Clinical Trials /

Ad/HER2/Neu Dendritic Cell Cancer Vaccine Testing

NCT01730118

Description:

Background: - HER2/neu (HER2) is a tumor protein that appears in almost a third of breast cancers and in several other types of cancers such as colon, prostate and non-small cell lung. Tumors that overexpress HER2 can be associated with a more aggressive cancer, higher recurrence rates, and reduced survival rates. Researchers are testing a therapeutic cancer vaccine designed to stimulate the immune system to recognize HER2. The vaccine, called AdHER2/neu dendritic cell vaccine, is custom-made using an individual's own immune cells. These cells will be collected and used to produce the vaccine. Objectives: - To test the safety and effectiveness of AdHER2 vaccination. Eligibility: - Individuals at least 18 years of age who have HER2-expressing tumors. Design: - Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will also be performed. - Participants will have an apheresis procedure to collect immune cells to create the vaccine. - Participants will receive five doses of the vaccine at study Weeks 0, 4, 8, 16 and 24. - Participants will be monitored with physical exams, frequent blood tests and imaging studies.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Ad/<span class="go-doc-concept go-doc-biomarker">HER2</span>/Neu Dendritic Cell Cancer Vaccine Testing

Title

  • Brief Title: Ad/HER2/Neu Dendritic Cell Cancer Vaccine Testing
  • Official Title: A Phase I Study of an Adenoviral Transduced Autologous Dendritic Cell Vaccine Expressing Human HER2/Neu ECTM in Adults With Tumors With 1-3+ HER2/Neu Expression
  • Clinical Trial IDs

    NCT ID: NCT01730118

    ORG ID: 130016

    NCI ID: 13-C-0016

    Trial Conditions

    Breast Neoplasms

    Breast Cancer

    Adenocarcinomas

    Metastatic Solid Tumors Characterized by HER2/Neu Expression

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    Background:

    - HER2/neu (HER2) is a tumor protein that appears in almost a third of breast cancers and in
    several other types of cancers such as colon, prostate and non-small cell lung. Tumors that
    overexpress HER2 can be associated with a more aggressive cancer, higher recurrence rates,
    and reduced survival rates. Researchers are testing a therapeutic cancer vaccine designed to
    stimulate the immune system to recognize HER2. The vaccine, called AdHER2/neu dendritic cell
    vaccine, is custom-made using an individual s own immune cells. These cells will be
    collected and used to produce the vaccine.

    Objectives:

    - To test the safety and effectiveness of AdHER2 vaccination.

    Eligibility:

    - Individuals at least 18 years of age who have HER2-expressing tumors.

    Design:

    - Participants will be screened with a physical exam and medical history. Blood and urine
    samples will be collected. Imaging studies will also be performed.

    - Participants will have an apheresis procedure to collect immune cells to create the
    vaccine.

    - Participants will receive four doses of the vaccine at study Weeks 0, 4, 8, and 24.

    - Participants will be monitored with physical exams, frequent blood tests and imaging
    studies....

    Detailed Description

    Background:

    - Human epidermal growth factor receptor 2 (HER2, also known as c-erbB2 or neu) is a
    proto-oncogene that encodes a 185-kd transmembrane tyrosine kinase receptor that
    participates in receptor-receptor interactions that regulate cell growth,
    differentiation and proliferation. Its over-expression contributes to neoplastic
    transformation.

    - HER2 is over-expressed in up to 25-30% of node-positive or node-negative primary breast
    cancers and is associated with clinically aggressive breast cancer, a high recurrence
    rate and reduced survival.

    - Trastuzumab (Herceptin (Registered trademark)) is a recombinant humanized mouse
    monoclonal antibody (MAb) that binds to the extracellular (EC) domain of the HER2
    receptor. Its clinical efficacy is limited to patients with 3+ HER2 tumor expression
    documented by immunohistochemistry (IHC) or a Vysis fluorescent in situ hybridization
    (FISH) ratio of greater than 2.2. IHC is a subjective measurement of HER2/neu protein
    while FISH is an objective measurement of amplification of the HER2 oncogene.

    - Although the use of trastuzumab has been associated with improved clinical outcomes, a
    significant number of patients are unresponsive to therapy and most eventually
    experience clinical progression. At present no vaccine is available that induces
    patients to make their own anti-HER2 antibodies.

    - We propose to investigate the use of an adenoviral vector (Ad5f35) expressing human
    HER2ECTM (Ad5f35HER2ECTM- AdHER2) to transduce autologous dendritic cells for
    therapeutic vaccination in patients with HER2 expressing solid tumors.

    Objectives:

    - To determine the safety and toxicity of autologous AdHER2 dendritic cell vaccination.

    --Specifically, to determine if the fraction of patients with cardiac toxicity, defined
    as a decrease in LVEF greater than or equal to 10% from baseline or a decrease in
    absolute LVEF to less than or equal to 50%, is sufficiently low to warrant further
    development in subsequent trials.

    - To determine the immunogenicity of autologous AdHER2 dendritic cell vaccination as
    measured by a 3-fold increase in anti-HER2/neu antibody concentration or a 4-fold
    increase in antibody dilution titers over baseline.

    Study Design:

    Open label, non-randomized, two part, phase I/ pilot study of 52 weeks duration for
    evaluation of primary endpoints with extended follow-up out to 30 months to monitor LVEF
    cardiac function.

    Part I involves vaccine dose escalation in a population with no prior exposure to
    trastuzumab or other HER2-targeted therapies to determine if there is a significant, adverse
    safety signal regarding cardiac toxicity, in addition to preliminary assessment of the
    vaccine s immunogenicity and clinical activity. Five doses of 5, 10 or 20 x 10(6) viable
    cells/AdHER2 DC vaccine will be given intradermally at Weeks 0, 4, 8, 16 and 24 in patients
    with metastatic solid tumors or high risk bladder cancer in the adjuvant setting
    characterized by some HER2/neu expression. Re-staging for clinical evidence of stable
    disease, partial response or better by immune-related response criteria will be assessed at
    Weeks 8, 16, 24, 36 and 48 with confirmatory scans (if indicated) at Weeks 12, 20, 28, 40
    and 52. Adjuvant bladder cancer patients will undergo re-staging for evidence of disease
    recurrence (with confirmatory scans 4 weeks later if recurrence is documented) at Weeks 8,
    16, 24, 36 and 48.

    Part II is identical to part I, but is conducted in a population with significant prior
    exposure to

    trastuzumab and other HER2-targeted therapies.

    Eligibility:

    Part I:

    - Adults greater than or equal to 18 with recurrent, metastatic solid tumors
    characterized by some HER2/neu expression but for whom trastuzumab is not clinically
    indicated:

    - Patients with ovarian, colon, non-small cell lung, renal cell, bladder and
    prostate cancer that is HER2 1+, 2+ or 3+ by IHC OR have a Vysis FISH result >
    1.8.

    - Patients with breast cancer that is HER2 1+ or 2+ by IHC or with a Vysis FISH
    result of 1.8 - < 2.2.

    - Measurable disease, with the exception of metastatic bladder cancer patients that
    have completed first line chemotherapy and may not have measurable disease.

    - Adults greater than or equal to 18 with HER2+ bladder cancer in the adjuvant setting

    - Tumor stage T3a, T3b, T4a and T4b or any node positive disease.

    - Tumors that are HER2 1+, 2+ or 3+ by IHC or have a Vysis FISH result > 1.8.

    - greater than or equal to 6 weeks status post primary surgery with curative intent.

    - ECOG 0-1.

    - Naive to trastuzumab, pertuzumab, lapatnib, ado-trastuzumab emtansine (TDM1) or
    other investigational HER2-directed therapies.

    Part II:

    - Adults greater than or equal to 18 with breast cancer with 3+ HER2/neu expression by
    IHC or a Vysis FISH result > 2.2.

    - Recurrent metastatic disease, ECOG 0-1.

    - Disease progression following 1 2 courses of therapies with known clinical benefit
    i.e. trastuzumab, pertuzumab, lapatinib, TDM1 or other investigational HER2 agents but
    NONE in the last 1 week prior to enrollment.

    - Documented response to HER2-directed therapy for metastatic disease.

    - Measurable disease.

    Trial Arms

    Name Type Description Interventions
    1 Experimental HER2+ metasatic solid tumors and bladder cancer
    2 Experimental HER2+ breast cancer

    Eligibility Criteria

    - INCLUSION PART I

    - Adults greater than or equal to 18 with recurrent or progressive, metastatic solid
    tumors characterized by some HER2/neu expression that have failed standard therapies
    with known benefit but for whom trastuzumab is not clinically indicated:

    - Patients with ovarian, colon, non-small cell lung, renal cell, bladder and prostate
    cancer that are known to be HER2 1+, 2+ or 3+ by IHC OR have a Vysis FISH result
    greater than 1.8.

    - Patients with breast cancer that is known to be HER2 1+ or 2+ by IHC or with a Vysis
    FISH result of 1.8 - less than 2.2.

    - Adults greater than or equal to 18 with HER2+ bladder cancer in the adjuvant setting
    (adjuvant bladder cancer patients):

    - Tumor stage T3a, T3b, T4a, T4b and any node positive disease regardless of tumor
    stage.

    - Tumors that are HER2 1+, 2+ or 3+ by IHC or have a Vysis FISH result greater than
    1.8.

    - Status-post primary cystectomy with curative intent.

    - May or may not have received neoadjuvant cisplatin-based combination chemotherapy per
    NCCN guidelines.

    - May or may not have received adjuvant radiotherapy or chemotherapy based on
    pathologic risk per NCCN guidelines.

    - Greater than or equal to 6 weeks s/p primary surgery with curative intent.

    2.1.1.3 Life expectancy of greater than or equal to 6 months,

    - Performance Status: ECOG 0-1.

    - Naive to trastuzumab, pertuzumab and lapatnib or other investigational HER2-directed
    therapies (e.g. T-DM1).

    - Recurrent or progressive disease on prior standard therapies with known clinical
    benefit (except adjuvant bladder cancer population).

    - For adults with recurrent, metastatic solid tumors: presence of measurable disease,
    defined as at least one lesion that can be accurately measured by CT scan in at least
    one dimension (longest diameter to be recorded for non-nodal lesions and short axis
    for nodal lesions) as greater than or equal to 20 mm with conventional techniques
    and/or measurable, clinically visible skin lesions, with the exception of metastatic
    bladder cancer patients that have completed first line chemotherapy and may not have
    measurable disease.

    - Baseline LVEF by 2D Echocardiogram greater than or equal to 55%.

    - Greater than or equal to 2 weeks since standard or investigational treatment for
    metastatic disease.

    - Stable, concurrent use of tamoxifen or aromatase inhibitors for ER+ status allowed.

    - Hematologic parameters: ANC greater than or equal to 1000 cells/mm(3), ALC greater
    than or equal to 500 cells/mm(3), Hemoglobin greater than or equal to 9.0 gm/dL, WBC
    greater than or equal to 2,500 cells/mm(3), platelet count greater than or equal to
    75,000/mm3, PT/PTT less than or equal to 1.5 times the upper limits of normal.

    - Chemistry paramters: SGOT and SGPT less than or equal to 3 times the upper limits of
    normal and total bilirubin less than or equal to 1.5 mg/dl, Alk PO4 less than or
    equal to 3 times the upper limits of normal (except for patients with documented
    metastatic diseease to bone and or liver).

    - Negative serum HCG if female and of childbearing potential.

    - Negative serology for HIV-1.

    - Negative serology for hepatitis B and C unless the result is consistent with prior
    vaccination or prior infection with full recovery.

    - Willingness of female and male subjects to use effective contraception e.g. oral
    contraceptives, barrier device, intrauterine device, or condoms, during the study and
    for three months following the last dose of study vaccine. We suggest that subjects
    do not become pregnant or father a child during the study, and for 3 months following
    receipt of the investigational AdHER2 DC vaccine. (FDA requested language)

    - Able to understand and provide Informed Consent.

    INCLUSION PART II:

    - Age greater than or equal to 18 years

    - Breast cancer patients with 3+ HER2/neu expression by IHC or a Vysis FISH result
    greater than 2.2.

    - Recurrent or progressive metastatic disease after at least 1-2 courses of standard
    therapies with known clinical benefit i.e. trastuzumab or lapatinib, ado-trastuzumab
    emtansine (TDM1) or other investigational HER2-directed therapies (e.g. MGAH22).

    - Life expectancy of greater than or equal to 6 months.

    - Performance Status: ECOG 0-1.

    - Presence of measurable disease, defined as at least one lesion that can be accurately
    measured by CT scan in at least one dimension (longest diameter to be recorded for
    non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm
    with conventional techniques and/or measurable clinical visible skin lesions.

    - Baseline LVEF by 2D Echocardiogram greater than or equal to 55%.

    - Greater than or equal to 2 weeks since receipt of standard or investigational HER2-
    directed therapy for metastatic or recurrent disease.

    - Stable, concurrent use of tamoxifen or aromatase inhibitors for ER+ status allowed.

    - Hematologic parameters: ANC greater than or equal to 1000 cells/mm(3), ALC greater
    than or equal to 500 cells/mm(3), absolute Hemoglobin greater than or equal to 9.0
    gm/dL, WBC greater than or equal to 2,500 cells/mm(3), platelet count greater than or
    equal to 75,000/mm(3), PT/PTT less than or equal to 1.5 times the upper limits of
    normal.

    - Chemistry parameters: SGOT and SGPT less than or equal to 3 times ULN, total
    bilirubin less than or equal to 1.5 times ULN and Alk PO4 less than or equal to 3
    times ULN (except for patients with documented metastatic disease to bone and or
    liver).

    - Negative serum HCG if of childbearing potential.

    - Negative serology for HIV-1.

    - Negative serology for hepatitis B and C unless the result is consistent with prior
    vaccination or prior infection with full recovery.

    - Willingness of female subjects to use effective contraception e.g. oral
    contraceptives, barrier device, intrauterine device, or condoms, during the study and
    for three months following the last dose of study vaccine. We suggest that subjects
    do not become pregnant during the study, and for 3 months following receipt of the
    investigational AdHER2 DC vaccine. (FDA requested language)

    - Able to understand and provide Informed Consent.

    EXCLUSION CRITERIA:

    - Females who are pregnant or breastfeeding.

    - Patients with active or previously treated CNS metastases or leptomeningeal
    involvement by tumor.

    - Patients with rapidly progressing disease in the opinion of the Principal
    Investigator.

    - Patients with inadequate bilateral peripheral venous or central venous catheter
    access for the required apheresis to allow generation of the autologous AdHER2 DC
    vaccine product.

    - Clinically significant cardiac dysfunction defined as a history of greater than or
    equal to NYHA Class II symptoms, angina, myocardial infarction or cardiac arrhythmias
    requiring treatment or discontinuation of chemotherapy.

    - History of changes in baseline LVEF that occurred during prior treatment with
    trastuzumab.

    - Cumulative doxorubicin dose greater than or equal to 400mg/m(2) or cumulative
    epirubicin dose greater than or equal to 800mg/m(2).

    - Use of any standard chemotherapy or other investigational agent(s) within 2 weeks of
    study enrollment.

    - Use of systemic corticosteroid therapy within 2 weeks of study enrollment, including
    patients receiving replacement corticosteroid therapy. Note: only topical, inhaled
    and intranasal steroid therapy is permitted.

    - Active systemic viral, bacterial or fungal infection requiring treatment.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Fraction of subjecs with cardiac toxicity

    Increase in anit-HER2/neu antibody concentration or increase in antibody dilution titers

    Secondary Outcome Measures

    ORR by immune related response criteria

    Trial Keywords

    Metastatic Solid Tumors

    Human Epidermal Growth Factor Receptor 2 Expression (HER2/neu)

    Trastuzumab Exposure

    Dendritic Cell Vaccine

    Breast Cancer