Patient case: 35-year-old female with Breast cancer. Genetic variant: NRAS Amplification. Other conditions: None.

Clinical trial: Ad/HER2/Neu Dendritic Cell Cancer Vaccine Testing

Summary: 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, 20 or 40 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.

Eligibility: -  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 lapatinib 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.

Relevance to patient case: not relevant