Ad/HER2/Neu Dendritic Cell Cancer Vaccine Testing

Study Overview
=================
Brief Summary
-----------------
Background: - Human epidermal growth factor receptor 2 (HER2, also known as c-erbB2 or neu)/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 adenoviral transduced autologous human epidermal growth factor receptor (AdHER)/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.

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 cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a decrease in left ventricular ejection fraction (LVEF) >=10 percentage points, to a value LVEF to less than or equal to 53% (normal reference value for two-dimensional (2-D) echocardiography), 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 study of 48 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 Response will be evaluated by a Modified Immune- Related Response Criteria (irRC) based on Response Evaluation Criteria in Solid Tumors (Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (modified irRC) at Weeks 8, 16, 24, 36 and 48 with confirmatory scans obtained not less than 4 weeks following initial documentation of objective response. Adjuvant bladder cancer patients will undergo re-staging at Weeks 8, 16, 24, 36 and 48 with confirmatory scans obtained not less than 4 weeks following initial documentation of objective response. Part II is identical to part I, in the schedule of treatment and response evaluation, but is conducted in a population with prior exposure to trastuzumab and other HER2-targeted therapies. Eligibility: Part I: Adults >= 18 with recurrent, metastatic solid tumors for whom trastuzumab is not clinically indicated in standard of care OR who are naive to HER2 targeted therapies: Patients with ovarian, cervical, colon, non-small cell lung, renal cell, bladder and prostate cancer, and malignant soft tissue and bone tumor or other solid tumors that is HER2 1+, 2+ or 3+ by IHC OR have a Vysis FISH result greater than or equal to 1.8. Patients with breast cancer that is HER2 1+ or 2+ by IHC or with a Vysis FISH result less than or equal to 1.8 - less than or equal to 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 greater than or equal to 1.8. greater than or equal to 6 weeks status post primary surgery with curative intent. Eastern Cooperative Oncology Group (ECOG) 0-1. Naive to trastuzumab, pertuzumab, lapatinib, ado-trastuzumab emtansine (TDM1) or other HER2-directed therapies. Part II: Adults >= 18 with breast, gastric or gastroesophageal junction or other cancers with 1+ to 3+ HER2/neu expression by IHC or a Vysis FISH result > 2.2. Recurrent metastatic disease, ECOG 0-1. Disease progression following HER2-targeted therapies. i.e., trastuzumab, pertuzumab, lapatinib, ado-trastuzumab emtansine or other HER2 agents. Measurable disease.

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

Conditions
-----------------
Breast Neoplasms, Breast Cancer, Adenocarcinomas, Metastatic Solid Tumors Characterized by HER2/Neu Expression

Intervention / Treatment
-----------------
* Biological: Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
ELIGIBILITY CRITERIA: Common Eligibility for Parts I and II Adults greater than or equal to 18 with malignant soft tissue and bone tumors and recurrent or progressive, metastatic solid tumors who have progressed on standard therapies except in adjuvant for high risk bladder cancer in Part I. Recurrent or progressive disease on prior standard therapies with known clinical benefit with the exception of adjuvant bladder cancer population. Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1. Baseline left ventricular ejection fraction (LVEF) by two-dimensional (2D) Echocardiogram greater than or equal to 53%. Greater than or equal to 1 week since standard or investigational treatment for metastatic disease. Stable, concurrent use of hormone therapy for hormone receptor positive breast cancer is permitted. Hematologic parameters: absolute neutrophil count (ANC) greater than or equal to 1000 cells/mm^3, absolute lymphocyte count (ALC) greater than or equal to 300 cells/mm^3, Hemoglobin greater than or equal to 9.0 gm/dL, white blood cell (WBC) greater than or equal to 2,500 cells/mm^3, platelet count greater than or equal to 75,000/mm^3, prothrombin time (PT)/partial thromboplastin time (PTT) less than or equal to 1.5X the upper limits of normal. Chemistry parameters: Creatinine less than or equal to 1.5 mg/dL, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) less than or equal to 3X the upper limits of normal and total bilirubin less than or equal to 1.5 mg/dl, Alkaline phosphatase (Alk PO4) less than or equal to 3X the upper limits of normal (except for patients with documented metastatic disease to bone and/or liver). Negative serum beta human chorionic gonadotropin (HCG) if female and of childbearing potential. Negative human immunodeficiency virus (HIV) 1/2 serology and sample drawn for human T-cell lymphotropic virus (HTLV). Patients with HIV are excluded from participating on this clinical trial because their immunodeficiency would confound the evaluation of adverse events which would hinder meeting the primary objective. 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 adenoviral transduced autologous human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine. Able to understand and provide Informed Consent. Patients with 1+ to 3+ human epidermal growth factor receptor 2 (HER2)/neu expression by immunohistochemistry (IHC) or an equivocal or positive fluorescence in situ hybridization (FISH) result by 2013 American Society of Clinical Oncology (ASCO)/Corrective Action Plan (CAP) guideline. Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Part I Eligibility Naive to trastuzumab (Herceptin), pertuzumab (Perjeta) and lapatinib (Tykerb), ado-trastuzumab emtansine (Kadcyla) or other HER2-directed therapies. Malignancy as follows: Malignant soft tissue and bone tumors and recurrent or progressive, metastatic solid tumors who have progressed on standard therapies; or, 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. Status-post primary cystectomy with curative intent. May or may not have received neoadjuvant cisplatin-based combination chemotherapy per National Comprehensive Cancer Network (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. NOTE: Patients with breast, ovarian, cervical, colon, gastric/gastroesophageal junction, non-small cell lung, renal cell, bladder, malignant soft tissue and bone tumor, prostate cancer or other solid tumors. Part II Eligibility Malignant soft tissue and bone tumors and recurrent or progressive, metastatic solid tumors who have progressed on standard therapies. Recurrent or progressive metastatic disease after standard of care HER2-targeted therapies, i.e., trastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), ado-trastuzumab emtansine (TDM1) (Kadcyla) or other HER2-directed therapies. Stable, concurrent use of tamoxifen or aromatase inhibitors for hormone receptor positive breast cancer is permitted. EXCLUSION CRITERIA: Pregnant women are excluded from this study because Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AdHER DC vaccine, breastfeeding should be discontinued if the mother is treated with AdHER DC vaccine. Patients with active central nervous system (CNS) metastases or leptomeningeal involvement by tumor (patients with a history of brain metastases who have successfully treated for brain metastasis by surgery or radiation and who have not had any evidence of the new or progressive CNS disease for more than 12 months are eligible). 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 > New York Heart Association (NYHA) Class II symptoms, angina, congestive heart failure, myocardial infarction, arrhythmias or cardiac dysfunction requiring treatment or discontinuation of chemotherapy. History of changes in baseline LVEF that occurred during prior treatment with anti-HER2 treatment. Cumulative doxorubicin dose > 400mg/m^2 (>450 mg/m^2 for malignant soft tissue and bone tumor patients) or cumulative epirubicin dose > 800mg/m^2. Use of any standard chemotherapy or other investigational agent(s) within 1 week 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. A medical history which the treating physician believes causes the patient to be excluded. This includes a remote history of cancer. Please note: Squamous cell carcinoma, basal cell carcinoma and remote history of cancer with no evidence of recurrence for the past 5 years are eligible.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Part I dose escalation<br>Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at escalating doses | Biological: Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine<br>* autologous AdHER2 transduced dendritic cell vaccine manufactured under Good Manufacturing Practices (GMP) conditions from cryopreserved patient monocytes here at the National Institutes of Health (NIH) Clinical Center (CC) Department of Transfusion Medicine (DTM). Vaccine is administered intradermally at assigned dose level at weeks 0, 4, 8, 16 and 24 of the study.<br>|
| Experimental: 2/Part I dose expansion<br>Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at a next lower dose or the highest dose | Biological: Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine<br>* autologous AdHER2 transduced dendritic cell vaccine manufactured under Good Manufacturing Practices (GMP) conditions from cryopreserved patient monocytes here at the National Institutes of Health (NIH) Clinical Center (CC) Department of Transfusion Medicine (DTM). Vaccine is administered intradermally at assigned dose level at weeks 0, 4, 8, 16 and 24 of the study.<br>|
| Experimental: 3/Part 1 dose escalation<br>Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at Dose Level 1 | Biological: Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine<br>* autologous AdHER2 transduced dendritic cell vaccine manufactured under Good Manufacturing Practices (GMP) conditions from cryopreserved patient monocytes here at the National Institutes of Health (NIH) Clinical Center (CC) Department of Transfusion Medicine (DTM). Vaccine is administered intradermally at assigned dose level at weeks 0, 4, 8, 16 and 24 of the study.<br>|
| Experimental: 4/Part II dose escalation<br>Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at Dose Level 1 | Biological: Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine<br>* autologous AdHER2 transduced dendritic cell vaccine manufactured under Good Manufacturing Practices (GMP) conditions from cryopreserved patient monocytes here at the National Institutes of Health (NIH) Clinical Center (CC) Department of Transfusion Medicine (DTM). Vaccine is administered intradermally at assigned dose level at weeks 0, 4, 8, 16 and 24 of the study.<br>|
| Experimental: 5/Part II dose expansion<br>Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at Arm 1 maximum tolerated dose (MTD) | Biological: Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine<br>* autologous AdHER2 transduced dendritic cell vaccine manufactured under Good Manufacturing Practices (GMP) conditions from cryopreserved patient monocytes here at the National Institutes of Health (NIH) Clinical Center (CC) Department of Transfusion Medicine (DTM). Vaccine is administered intradermally at assigned dose level at weeks 0, 4, 8, 16 and 24 of the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Cardiac Toxicity | Cardiac toxicity defined as cardiac dysfunction due to damage to the heart muscles or valves. Cardiac toxicity was assessed by serial echocardiography to determine left ventricular ejection fraction (LVEF) at baseline and following receipt of the last dose of vaccine. Cardiac toxicity is at least a 10% decline from the baseline in cardiac function. Normal LVEF is >-53%. Below 53% is a cardiac dysfunction. | Baseline through receipt of last dose of vaccine, up to 24 weeks | 
| Number of Participants Who Develop at Least a 4-fold or 2.5- Fold Increase in Anti-Human Epidermal Growth Factor Receptor (HER2)/Neu Antibody Dilution Titers | Vaccine immunogenicity was determined by the number of participants who develop at least a 4-fold increase in antibody dilution titers over baseline at the time points measured. The antibody response following the vaccination was assessed using peptide-array and reported as fold increase compared to the baseline values using the cut-off of 4 fold per study definition of the vaccine immunogenicity and also of 2.5 fold to aid the interpretation of the result. | Baseline through last dose of vaccine, up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Tumor Shrinkage or Stabilization That is Sufficient by Modified Immune Response Related Criteria (irRC) to be Considered Stable Disease (SD), a Partial Response (PR) or Better (Complete Response (CR) | Number of participants who experienced tumor shrinkage or stabilization that is sufficient by modified immune response related criteria (irRC) to be considered stable disease (SD), a partial response (PR) or better (complete response (CR). SD is neither partial response nor progressive disease (PD). PR is ≥ 30% decrease in tumor burden compared with baseline, confirmation required. CR is disappearance of all target and non-target lesions. Lymph nodes must regress to <10mm short axis. No new lesions, confirmation required. PD ≥ 20% increase in tumor burden compared with baseline, with nadir, or reset baseline. New lesions added to the tumor burden, confirmation required. | At 8, 16, 24, 36, 48, 76, 100, and 124 weeks after initial vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic Solid Tumors, Human Epidermal Growth Factor Receptor 2 Expression (HER2/neu), Trastuzumab Exposure, Dendritic Cell Vaccine, Breast Cancer