Ad/HER2/Neu Dendritic Cell Cancer Vaccine Testing

Phase 1

Completed

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

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

Registration Number: NCT01730118

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 33

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
2/Part I dose expansion	Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine	Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at a next lower dose or the highest dose
4/Part II dose escalation	Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine	Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at Dose Level 1
1/Part I dose escalation	Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine	Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at escalating doses
3/Part 1 dose escalation	Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine	Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at Dose Level 1
5/Part II dose expansion	Adenoviral Transduced Autologous Human Epidermal Growth Factor Receptor (AdHER)2/neu Dendritic Cell (DC) Vaccine	Adenoviral Transduced Autologous Human epidermal growth factor receptor (AdHER) dendritic cell (DC) vaccine administered at Arm 1 maximum tolerated dose (MTD)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Cardiac Toxicity	Baseline through receipt of last dose of vaccine, up to 24 weeks	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.
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	Baseline through last dose of vaccine, up to 24 weeks	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.

Secondary Outcome Measures

Name	Time	Method
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)	At 8, 16, 24, 36, 48, 76, 100, and 124 weeks after initial vaccination	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.