Vaccine Therapy in Treating Patients With Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. To perform early phase clinical trial assessing safety and clinical toxicity of
immunization, and as well as to establish an optimal biological dose (OBD) of combination
vaccines with n-muramyldipeptide derivative (nor-MDP) as adjuvant emulsified in Montanide
(ISA 720).

II. To establish whether an OBD of two combination vaccines is achieved. III. To measure both
humoral and cellular immune responses including the specificity, class and kinetics of
anti-human epidermal growth factor receptor-2 (HER-2) peptide.

IV. To evaluate whether the combination of HER-2 epitopes show therapeutic benefit, provide
synergistic and/or additive effects and to enumerate mechanisms of action.

SECONDARY OBJECTIVES:

I. To collect and analyze post-immune sera and peripheral blood cells for additional six
months post the last injection.

II. To document any clinical responses that may occur.

OUTLINE: This is a dose-escalation study.

Patients receive a HER2/neu peptide vaccine comprising measles virus epitope MVF-HER-2
(266-296) and MVF-HER-2 (597-626) emulsified with nor-MDP in ISA 720 intramuscularly (IM) on
day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

OUTLINE: EXTENSION TRIAL AT OBD

The dose-escalation (4 cohorts) has successfully completed with the accrual of 24 patients
and the Optimum biological dose (OBD) has been determined as the dose at cohort level 2.

The next phase of the study progresses directly into an extension trial at the OBD. 12
patients will be accrued at that level. The extension cohort will be open to only HER-2
and/or EGFR overexpressing cancers. Patients (all gastrointestinal,ovarian and breast must
have received no more than three prior cytotoxic chemotherapy regimens in the last two years
after standard therapy. Patients (breast, ovarian and gastrointestinal cancers) must have
received no more than three prior cytotoxic chemotherapy regimens in the last two years after
standard therapy.

Inclusion Criteria:

- Must have histologically confirmed metastatic solid tumor; the malignancy should be
considered incurable using standard treatment

- Patients are not required to have HER-2 over-expression to be on this study

- If the patient has had HER-2 expression measured prior to enrollment, the report alone
will be accepted

- If the patient has not had HER-2 expression measured prior to enrollment on this study
tumor tissue blocks and/or freshly isolated tissue must be available for determination
of HER-2 expression

- Patients are not required to have epidermal growth factor receptor (EGFR)
over-expression to be on this study

- If the patient has had EGFR expression measured prior to enrollment, the report alone
will be accepted

- If the patient has not had EGFR expression measured prior to enrollment on this study
tumor tissue blocks and/or freshly isolated tissue must be available for determination
of EGFR expression

- Patients with prior history of treated brain metastases who are off steroids and have
stable metastatic brain disease for at least 3 months are eligible

- Patients must be ambulatory with an Eastern Cooperative Oncology Group (ECOG)
performance status of 0, 1, or 2

- White blood cells > 3500/mm^3

- Platelet count > 100,000/mm^3

- Serum bilirubin < 1.5 mg %, regardless of whether patients have liver involvement
secondary to tumor

- Alanine aminotransferase (ALT) must be < 2 times upper limit of normal

- Creatinine < 1.5 mg/dL or calculated creatinine clearance > 60 mL/min

- Patients will be tested for reactivity to a panel of four common microbial skin test
antigens: candida, trichophyton, intermediate strength purified protein derivative
(PPD), and tetanus toxoid; determination of patient eligibility for this trial will
proceed independently of these skin test results; patients who have previously been
tested for these antigens but were excluded from participation in the trial due to
non-reactivity may be considered as eligible provided that all other eligibility
criteria are met

- Patients must be at least 4 weeks past any prior surgery, cytotoxic, chemotherapy,
other immunotherapy, hormonal therapy, or radiation therapy; patients having been
treated with monoclonal antibodies may enter the trial after a specified period of
time (2 times the mean half life of the agent); patients must have recovered from any
toxicity of prior therapy prior to enrolling on study except for neuropathy where
patients need to recover to less than grade 2

- Women of child-bearing potential must not be pregnant and must have a negative
pregnancy test; men and women must agree to practice effective contraception while on
this study

- Patients must obtain a base line Echocardiogram or multi gated acquisition scan (MUGA)
and require the left ventricular ejection fraction to be within normal limits (or 50%
or higher)

- Ability to understand and the willingness to sign a written informed consent document;
the patient must be aware that his/her disease is neoplastic in nature and willingly
consent after being informed of the procedure to be followed, the experimental nature
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts

Exclusion Criteria:

- Patients who are {MVF-HER-2(266-296) and MVF-HER-2 (597-626)} immediate
hypersensitivity skin test positive

- Patients who have evidence of active infection that requires antibiotic therapy;
patients must have been off antibiotic treatment for at least 3 weeks prior to
initiating treatment and must be confirmed to be clear of the infection; if patient
develops an infection requiring antibiotic treatment while on the treatment portion of
the study patients will be treated for the active infection with antibiotics and will
resume vaccine treatment when the infection is healed

- Patients with known active human immunodeficiency virus (HIV), hepatitis A, hepatitis
B, or hepatitis C infection

- Patients with serious cardiopulmonary disorders, including congestive heart failure,
symptomatic coronary artery disease, serious cardiac arrhythmia, and symptomatic
chronic obstructive pulmonary disease or patients with other serious uncontrolled
medical diseases

- Patients who require or likely to require corticosteroids or other immunosuppressives
for intercurrent disease are NOT eligible

- Splenectomized patients

- Autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, polymyositis dermatomyositis, or a vasculitic syndrome

- Patients who have developed anaphylactic responses to other vaccines

- History of congestive heart failure, coronary artery disease and myocardial
infarction; active or unstable cardiovascular disease or cardiac disease requiring
drug or device intervention

ADDITIONAL KEY ELIGIBILITY CRITERIA FOR EXTENSION & EXPANSION COHORT:

- Histologically documented metastatic or unresectable breast, ovarian and
gastrointestinal cancers

- Progressive disease after at least one line of standard therapy

- Patients must have received or refused first line standard systemic therapy for their
metastases (if applicable)

- Patients (pancreatic and esophageal cancers) must have received no more than two prior
cytotoxic chemotherapy regimens in the last two years after standard therapy. Patients
(breast and gastrointestinal cancers) must have received no more than three prior
cytotoxic chemotherapy regimens in the last two years after standard therapy.

- Measurable disease, defined as ≥ 1 lesions that can be accurately measured in ≥ 1
dimensions as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan

- Disease that is amenable to biopsy and be willing to undergo tumor biopsy