Active Immunotherapy CEA Vaccine in Patients With Malignancies Expressing CEA

This is a phase I/II study with the primary purpose to determine the safety of immunization
with Ad5 [E1-, E2B-]-CEA(6D), in patients with advanced or metastatic CEA-expressing
malignancies. The secondary objectives are to evaluate CEA-specific immune responses to the
immunizations and to obtain preliminary data on clinical response rate. The study population
consists of patients with a histologically confirmed diagnosis of metastatic malignancy that
is CEA positive who were previously treated with standard therapy known to have a possible
survival benefit or refused such therapy. The study will determine the safety of three dosage
levels of Ad5 [E1-, E2B-]-CEA(6D) vaccine (phase I component), and the maximally tolerated
dose of Ad5 [E1-, E2B-]-CEA(6D) vaccine (phase II component). The study drug is Ad5 [E1-,
E2B-]-CEA(6D) given by subcutaneous (SQ) injection every 3 weeks for 3 immunizations. We will
evaluate safety in each cohort at least 3 weeks after the last patient in the previous cohort
has received their first injection. A dosing scheme will be considered safe if <33% of
patients treated at a dosage level experience DLT (e.g., 0 of 3, ≤1 of 6, ≤3 of 12 or ≤5 of
18 patients).

Criteria for Patient Eligibility

1. Histologically confirmed diagnosis of malignancy expressing CEA. Because this is a
safety and immunogenicity study, patients are NOT required to have measurable or
evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST).

2. For all tumor types other than colorectal, the tumor must express CEA as defined by
immunohistochemical staining (at least 50% of the tumor with at least moderate
intensity of staining) or a tumor known to be universally CEA positive (i.e. colon and
rectal cancer). If colorectal cancer then, pathologic or clinical confirmation of
adenocarcinoma is required.

3. Patients must have received treatment with standard therapy known to have a possible
overall survival benefit.

For the following common cancers, the following eligibility criteria apply:

- Colorectal cancer: Must have received and progressed through at least one line of
palliative chemotherapy consisting of one of the following regimens:

- Palliative chemotherapy for metastatic colorectal cancer with 5 fluorouracil
(or capecitabine) and oxaliplatin.

- Palliative chemotherapy for metastatic colorectal cancer with 5 fluorouracil
(or capecitabine) and irinotecan.

- Palliative chemotherapy regimen for metastatic colorectal cancer that
includes bevacizumab.

- Colorectal cancer patients currently receiving palliative single-agent
bevacizumab or cetuximab will be eligible for this trial and may continue
these therapies concomitant with study treatment (if they have been on these
single agent therapies for at least 3 months).

- Breast cancer: Must have received and progressed through at least one line of
chemotherapy for metastatic breast cancer consisting of one of the following
regimens:

- Palliative anthracycline- or taxane-based chemotherapy

- Patients with tumors that over express HER2 (IHC 3+ or FISH+) must have
received and progressed through at least one line of palliative therapy that
combines trastuzumab with chemotherapy.

- Breast cancer patients currently receiving palliative endocrine therapy or
single-agent trastuzumab will be eligible for this trial and may continue
these therapies concomitant with study treatment (if they have been on these
single agent therapies for at least 3 months).

- Patients who have been treated or offered the options of treatment with
Bevacizumab (option clearly stated in the consent form).

- Patients who have been treated or offered the options of treatment with
Lapatinib (option clearly stated in the consent form).

- Lung cancer: Must have received and progressed through chemotherapy for
metastatic disease consisting of one of the following regimens:

- Palliative platinum-based (cisplatin or carboplatin) chemotherapy if the
patient has not received chemotherapy previously.

- Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine
chemotherapy if the patient has received chemotherapy previously.

- Lung cancer patients currently receiving palliative single-agent erlotinib
or gefitinib will be eligible for this trial and may continue these
therapies concomitant with study treatment (if they have been on these
single agent therapies for at least 3 months).

- Pancreatic cancer: Must have received and progressed through chemotherapy
including gemcitabine.

- Pancreatic cancer patients currently receiving palliative single-agent
erlotinib will be eligible for this trial and may continue this therapy
concomitant with study treatment (if they have been on this single agent therapy
for at least 3 months).

- For other malignancies, if a first line therapy with survival or palliative
benefit exists, it should have been administered and there should have been
progressive disease.

- Patients who have received and progressed through first-line palliative
chemotherapy must be advised regarding second-line therapy before being enrolled
on this investigational study.

4. Karnofsky performance score of 70% or higher

5. Estimated life expectancy > 3 months

6. Age ≥ 21 years, but < 75

7. Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin ≥ 9 g/dL (it is
acceptable to have had prior transfusion), platelets ≥ 75,000/microliter; PT-INR <1.5,
PTT <1.5X ULN

8. Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin <
1.5 mg/dL (except for Gilbert's syndrome which will allow bilirubin ≤ 2.0 mg/dL), ALT
and AST ≤ 2.5 x upper limit of normal.

9. Patients who have received prior CEA-targeted immunotherapy are eligible for this
trial, if this treatment was discontinued at least 3 months prior to enrollment.

10. Patients who are taking medications that do not have a known history of
immunosuppression are eligible for this trial.

11. Ability to understand and provide signed informed consent that fulfills Institutional
Review Board's guidelines.

12. Ability to return to the clinical site for adequate follow-up, as required by this
protocol.

Criteria for Patient Exclusion

1. Patients with concurrent cytotoxic chemotherapy or radiation therapy should be
excluded. There are no exclusions based on the number of prior chemotherapy, biologic,
hormonal, or experimental regimens. Except for the permitted concomitant therapies
(bevacizumab, cetuximab, trastuzumab, erlotinib, gefitinib, or hormonal therapy which
patients must have been on for at least 3 months at the time of enrollment if they
intend to continue them with the vaccine), there must be at least 3 months between any
prior CEA-targeted immunotherapy and study treatment and at least 4 weeks between any
other prior therapy (including radiotherapy) and study treatment. Patients must have
recovered to grade 1 acute toxicities from prior treatment.

2. Patients with a history of or current brain metastases will not be permitted.

3. Patients with a history of autoimmune disease, such as but not restricted to,
inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis,
scleroderma, or multiple sclerosis. Autoimmune related thyroid disease and vitiligo
are permitted.

4. Patients with serious intercurrent chronic or acute illness, such as cardiac disease
(NYHA class III or IV), hepatic disease, or other illness considered by the Principal
Investigator as unwarranted high risk for investigational drug treatment.

5. Patients with a medical or psychological impediment to probable compliance with the
protocol should be excluded.

6. Concurrent (or within the last 5 years) second malignancy other than non melanoma skin
cancer, cervical carcinoma in situ, controlled superficial bladder cancer, or other
carcinoma in situ that has been treated.

7. Presence of an active acute or chronic infection including: a urinary tract infection,
HIV (as determined by ELISA and confirmed by Western Blot). Patients with HIV are
excluded based on immunosuppression, which may render them unable to respond to the
vaccine; patients with chronic hepatitis are excluded because of concern that
hepatitis could be exacerbated by the injections.

8. Patients on steroid therapy (or other immunosuppressives, such as azathioprine or
cyclosporin A) are excluded on the basis of potential immune suppression. Patients
must have had 6 weeks of discontinuation of any steroid therapy (except that used as
pre-medication for chemotherapy or contrast-enhanced studies) prior to enrollment.

9. Pregnant and nursing women should be excluded from the protocol since this research
may have unknown and harmful effects on an unborn child or on young children. If the
patient is sexually active, the patient must agree to use a medically acceptable form
of birth control while receiving treatment and for a period of 4 months following the
last vaccination therapy. It is not known whether the treatment used in this study
could affect the sperm and could potentially harm a child that may be fathered while
on this study.

10. Patients 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.

11. Patients will be allowed warfarin 1mg po qd other than for port prophylaxis.

12. Patients with metastatic disease which is determined to be resectable will be
excluded.