Vaccine Treatment for Advanced Non-Small Cell Lung Cancer

Background:

- Lung cancer remains the leading cause of cancer death with an estimated 174,400 new
cases and 162,400 deaths each year in the U.S.

- Despite attempts at early diagnosis and the development of new therapeutic agents, there
has been only limited improvement in the outcome for patients with advanced lung cancer.

- A enzyme called alpha(1,3)galactosyltranferase (alphaGT) that is not found in humans can
transfer sugars on to proteins in human cells that can make them highly immunogenic and
cause them to be rejected by the body.

- Antitumor vaccination using killed donor human lung cancer cells expressing alphaGT may
stimulate immune responses in patients against their own lung cancer because their lung
cancer may share antigens with the vaccine cells that have been made more immunogenic by
expression of alphaGT.

Objectives:

Phase I has been completed.

Phase II

- To assess the tumor response rate of anti-tumor vaccination using irradiated allogeneic
lung cancer cell lines genetically engineered to express the murine
alpha(1,3)galactosyltransferase enzyme in patients with advanced, recurrent or
refractory non-small cell lung cancer.

- To assess the immunological response of patients with lung cancer undergoing antitumor
vaccination with irradiated allogeneic lung cancer cell lines genetically engineered to
express murine alpha(1,3)galactosyltransferase.

- Assess the survival distribution as well as the duration of response.

Eligibility:

- Non-small cell lung cancer (Adenocarcinoma, squamous cell carcinoma, large cell
anaplastic carcinoma and bronchoalveolar carcinoma).

- Stage IV, recurrent or treatment refractory disease.

- No exclusion for prior therapy. Prior therapy may include surgery, radiation,
immunotherapy, and chemotherapy regimens. EGFR inhibitors or monoclonal antibodies are
included as chemotherapy.

- Patients must have a granulocyte count of greater than or equal to 1000/microL,
platelets greater than or equal to 100,000/microL, hemoglobin greater than 10.0 gm/dL,
albumin greater than or equal to 3.0 gm/dL and acceptable hepatic and renal function.

- No systemic corticosteroids.

Design (Phase II):

- Patients will be intradermally vaccinated with 300 million
alpha(1,3)galactosyltranferase-expressing vaccine cells every 2-weeks to complete a
total of eight vaccinations.

- Patients will be monitored for tumor and immunological responses and safety.

- Phase II Eligibility Criteria

Must be confirmed within 4-weeks of vaccination except for Beta-HCG (confirm within 1-week)
when appropriate. Tumor measurements must be performed within 2-weeks of enrollment.

INCLUSION CRITERIA:

Histological diagnosis of non-small cell lung cancer (NSCLC). Squamous cell (epidermoid),
adenocarcinoma, bronchoalveolar carcinoma and large cell anaplastic lung carcinoma
histologies are eligible. Mixed histologies of NSCLC (i.e., adenosquamous) are eligible.
Mixed NSCLC/small cell lung carcinoma (SCLC), and variant large and small cell lung cancer
are NOT eligible for this study.

Patients being treated at the NCI must have their pathology reviewed and confirmed by the
NCI Laboratory of Pathology. Patients being treated at MCG must have their pathology
reviewed and confirmed by the MCG Pathology Department.

Metastatic (AJCC Stage IV- any T, any N, M1), progressive, recurrent or refractory NSCLC.
Patients may not be eligible for other curative intent treatment (e.g., surgical
resection).

For the purpose of eligibility for this trial, the above-cited disease states are defined
as follows:

Progressive NSCLC- Defined as increasing measurable disease or the appearance of new
measurable disease by RECIST criteria despite treatment.

Recurrent NSCLC- Defined as the re-appearance of measurable disease or the appearance of
new measurable disease by RECIST criteria after prior successful treatment or complete
response.

Refractory NSCLC- Defined as achieving less than a complete response and having residual
measurable by RECIST criteria after prior treatment with chemotherapy, targeted or small
molecules, monoclonal antibodies or any combination of these.

Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.

Serum albumin greater than or equal to 3.0 gm/dL.

Expected survival greater than or equal to 4 months.

Adequate organ function including:

- Marrow: Hemoglobin greater than or equal to 10.0 gm/dL, absolute granulocyte count
(AGC) greater than or equal to 1,000/mm(3) platelets greater than or equal to
100,000/mm(3), absolute lymphocyte count greater than or equal to 475/mm(3).

- Hepatic: Serum total bilirubin less than or equal to 1.5 times the upper limit of
normal (ULN) with the exception of less than 2.9 mg/dL for patients with Gilbert's
disease, ALT (SGPT) and AST (SGOT) less than or equal to 2.5 times the ULN.

- Renal: Serum creatinine (sCr) less than or equal to 1.5 times the upper limit of
normal, or creatinine clearance (Ccr) greater than or equal to 50 mL/min.

All On-Study Tests must be less than or equal to CTC Grade I toxicity for patients to be
eligible for study, excluding serum LDH levels. PT, PTT must be less than or equal to 1.5
times ULN except for patients who are on therapeutic anticoagulant therapy.

Measurable disease as defined by RECIST Criteria.

Subjects must have negative serologies for hepatitis viruses B and C, and HIV prior to
entering study.

Prior therapy for NSCLC that may include surgery, radiation therapy, immunotherapy, and/or
prior chemotherapy regimens (including neoadjuvant and adjuvant treatment). There are no
restrictions to the number of prior therapies subjects have received.

Treatment with a single course of gefitinib or (Iressa), or erlotinib (Tarceva), or other
small molecule or targeted therapies, or monoclonal antibody therapy will be considered and
count as prior chemotherapy.

Patients that refuse chemotherapy are eligible.

Patients must be greater than or equal to 4 weeks since major surgery, radiotherapy,
chemotherapy (6-weeks if they were treated with a nitrosourea or mitomycin) or
biotherapy/targeted therapies and recovered from the toxicity of prior treatment to less
than or equal to CTC grade 1, exclusive of alopecia or fatigue.

Patients must have the ability to understand the study, its risks, side effects, potential
benefits and be able to give written informed consent to participate. Patients may NOT be
consented by a durable power of attorney (DPA).

Male and female subjects of child producing potential must agree to use contraception or
avoidance of pregnancy measures while enrolled on study and receiving the experimental
drug, and for one month after the last immunization.

Patients should have sites of NSCLC that are accessible to needle, punch or other limited
biopsy, be at low risk for biopsy and be willing to undergo tumor core needle biopsy, punch
or other similar biopsy pre-vaccination and again post-vaccination. Such sites may include
skin and soft tissue metastases, adrenal gland metastases, peripheral lymph nodes
(supraclavicular, axillary, or inquinal), a pulmonary lesion at low risk for complications
defined as lesions greater than 1.5 cm surrounded by aerated lung, pleural based masses
greater than 1.5 cm and lesions not associated with a major pulmonary vessel, or other
disease sites that may undergo biopsy with minimal discomfort and risk to the patient.
These biopsies are optional.

EXCLUSION CRITERIA:

Age less than 18-years-old.

Active CNS metastases or carcinomatous meningitis.

Hypercalcemia greater than 2.9 mmol/L, unresponsive to standard therapy (e.g., I.V.
hydration, diuretics, calctonin and/or bisphosphate therapy).

Pregnant or nursing women due to the unknown effects of vaccination on the developing fetus
or newborn infant.

Other malignancy within five years, unless the probability of recurrence of the prior
malignancy is less than 5%. Patient's curatively treated for squamous cell carcinoma and
basal cell carcinoma of the skin and carcinoma in situ of the uterine cervix (CIN) or
patients with a history of malignant tumor in the past that have been disease free for at
least five years are also eligible for this study.

History of organ transplant, or current active immunosuppressive therapy (such as
cyclosporine, tacrolimus, etc.).

Subjects taking systemic corticosteroid therapy for any reason including replacement
therapy for hypoadrenalism, are not eligible. Subjects receiving inhaled or topical
corticosteroids are eligible. Subjects who require systemic corticosteroids after beginning
vaccinations, will be removed from the study.

Significant or uncontrolled congestive heart failure (CHF), myocardial infarction,
significant ventricular arrhythmias within the last six months or significant pulmonary
dysfunction.

Active infection or antibiotics within 1-week prior to study, including unexplained fever
(Temp. greater than 38.1 degrees C).

Autoimmune disease (e.g., systemic lupus erythematosis, active rheumatoid arthritis, etc)
with the exception of vitiligo. Patients with a remote history of asthma or mild active
asthma are eligible.

Other serious medical conditions that may be expected to limit life expectancy to less than
2-years (e.g., liver cirrhosis).

Any condition, psychiatric or otherwise, that would preclude informed consent, consistent
follow-up or compliance with any aspect of the study (e.g., untreated schizophrenia or
other significant cognitive impairment, etc).

A known allergy to any component of the alpha(1,3)galactosyltransferase tumor vaccine or
cell lines from which it is derived.

Patients having undergone splenectomy or prior vaccine therapy for their NSCLC.