Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-risk HER2+ Breast Cancer Patients
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: NeuVax vaccine; Trastuzumab; GM-CSF
Intervention description: At the time of vaccine administration, a frozen solution of E75 acetate (1.5 mg/mL) is thawed and 1000mcg E75 peptide mixed thoroughly with 250mcg GM-CSF. This constitutes the NeuVax vaccine. Patients randomized to this arm will receive vaccinations of nelipepimut-S/GM-CSF administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series.; Herceptin will be administered to patients every three weeks as monotherapy for one year, to be given upon completion of standard of care chemotherapy/radiotherapy. The first trastuzumab infusion will be given no sooner than three weeks and no later than 12 weeks after completion of chemotherapy/radiotherapy. Trastuzumab will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk.; For patients randomized to the GM-CSF alone arm, they will receive inoculations of GM-CSF (250mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first injection will be given with the third dose of maintenance trastuzumab administered as monotherapy optimally, but may be given with later maintenance doses of trastuzumab, provided there are at least six remaining doses of trastuzumab to overlap with the primary vaccine series.
Intervention MeSH terms: Trastuzumab; Sargramostim
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 100.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast cancer, NeuVax

Summary:

      This will be a multi-center, prospective, randomized, single-blinded, placebo-controlled
      phase II trial of trastuzumab + nelipepimut-S/GM-CSF versus trastuzumab + GM-CSF alone. Our
      target study population is high-risk HER2-positive breast cancer patients. High-risk
      HER2-positive breast cancer patients are defined as:

      Those with HER2-positive breast cancer, regardless of hormone receptor status, who receive
      neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four
      cycles (12 weeks) of taxane-containing chemotherapy, and fail to achieve a pCR.

      Those with HER2-positive breast cancer, regardless of hormone receptor status, who undergo
      surgery as a first intervention and are found to have ≥ 4 positive lymph nodes.

      Those with HER2-positive, hormone receptor negative breast cancer who undergo surgery as a
      first intervention and are found to have 1-3 positive lymph nodes.

      Disease-free subjects after standard of care multi-modality therapy will be screened and
      HLA-typed.
    

Eligibility criteria:

        Inclusion criteria:

          -  18 years or older

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0,1

          -  AJCC stage I - III non-inflammatory, HER2-positive (according to ASCO-CAP guidelines
             5) breast cancer

          -  Completed neoadjuvant therapy with an approved regimen that includes trastuzumab and
             at least four cycles (12 weeks) of taxane-containing chemotherapy and underwent
             surgery with final pathology showing evidence of residual disease in the breast or
             axilla (residual ductal carcinoma in situ or microinvasive disease not eligible) or
             underwent surgery as a first intervention and was found to be pathologically
             node-positive: ≥ 4 positive lymph nodes (pN2 or pN3) regardless of hormone receptor
             status or 1-3 positive lymph nodes (pN1) if hormone receptor negative. Patients with
             micrometastases (pN1mi) are not eligible.

          -  Completed an approved regimen of neoadjuvant or adjuvant therapy with an approved
             regimen that includes trastuzumab and at least four cycles (12 weeks) of
             taxane-containing chemotherapy with plan for completion of one year of trastuzumab
             therapy.

          -  Completed appropriate surgical therapy to include:

               1. Total mastectomy and axillary staging with sentinel lymph node dissection or
                  axillary lymph node dissection (level I/II). Patients with a positive sentinel
                  lymph node must have undergone a completion axillary lymph node dissection.

               2. Breast conserving surgery (BCS) and axillary staging with sentinel lymph node
                  dissection or axillary lymph node dissection. Patients undergoing surgery as a
                  first intervention with a positive sentinel lymph node must have undergone a
                  completion axillary dissection level I/II unless they had clinically node
                  negative T1-T2 tumors and fewer than 3 involved lymph nodes. Patients receiving
                  neoadjuvant chemotherapy that have a positive sentinel lymph node must have
                  undergone a completion axillary lymph node dissection.

               3. Completed or receiving appropriate radiation therapy if indicated:

        For patients undergoing total mastectomy surgery as a first intervention, post-mastectomy
        radiation to the chest wall, infraclavicular and supraclavicular areas is required for
        patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is
        not required per protocol but is allowed at the discretion of the patient's treating
        radiation oncologist. For patients with 1-3 positive lymph nodes, post-mastectomy radiation
        to the chest wall, infraclavicular, supraclavicular, and internal mammary areas is not
        required per protocol but is allowed at the discretion of the patient's treating radiation
        oncologist.

          -  For patients undergoing breast conserving surgery (BCS) as a first intervention, whole
             breast irradiation with or without a boost, and radiation to the infraclavicular and
             supraclavicular areas is required for patients with ≥ 4 positive lymph nodes.
             Radiation to the internal mammary lymph nodes is not required but is allowed at the
             discretion of the patient's treating radiation oncologist. For patients with 1-3
             positive lymph nodes, whole breast irradiation with or without a boost is required.
             Radiation to the infraclavicular, supraclavicular, and internal mammary areas is not
             required per protocol but is allowed at the discretion of the patient's treating
             medical oncologist.

          -  For patient's undergoing mastectomy after neoadjuvant chemotherapy post-mastectomy
             radiation to the chest wall, infraclavicular and supraclavicular areas is required for
             patients presenting with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes
             identified pathologically at the time of surgery. Radiation to the internal mammary
             lymph nodes is not required per protocol but is allowed at the discretion of the
             patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes
             identified pathologically, post-mastectomy radiation to the chest wall,
             infraclavicular, supraclavicular and internal mammary areas is not required per
             protocol but is allowed at the discretion of the patient's treating radiation
             oncologist.

          -  For patient's undergoing BCS after neoadjuvant chemotherapy, whole breast irradiation
             with or without a boost is required. For patients with clinical N2 or N3 disease or
             with ≥ 4 positive lymph nodes identified pathologically at the time of surgery,
             radiation to the infraclavicular and supraclavicular areas is required. Radiation to
             the internal mammary lymph nodes is not required per protocol but is allowed at the
             discretion of the patient's treating radiation oncologist. For patients with 0-3
             positive lymph nodes identified pathologically, radiation to the infraclavicular,
             supraclavicular and internal mammary areas is not required per protocol but is allowed
             at the discretion of the patient's treating radiation oncologist.

               -  HLA-A2+ or HLA-A3+ or HLA-A24+ or HLA-A26+

               -  LVEF >50%, or an LVEF within the normal limits of the institution's specific
                  testing (MUGA or ECHO)

               -  Adequate organ function as determined by the following laboratory values:

                    1. ANC ≥ 1,000/μL

                    2. Platelets ≥ 75,000/μL

                    3. Hgb ≥ 9 g/dL

                    4. Creatinine ≤ 1.5 x upper limit of normal (ULN) of institution's range or
                       Creatinine clearance ≥ 50%

                    5. Total bilirubin ≤ 1.5 ULN of institution's range

                    6. ALT and AST ≤ 1.5 ULN of institution's range

                    7. For women of child-bearing potential, agreement to use adequate birth
                       control (abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal
                       ligation, oral contraception, IUD, or use of condoms or diaphragms)

               -  Signed informed consent

        Exclusion criteria:

          -  AJCC Stage IV breast cancer

          -  NYHA stage 3 or 4 congestive heart failure

          -  Immune deficiency disease or known history of HIV, HBV, HCV

          -  Receiving immunosuppressive therapy including chronic steroids, methotrexate, or other
             known immunosuppressive agents

          -  Pregnancy (assessed by urine HCG)

          -  Breast feeding

          -  Any active autoimmune disease requiring treatment, with the exception of vitiligo

          -  Active pulmonary disease requiring medication to include multiple inhalers (>3
             inhalers including one containing steroids)

          -  Involved in other experimental protocols except with permission of other PI