A Pilot Trial of GI-4000 Plus Bevacizumab and Either FOLOFOX or FOLFIRI

Subject visits will occur 1-4 weeks prior to initiation of GI-4000, then

- In newly diagnosed (Group A) patients, at every FOLFOX/FOLFIRI plus bevacizumab visit,
bevacizumab and GI-4000 dosing visit, GI-4000 dosing visit and then quarterly after
completion of therapy

- In patients with stable disease who have completed a first line therapy with an
oxaliplatin or irinotecan plus fluoropyrimidine and bevacizumab containing regimen
(Group B), at every bevacizumab and GI-4000 dosing visit, GI-4000 dosing visit and then
quarterly after completion of therapy

Group A patients (N=26) will be enrolled into the study prior to the initiation of first
line therapy with bevacizumab plus either FOLFOX (N=13) or FOLFIRI (N=13)

- Subjects will receive 1 40YU dose of GI-4000 prior to initiation of FOLFOX or FOLFIRI
plus bevacizumab, then intercycle doses of GI-4000 will be given 7 days after each
cycle while first line therapy is given (up to 8 cycles)

- After completion of first line therapy, subjects will enter the maintenance phase in
which bevacizumab and GI-4000 will be given concurrently every 2 weeks for as long as
therapy can be tolerated or until progression

- If a subject discontinues bevacizumab therapy due to intolerance, the subject will
continue GI-4000 every 2 weeks until progression, intolerance or withdrawal from the
study

Group B patients (N=26) with stable disease who have completed a first line therapy with an
oxaliplatin or irinotecan plus fluoropyrimidine and bevacizumab containing regimen ) will
enter the trial prior to receiving therapy with bevacizumab

- Subjects will receive 40 YU GI-4000 concurrently with each bevacizumab dose for as long
as therapy can be tolerated or until progression

- If a subject discontinues bevacizumab therapy due to intolerance, the subject will
continue GI-4000 every 2 weeks until progression, intolerance or withdrawal from the
study

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of metastatic colorectal cancer
with a Ras mutation

- Measurable or evaluable disease

- No prior therapy fore metastatic disease except for group A: > 6 months since
completion of adjuvant therapy and Group B: those patients who enroll just after
completing bevacizumab plus FOLFOX or FOLFIRI

- Anticipated survival of at least 6 months

- Ambulatory with ECOG performance status of 0 or 1

- Ability to maintain weight

- Normal organ and marrow function

- Women of child-bearing potential and men must agree to avoid pregnancy or fathering a
child for the duration of study participation and for 6 months after the final
scheduled study visit.

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

- Prior chemotherapy other than that listed in inclusion criteria

- Receiving any other investigational agent

- Known brain metastases, uncontrolled seizure disorders, encephalitis, or multiple
sclerosis

- History of known hypersensitivity to S. cerevisiae, bevacizumab or any component of
FOLFOX or FOLFIRI

- Concurrent and chronic therapy with corticosteroids or any other immunosuppressive
drugs

- Uncontrolled hypertension, unstable angina, congestive heart failure, peripheral
vascular disease, serious cardiac arrythmias requiring medication

- History of heart attack or stroke within 6 months before enrollment

- History of intra-abdominal abscess, abdominal fistula, gastrointestinal perforation,
or active peptic ulcer disease

- Bleeding disorder or coagulopathy

- Serious non-healing wound, ulcer or bone fracture

- Major surgical procedure, open biopsy, or traumatic injury within 4 weeks prior to
enrollment or anticipation of need for surgery during the study

- Known active infection with HIV, hepatitis B or C

- History of splenectomy

- History of Crohn's disease or ulcerative colitis

- History of organ transplantation

- Evidence of immunodeficiency or immune suppression

- Any Autoimmune disease

- Active infection

- Concurrent malignancy

- Pregnant or nursing