An Open Label Phase I Study to Eval the Safety and Tolerability of a Vaccine (GI-6207) Consisting of Whole, Heat-killed Recombinant Saccharomyces Cerevisiae (Yeast) Genetically Modified to Express CEA Protein in Adults With Metastatic CEA-expressing ...

Background:

Carcinoembryonic antigen (CEA) is overexpressed in multiple adenocarcinomas.

Previous clinical studies utilizing CEA-based vaccine therapy have demonstrated safety,
T-cell immune responses against CEA, and preliminary evidence of clinical benefit.

Preclinical studies have shown that Saccharomyces-CEA (yeast-CEA) can induce a strong immune
response to CEA as well as therapeutic antitumor responses in a CEA-transgenic host.

Previous and ongoing clinical studies utilizing whole, heat-killed recombinant Saccharomyces
cerevisiae yeast genetically modified to express mutated Ras (GI-4000) or hepatitis C
(GI-5005) proteins demonstrated this vaccine vehicle to be well tolerated, with no
product-related serious adverse events in >200 treated subjects.

Objectives:

Primary

-To determine the safety and tolerability of escalating doses of a heat-killed yeast-based
vaccine that targets tumors that express CEA.

Secondary

- To evaluate CD4 and CD8 immunologic response as measured by an increase in CEA-specific
T cells measured by ELISPOT in HLA-A2, -A3 and -A24(+) patients, and proliferation in
response to CEA protein.

- To evaluate evidence of clinical benefit, such as progression-free survival, RECIST
criteria, reduction in serum markers, and/or reduction in circulating tumor cells.

Eligibility: (dose escalation phase)

Must have metastatic cancer that is CEA-positive (either a CEA serum level > 5 ng/mL or a
tumor that stains positive for CEA in > 20% of a tumor block).

Must have completed or had disease progression on at least one prior line of
disease-appropriate therapy, or not be a candidate for therapy of proven efficacy for their
disease.

Must be ECOG Performance Status 0 2.

Should have no autoimmune diseases; no evidence of immune dysfunction; no serious
intercurrent medical illness;

No untreated brain metastasis (or local treatment of brain metastases within the last 6
months)

Any hypersensitivity reaction to yeast-based products.

Eligibility: (extension phase: 10 additional patients at highest tested dose/MTD)

Same as for the dose escalation phase with the following exceptions:

- Patients must be HLA-A2, -A3, or -A24(+) for immunologic monitoring

- ECOG PS = 0 1

Design:

This is an open label, phase I trial with sequential cohorts of patients (3-6 patients per
dose cohort) with dose escalation of heat-killed GI-6207 vaccine (see statistical analysis
section).

GI 6207 vaccine will be administered subcutaneously at 4 sites biweekly for 7 visits (days 1,
15, 29, 43, 57, 71, 85), then monthly until patients meet off-study criteria.

All patients on a given dose level will have completed 1 month on-study before enrollment can
begin on the next dose level or on the extension phase (see statistical analysis section).

- INCLUSION CRITERIA:

A. Histologically confirmed carcinoma by the NIH Laboratory of Pathology that has been
shown to express CEA (either a CEA serum level > 5 microg/L or a tumor that stains positive
for CEA in > 20% of a tumor block).

B. Completed or had disease progression on at least one prior line of disease-appropriate
therapy for metastatic disease, or not be a candidate for therapy of proven efficacy for
their disease.

C. 18 years of age or greater.

D. Must have metastatic disease that is measurable or non-measurable but evaluable (e.g.,
pleural effusion or present on bone scan).

E. Ability to understand and the willingness to sign a written informed consent document.

F. ECOG performance status of 0 2 (Karnofsky greater than or equal to 50).

G. Serum creatinine less than or equal to 1.5 times upper limit of normal OR creatinine
clearance on a 24-h urine collection of greater than or equal to 60 mL/min.

H. ALT and AST less than or equal to 2.5 times the upper limits of normal.

I. Total bilirubin less than or equal to 1.5 times upper limit of normal OR in patients
with Gilbert s syndrome, a total bilirubin less than or equal to 3.0.

J. Recovered completely from any reversible toxicity associated with recent therapy.
Typically this is 3 4 weeks for patients who most recently received cytotoxic therapy,
except for the nitrosoureas and mitomycin C for which 6 weeks is needed for recovery. There
should be a minimum of 2 weeks from any prior chemotherapy, immunotherapy and/or radiation.

K. Hematological eligibility parameters (within 16 days of starting therapy):

- Granulocyte count greater than or equal to 1,500/mm(3)

- Platelet count greater than or equal to 100,000/mm(3)

L. Prior immune therapy (e.g. related vaccinia and fowlpox vaccines or antigen-specific
peptides) is allowed.

M. Men and women must agree to use effective birth control or abstinence during and for a
period of 4 months after the last vaccination therapy.

N. Patients with prostate cancer must continue to receive GnRH agonist therapy (unless
orchiectomy has been done).

O. Patients must be negative for yeast allergy skin test.

P. Patients must have baseline pulse oximetry greater than 90% on room air.

INCLUSION CRITERIA (EXTENSION PHASE: 10 ADDITIONAL PATIENTS AT HIGHEST TESTED DOSE/MTD):

Eligibility: Same as with the dose escalation phase with the following exceptions:

- Patients must be HLA-A2, A3, or A24 positive for immunologic monitoring.

- ECOG PS equal to 0 1.

EXCLUSION CRITERIA:

A. Patients should have no evidence of immune dysfunction as listed below.

- Human immunodeficiency virus positivity due to the potential for decreased immune
response to the vaccine.

- Active autoimmune diseases requiring treatment or a history of autoimmune disease that
might be stimulated by vaccine treatment. This requirement is due to the potential
risks of exacerbating autoimmunity. Patients with endocrine autoimmune disease that is
controlled by replacement therapy, including thyroid disease and adrenal disease; or
those with vitiligo, may be enrolled.

- Concurrent use of systemic steroids, except for physiologic doses for systemic steroid
replacement or local (topical, nasal, or inhaled) steroid use. Limited doses of
systemic steroids to prevent IV contrast, allergic reaction, or anaphylaxis (in
patients who have known contrast allergies) are allowed.

B. History of allergy or untoward reaction to yeast-based products (any hypersensitivity to
yeast-based products will be excluded).

C. Pregnant or breast-feeding women.

E. Serious intercurrent medical illness which would interfere with the ability of the
patient to carry out the treatment program, including, but not limited to, inflammatory
bowel disease, Crohn's disease, ulcerative colitis, or active diverticulitis.

F. Untreated brain metastases (or local treatment of brain metastases within the last 6
months) due to the poor prognosis of these patients and difficulty ascertaining the cause
of neurologic toxicities.

G. Concurrent chemotherapy. An exception is to allow for patients on the extension phase
only with breast cancer who are receiving trastuzumab to continue therapy with trastuzumab
while receiving the vaccine treatment.

K. Chronic hepatitis infection, including B and C, because of potential immune impairment.

L. Patients requiring continuous tricyclic antidepressant therapy should be excluded due to
the interference with the yeast skin test in creating false negative test results.