Clinical Trials /

Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-risk HER2+ Breast Cancer Patients

NCT02297698

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Phase II Trial of Combination <span class="go-doc-concept go-doc-intervention">Immunotherapy</span> With NeuVax and <span class="go-doc-concept go-doc-intervention">Trastuzumab</span> in High-risk <span class="go-doc-concept go-doc-biomarker">HER2</span>+ <span class="go-doc-concept go-doc-disease">Breast Cancer</span> Patients

Title

  • Brief Title: Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-risk HER2+ Breast Cancer Patients
  • Official Title: Phase II Trial of Combination Immunotherapy With Nelipepimut-S + GM-CSF (NeuVax) and Trastuzumab in High-risk HER2+ Breast Cancer Patients
  • Clinical Trial IDs

    NCT ID: NCT02297698

    ORG ID: 2014-0443

    Trial Conditions

    Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Trastuzumab Herceptin Trastuzumab + NeuVax, Trastuzumab + GM-CSF
    GM-CSF Leukine, Sargramostim Trastuzumab + GM-CSF

    Trial Purpose

    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.

    Detailed Description

    In this study, the investigators intend to assess the ability of the combination of
    trastuzumab and the HER2 vaccine nelipepimut-S (administered with the immunoadjuvant GM-CSF)
    given in the adjuvant setting to prevent recurrences in patients with high-risk
    HER2-positive breast cancer. High-risk is defined as those patients that do not achieve a
    pCR after neoadjuvant therapy with an approved regimen that includes trastuzumab and at
    least four cycles (12 weeks) of taxane-containing chemotherapy or those who undergo upfront
    surgery and are found to have greater than or equal to four positive lymph nodes regardless
    of hormone receptor status or 1-3 positive lymph nodes and are hormone receptor negative.

    Following surgery, patients will be screened and HLA-typed (consent #1). Nelipepimut-S is a
    CD8-eliciting peptide vaccine that is restricted to HLA-2+ or HLA-A3+ patients
    (approximately two-thirds of the US population). HLA-A2+ and/or A3+ patients who meet all
    other eligibility criteria will be randomized to receive trastuzumab + nelipepimut-S/GM-CSF
    or trastuzumab + GM-CSF alone (consent #2). The trastuzumab will be administered to all
    patients consistent with current standard of care. Patients randomized to the
    nelipepimut-S/GM-CSF arm will receive vaccinations of nelipepimut-S (1000 mcg) and GM-CSF
    (250 mcg) 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. Patients randomized
    to the GM-CSF alone arm will receive inoculations of GM-CSF (250 mcg) administered in an
    identical manner to those receiving nelipepimut-S/GM-CSF. Patients will be blinded as to
    whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone.

    Upon completion of the primary vaccination/inoculation series, booster inoculations (same
    dose and route) will be administered every six months x 4. The first booster inoculation
    will occur 12 months 2 weeks after the initiation of trastuzumab maintenance therapy, with
    subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the
    following timepoints after initiation of trastuzumab maintenance therapy: 12 months 2
    weeks, 18 months 2 weeks, 24 months 2 weeks and 30 months 2 weeks. Booster
    inoculations will occur for patients randomized to receive nelipepimut-S/GM-CSF as well as
    patients randomized to receive GM-CSF alone, and will consist of the same treatment drugs
    and dosing (i.e. nelipepimut-S/GM-CSF patients will be boosted with nelipepimut-S/GM-CSF
    while GM-CSF alone patients will be boosted with GM-CSF alone). Patient blinding will be
    maintained throughout the study.

    Subjects will be followed for safety issues, immunologic response and clinical recurrence.
    Patients will be monitored 48-72 hours after each inoculation for reaction to the
    inoculation as well as documentation of any adverse effects experienced. Immunologic
    response will be monitored primarily by in vivo delayed type hypersensitivity (DTH)
    reactions but also may be documented by other immunologic assays. All patients will be
    followed for a total of 36 months from the time of initiation of trastuzumab maintenance
    therapy to document disease-free status.

    Trial Arms

    Name Type Description Interventions
    Trastuzumab + NeuVax Experimental Patients randomized to this arm will receive vaccinations of nelipepimut-S (1000 g) and GM-CSF (250 g) 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. Upon completion of the primary vaccination series (PVS), booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 12 months 2 weeks after the initiation of trastuzumab maintenance therapy, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following timepoints after initiation of trastuzumab maintenance therapy: 12 months 2 weeks, 18 months 2 weeks, 24 months 2 weeks and 30 months 2 weeks. Trastuzumab
    Trastuzumab + GM-CSF Active Comparator Patients randomized to this arm will receive inoculations of GM-CSF (250 g) administered in an identical manner to those receiving nelipepimut-S/GM-CSF (NeuVax). Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone. Upon completion of the primary vaccination series (PVS), booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 12 months 2 weeks after the initiation of trastuzumab maintenance therapy, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following timepoints after initiation of trastuzumab maintenance therapy: 12 months 2 weeks, 18 months 2 weeks, 24 months 2 weeks and 30 months 2 weeks. Trastuzumab, GM-CSF

    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 and/or HLA-A3 positive

    - 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/L

    2. Platelets 75,000/L

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Invasive Disease-free survival (DFS)

    Secondary Outcome Measures

    Distant recurrence-free survival (DRFS)

    Local and systemic toxicities

    Evaluate in vivo and in vitro immune responses

    Trial Keywords

    Breast cancer, NeuVax