ 6 cycles of T-DM1 maintenance therapy after surgery.
• Have residual disease with ≥ 1 cm residual tumor in the breast (≥ ypT1c) and/or persistent lymph node positivity after trastuzumab ± pertuzumab based neoadjuvant chemotherapy.

* Part of the Active Monitoring Phase of a study. Participants will be required to return to the consenting site for follow-up. Booster vaccinations will occur at 3 and 12 months post completion of the 6 cycles of vaccinations and maintainence TDM-1.