Multi-Targeted Recombinant Ad5 (CEA/MUC1/Brachyury) Based Immunotherapy Vaccine Regimen in People With Advanced Cancer

Background:

- The overall goal of the current project is to expand our immunotherapeutic approach for
the treatment of advanced cancer employing a multi-targeted approach.

- Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to
activate T cells against tumors.

- A novel adenovirus based vaccine targeting three (3) human tumor associated antigens
(TAA), CEA, MUC1, and brachyury, respectively has demonstrated anti-tumor cytolytic T
cell responses in pre-clinical animal models of cancer.

Objectives:

-To determine the overall safety and recommended phase 2 dose of a combination of three
immunotherapeutic vaccines (ETBX-011/ETBX-061/ETBX-051), when administered subcutaneously
(SC) to subjects with advanced solid tumors

Eligibility:

- Subjects age 18 and older with cytologically or histologically confirmed locally
advanced or metastatic solid tumor malignancy who have completed or had disease
progression on at least one prior line of disease-appropriate therapy or who are not
candidates for therapy of proven efficacy for their disease.

- Subjects may have measurable or non-measurable but evaluable disease. Subjects with
surgically resected metastatic disease at high risk of relapse are also eligible.

- ECOG performance status less than or equal to 1

- Adequate organ and bone marrow function

- Subjects with active autoimmune diseases requiring systemic treatment and subjects
requiring systemic steroids (except for physiologic doses for steroid replacement) are
not allowed

Design:

- This is a Phase I trial in subjects with advanced cancer. A combination of three
therapeutic vaccines (ETBX-011, ETBX-51, EBX-61) using the same modified Adenovirus
vector backbone, separately encoding three well-studied tumor-associated antigens will
be assessed. The vaccine will be tested at a single dose level, and a dose de-escalation
design (if required). The dose level of each vaccine tested will be 5x1011 VP. This dose
has been found in prior phase 1 testing of Ad5 [E1-, E2b-]-CEA(6D) (ETBX-011) to be well
tolerated (with no dose-limiting toxicities (DLTs) or related Serious adverse events
(SAEs), and optimal for induction of immune responses. Each of the three vaccines will
be administered subcutaneously (SC) at separate injection sites (proximal limb,
preferably the thigh), every 3 weeks for 3 doses, then bi-monthly (every 8 week) boosts
for up to a year.

- Up to six patients will be enrolled at Dose Level 1. If less than or equal to l of 6
patients experience a DLT, initiation of the dose expansion phase will occur. If greater
than or equal to 2 of 6 experience DLT at Dose Level 1, then dose de-escalation will
occur. Up to six patients will be enrolled at the lower dose level Dose Level -1
(1x10^11 VP). If less than or equal to 1 of 6 patients experience a DLT, then the
maximum tolerated (MTD) will be declared at this dose, and initiation of the dose
expansion phase will occur. If greater than or equal to 2 of 6 experience DLT at Dose
Level -1, then a protocol amendment may be written to evaluate a further dose
de-escalation.

- A dose expansion phase of study will be enrolled after the MTD of the combination
vaccine has been determined. An additional 4 subjects will be enrolled in the dose
expansion component of the trial, for a total of 10 subjects at the MTD.

- The ETBX-011, ETBX-51 and ETBX-61 vaccines will be administered SC every 3 weeks for 3
doses, and then bi monthly boosts for up to a year. Evaluations including immunological
assessments will be carried out at baseline, on days of vaccination, and after the last
vaccination.

- INCLUSION CRITERIA:

- Age greater than or equal to 18 years (male and female).

- Ability to understand and provide signed informed consent that fulfills Institutional
Review Board (IRB)'s guidelines.

- Subjects with cytologically or histologically confirmed locally advanced or metastatic
solid tumor malignancy.

- Subjects must have completed or had disease progression on at least one prior line of
disease-appropriate therapy or not be candidates for therapy of proven efficacy for
their disease.

- Subjects may have measurable or non-measurable but evaluable. Subjects with surgically
resected locally advanced or metastatic disease at high risk of relapse are also
eligible.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1.

- Subjects who have received prior CEA, MUC1, and/or Brachyury-targeted immunotherapy
(vaccine) are eligible for this trial if this treatment was discontinued at least 4
weeks prior to enrollment.

- Resolution of clinically significant side effects of prior chemotherapy, radiotherapy,
immunotherapy or surgical procedures to NCI CTCAE Grade less than or equal to 1 or
grade less than or equal to 2 for neuropathy.

- Adequate hematologic function at screening, as follows:

- Absolute neutrophil count (ANC) >= 1 x 10^9/L

- Hemoglobin >= 9 g/dL

- Platelets >= 75,000/mcL.

- Adequate renal and hepatic function at screening, as follows:

- Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) OR
creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula
below):

- Female CrCl = ((140 - age in years) x weight in kg x 0.85) / (72 x serum
creatinine in mg/dL)

- Male CrCl = ((140 - age in years) x weight in kg x 1.00)/ 1.00) / (72 x
serum creatinine in mg/dL)

- Bilirubin less than or equal to 1.5 x ULN OR in subjects with Gilbert s syndrome,
a total bilirubin less than or equal to 3.0 x ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
to 2.5 x ULN, unless liver metastases are present, then values must be less than or
equal to 3 x ULN)

- The effects of the combination ETBX-011, ETBX-051, ETBX-061 vaccine regimen on the
developing human fetus are unknown. For this reason, female subjects of childbearing
potential defined as any female who has experienced menarche and who has not undergone
surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or
who is not postmenopausal (menopause being defined clinically as 12 months of
amenorrhea in a woman over 45 in the absence of other biological or physiological
causes) and male patients who are not surgically sterile (vasectomy etc.), must agree
to use acceptable contraceptive methods for the duration of the study and for one
month after the last vaccination. Acceptable forms of contraception include oral
contraceptives, intrauterine device, condom or vaginal diaphragm plus spermicidal
(gel/foam/cream/vaginal suppository), or total abstinence.

- Ability to attend required study visits and return for adequate follow up, as required
by this protocol.

EXCLUSION CRITERIA:

- Pregnant and nursing women. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with combination
ETBX-011, ETBX-051, ETBX-061, breastfeeding should be discontinued if the mother is
treated with combination ETBX-011, ETBX-051, ETBX-061. These potential risks may also
apply to other agents used in this study.

- There should be a minimum of 4 weeks from any prior investigational drug,
chemotherapy, immunotherapy, with the exception of hormonal therapy for prostate and
breast cancers, HER2-directed therapy for HER2+ breast or stomach cancer (3+ IHC or
FISH+), drugs targeting EGFR, ALK or ROS1 in EGFR,ALK, ROS1-mutated lung cancer,
respectively, or standard maintenance therapies for any solid tumor under the
condition that subjects are on these therapies for at least two months before start of
trial treatment.

- There should also be a minimum of 4 weeks from any prior radiotherapy except for
palliative bone directed therapy.

- Known active brain or central nervous system metastasis (less than 1 month out from
definitive radiotherapy or surgery), or seizures requiring anticonvulsant treatment,
or clinically significant cerebrovascular accident or transient ischemic attack (<3
months).

- Subjects with active autoimmune disease requiring systemic immunosuppressive treatment
within the past 4 weeks such as but not restricted to inflammatory bowel disease,
systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple
sclerosis. A history of autoimmune disease which is not active nor has required recent
systemic immunosuppressive therapy (< 4 weeks prior to enrollment) is not reason for
exclusion.

- Subjects with serious intercurrent chronic or acute illness, such as cardiac or
pulmonary disease, hepatic disease, or other illness considered by the Investigator as
high risk for investigational drug treatment.

- Subjects with clinically significant heart disease, such as congestive heart failure
(class II, III, or IV defined by the New York Heart Association functional
classification), history of unstable or poorly controlled angina, or history (< 1
year) of ventricular arrhythmia.

- Subjects with a medical or psychological impediment that would impair the ability of
the subject to receive therapy per protocol or impact ability to comply with the
protocol or protocol-required visits and procedures.

- History of second malignancy within 3 years prior to enrollment except for the
following: adequately treated non-melanoma skin cancer, cervical carcinoma in situ,
superficial bladder cancer or other localized malignancy after discussion with the
medical monitor.

- Presence of a known active acute or chronic infection, including human
immunodeficiency virus (HIV, as determined by enzyme-linked immunosorbent assay
(ELISA) and confirmed by western blot) and hepatitis B and hepatitis C virus (HBV/HCV,
as determined by HBsAg and hepatitis C serology).

- Subjects on systemic intravenous or oral corticosteroid therapy with the exception of
physiologic doses of corticosteroids (less than or equal to the equivalent of
prednisone 10 mg/day) or other immunosuppressives such as azathioprine or cyclosporin
A are excluded on the basis of potential immune suppression. For these subjects these
excluded treatments must be discontinued at least 2 weeks prior to enrollment for
recent short course use (less than or equal to 14 days) or discontinued at least 4
weeks prior to enrollment for long term use (> 14 days). In addition, the use of
corticosteroids as premedication for contrast-enhanced studies is allowed prior to
enrollment and on study.

- Subjects with known allergy or hypersensitivity to any component of the
investigational product will be excluded.

- Subjects with acute or chronic skin disorders that will interfere with injection into
the skin of the extremities or subsequent assessment of potential skin reactions will
be excluded.

- Subjects vaccinated with a live (attenuated) vaccine (e.g., FluMist(R)) or a killed
(inactivated)/subunit vaccine (e.g., PNEUMOVAX(R), Fluzone(R)) within 28 days or 14
days, respectively, of the first planned dose of ETBX vaccine.