Ad/HER2/Neu Dendritic Cell Cancer Vaccine Testing

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 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

(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.

- ECOG 0-1.

- Naive to trastuzumab, pertuzumab, lapatnib, 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 emtamsine or other
HER2 agents.

- Measurable disease.

- INCLUSION CRITERIA for PART I

- 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 with known benefit but for whom anti-HER2 therapy is not clinically
indicated:

- Patients with 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 that is known to be 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 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.

- Performance Status: ECOG 0-1.

- Naive to trastuzumab (Herceptin(TM)), pertuzumab (Perjeta(TM)) and lapatinib
(Tykerb(TM)), ado-trastuzumab emtansine (Kadcyla(TM)) or other HER2-directed
therapies.

- Recurrent or progressive disease on prior standard therapies with known clinical
benefit with the exception of adjuvant bladder cancer population.

- Patients must have measurable disease, per RECIST 1.1 for the evaluation of measurable
disease.

- Baseline LVEF by 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 tamoxifen or aromatase inhibitors for hormone receptor
positive breast cancer.

- Hematologic parameters: ANC >= 1000 cells/mm^3, ALC >= 300 cells/mm^3, Hemoglobin >=
9.0 gm/dL, WBC >= 2,500 cells/mm^3, platelet count >= 75,000/mm^3, PT/PTT less than or
equla to1.5X the upper limits of normal.

- Chemistry parameters: Creatinine less than 1.5 mg/dL, SGOT and SGPT less than or equal
to 3X the upper limits of normal and total bilirubin less than or equal to 1.5 mg/dl,
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 HCG if female and of childbearing potential.

- Negative serology for anti-HIV-1/2 and anti-HTLV 1/2.

- 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 CRITERIA for PART II:

- Age greater than or equal to 18 years

- Patients with breast cancer, gastric, gastroesophageal junction or other cancers with
1+ to 3+ HER2/neu expression by IHC or a Vysis FISH result > 2.2.

- Recurrent or progressive metastatic disease after standard of care HER2-targeted
therapies i.e. trastuzumab (Herceptin(TM)), pertuzumab (Perjeta(TM)), lapatinib
(Tykerb(TM)), ado-trastuzumab emtansine (TDM1) (Kadcyla(TM)) or other HER2-directed
therapies.

- Perormance Status: ECOG 0-1.

- Patients must have measurable disease, per RECIST 1.1.

- Baseline LVEF by 2D Echocardiogram greater than or equal to 53%.

- Greater than or equal to 1 week since receipt of standard or investigational HER2-
directed therapy for metastatic or recurrent disease.

- Stable, concurrent use of tamoxifen or aromatase inhibitors for hormone receptor
positive breast cancer are allowed.

- Hematologic parameters: ANC >= 1000 cells/mm^3, ALC >= 300 cells/mm^3, absolute
Hemoglobin >=9.0 gm/dL, WBC >=2500 cells/mm3, platelet count >=75,000/mm^3, PT/PTT
1.5X the upper limits of normal.

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

- Negative serum beta HCG if of childbearing potential.

- Negative serology for anti-HIV-1/2 and anti-HTLV 1/2.

- 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:

-Pregnant women are excluded from this study because AdHER 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 CNS metastases or leptomeningeal involvement by tumor (patients
with a history of brain metastases who have been successfully treated for brain
metastasis by surgery or radiation and who have not had any evidence of the new or
progressive CNS disease fot 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 >= 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.